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Sample records for interstitial pulmonary fibrosis

  1. Chronic pulmonary interstitial fibrosis in a blue-fronted Amazon parrot (Amazona aestiva aestiva).

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    Amann, Olga; Kik, Marja J L; Passon-Vastenburg, Maartje H A C; Westerhof, Ineke; Lumeij, Johannes T; Schoemaker, Nico J

    2007-03-01

    A 30-yr-old blue-fronted Amazon parrot (Amazon aestiva aestiva) was presented to the clinic with a history of sneezing more often during the last 2 mo. Physical examination revealed only a mild nasal discharge. Complete hematologic and plasma biochemical examination showed no abnormalities. Computerized tomography (CT) of the complete bird showed generalized lung alterations consistent with lung fibrosis. Two lung biopsies were taken. The results of the histologic examination of the biopsies confirmed the tentative CT diagnosis of pulmonary interstitial fibrosis. To our knowledge this is the first reported case of chronic pulmonary interstitial fibrosis diagnosed by means of a lung biopsy in an avian species. The histologic characteristics are discussed and compared with those of human idiopathic pulmonary fibrosis.

  2. Familial Interstitial Pulmonary Fibrosis: A Large Family with Atypical Clinical Features

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    Ranji Chibbar

    2010-01-01

    Full Text Available A large kindred of familial pulmonary fibrosis is reported. Six members from the first two generations of this particular kindred were described more than 40 years previously; six more individuals from the third and fourth generations have also been evaluated. The proband, now 23 years of age, has mild disease; the other 11 documented affected family members all died from their disease at an average age of 37 years (range 25 to 50 years. The pathology was that of usual interstitial pneumonia, as is typical in idiopathic pulmonary fibrosis. However, the initial radiographic pattern in many of these individuals was upper lobe and nodular and, along with the young age, was atypical for idiopathic pulmonary fibrosis. Several genetic abnormalities have been associated with familial pulmonary fibrosis. The present study examined the genes coding for surfactant protein-C, ATP-binding cassette protein A3 and telomerase, and found no abnormalities.

  3. Usual interstitial pneumonia in asbestos-exposed cohorts - concurrent idiopathic pulmonary fibrosis or atypical asbestosis?

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    Attanoos, Richard L; Alchami, Fouad S; Pooley, Frederick D; Gibbs, Allen R

    2016-09-01

    To determine whether usual interstitial pneumonia (UIP) pattern fibrosis is seen in asbestosis. The occurrence of UIP pattern fibrosis was studied in four asbestos cohorts systematically referred following postmortem to the UK Pneumoconiosis Unit, Cardiff. The combined exposed workforce comprised >25 000 persons. Over the 17-year period, 233 subjects were identified; 210 had degrees of interstitial fibrosis with a fibrotic non-specific interstitial pneumonia pattern and subpleural accentuation, and three showed UIP pattern fibrosis. All three of these cases showed grade 4 fibrosis (honeycombing) with no asbestos fibre dose-response correlation. A Poisson distribution of probability analysis indicated that the observed cases of UIP in this workforce could be wholly accounted for by the prevalence of idiopathic pulmonary fibrosis (IPF) in the population. UIP pattern fibrosis is rarely observed in asbestos-exposed subjects, and shows no dose-response correlation with asbestos fibres on mineral analysis; this points to an alternative disease, such as IPF. The results indicate that UIP pattern fibrosis should not be regarded as genuine asbestosis, irrespective of the status of asbestos biomarkers, and this impacts upon the postmortem handling of asbestos-related deaths. © 2016 John Wiley & Sons Ltd.

  4. [Lung transplantation in pulmonary fibrosis and other interstitial lung diseases].

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    Berastegui, Cristina; Monforte, Victor; Bravo, Carlos; Sole, Joan; Gavalda, Joan; Tenório, Luis; Villar, Ana; Rochera, M Isabel; Canela, Mercè; Morell, Ferran; Roman, Antonio

    2014-09-15

    Interstitial lung disease (ILD) is the second indication for lung transplantation (LT) after emphysema. The aim of this study is to review the results of LT for ILD in Hospital Vall d'Hebron (Barcelona, Spain). We retrospectively studied 150 patients, 87 (58%) men, mean age 48 (r: 20-67) years between August 1990 and January 2010. One hundred and four (69%) were single lung transplants (SLT) and 46 (31%) bilateral-lung transplants (BLT). The postoperative diagnoses were: 94 (63%) usual interstitial pneumonia, 23 (15%) nonspecific interstitial pneumonia, 11 (7%) unclassifiable interstitial pneumonia and 15% miscellaneous. We describe the functional results, complications and survival. The actuarial survival was 87, 70 and 53% at one, 3 and 5 years respectively. The most frequent causes of death included early graft dysfunction and development of chronic rejection in the form of bronchiolitis obliterans (BOS). The mean postoperative increase in forced vital capacity and forced expiratory volume in the first second (FEV1) was similar in SLT and BLT. The best FEV1 was reached after 10 (r: 1-36) months. Sixteen percent of patients returned to work. At some point during the evolution, proven acute rejection was diagnosed histologically in 53 (35%) patients. The prevalence of BOS among survivors was 20% per year, 45% at 3 years and 63% at 5 years. LT is the best treatment option currently available for ILD, in which medical treatment has failed. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

  5. Ultrasound lung comets in systemic sclerosis: a chest sonography hallmark of pulmonary interstitial fibrosis.

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    Gargani, Luna; Doveri, Marica; D'Errico, Luigia; Frassi, Francesca; Bazzichi, Maria L; Delle Sedie, Andrea; Scali, Maria C; Monti, Simonetta; Mondillo, Sergio; Bombardieri, Stefano; Caramella, Davide; Picano, Eugenio

    2009-11-01

    To assess the correlation between ultrasound lung comets (ULCs, a recently described echographic sign of interstitial lung fibrosis) and the current undisputed gold-standard high-resolution CT (HRCT) to detect pulmonary fibrosis in patients with SSc. We enrolled 33 consecutive SSc patients (mean age 54 +/- 13 years, 30 females) in the Rheumatology Clinic of the University of Pisa. We assessed ULCs and chest HRCT within 1 week independently in all the patients. ULC score was obtained by summing the number of lung comets on the anterior and posterior chest. Pulmonary fibrosis was quantified by HRCT with a previously described 30-point Warrick score. Presence of ULCs (defined as a total number more than 10) was observed in 17 (51%) SSc patients. Mean ULC score was 37 +/- 50, higher in the diffuse than in the limited form (73 +/- 66 vs 21 +/- 35; P < 0.05). A significant positive linear correlation was found between ULCs and Warrick scores (r = 0.72; P < 0.001). ULCs are often found in SSc, are more frequent in the diffuse than the limited form and are reasonably well correlated with HRCT-derived assessment of lung fibrosis. They represent a simple, bedside, radiation-free hallmark of pulmonary fibrosis of potential diagnostic and prognostic value.

  6. Pulmonary Fibrosis

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    Pulmonary fibrosis is a condition in which the tissue deep in your lungs becomes scarred over time. This tissue gets thick ... blood may not get enough oxygen. Causes of pulmonary fibrosis include environmental pollutants, some medicines, some connective ...

  7. Acute lyme infection presenting with amyopathic dermatomyositis and rapidly fatal interstitial pulmonary fibrosis: a case report

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    Nguyen Hanh

    2010-06-01

    Full Text Available Abstract Introduction Dermatomyositis has been described in the setting of lyme infection in only nine previous case reports. Although lyme disease is known to induce typical clinical findings that are observed in various collagen vascular diseases, to our knowledge, we believe that our case is the first presentation of acute lyme disease associated with amyopathic dermatomyositis, which was then followed by severe and fatal interstitial pulmonary fibrosis only two months later. Case presentation We present a case of a 64-year-old African-American man with multiple medical problems who was diagnosed with acute lyme infection after presenting with the pathognomonic rash and confirmatory serology. In spite of appropriate antimicrobial therapy for lyme infection, he developed unexpected amyopathic dermatomyositis and then interstitial lung disease. Conclusions This case illustrates a potential for lyme disease to produce clinical syndromes that may be indistinguishable from primary connective tissue diseases. An atypical and sequential presentation (dermatomyositis and interstitial lung disease of a common disease (lyme infection is discussed. This case illustrates that in patients who are diagnosed with lyme infection who subsequently develop atypical muscular, respiratory or other systemic complaints, the possibility of severe rheumatological and pulmonary complications should be considered.

  8. Pulmonary adenocarcinoma mutation profile in smokers with smoking-related interstitial fibrosis

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    Primiani A

    2014-05-01

    Full Text Available Andrea Primiani,1 Dora Dias-Santagata,1 A John Iafrate,1 Richard L Kradin1,2 1Pathology Service, 2Pulmonary Medicine/Critical Care Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Abstract: Cigarette smoking is an established cause of lung cancer. However, pulmonary fibrosis is also an independent risk factor for the development of lung cancer. Smoking-related interstitial fibrosis (SRIF has recently been reported. We hypothesized that adenocarcinomas in lungs with SRIF might show distinct molecular changes and examined the molecular phenotype of 168 resected lung adenocarcinomas in lungs with and without SRIF. The diagnosis of SRIF was determined by histological examination, based on the presence of alveolar septal thickening, due to pauci-inflamed, hyalinized, “ropy” collagen, in areas of lung greater than 1 cm away from the tumor. Tumors were concomitantly examined genotypically for mutations in genes frequently altered in cancer, including EGFR and KRAS, by SNaPshot and by fluorescence in situ hybridization for possible ALK rearrangements. Fluorescence in situ hybridization for ROS1 rearrangement (n=36 and/or MET amplification (n=31 were performed when no mutation was identified by either SNaPshot or ALK analysis. Sixty-five cases (38.7% showed SRIF, which was distributed in all lobes of the lungs examined. No differences were observed in sex, average age, or smoking history in patients with and without SRIF. There was no difference in either the percent or types of adenocarcinoma genetic mutations in patients with SRIF versus those without. This data suggests that SRIF does not represent an independent risk factor for the development of the major known and targeted mutations seen in pulmonary adenocarcinoma. However, additional research is required to investigate the potential significance of SRIF in the pathogenesis of lung cancer. Keywords: lung, cancer, smoking, SRIF

  9. Introduction to Pulmonary Fibrosis

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    ... Events Become An Advocate Volunteer Ways To Give Pulmonary Fibrosis www.lung.org > Lung Health and Diseases > ... Pulmonary Fibrosis > Introduction Share this page: Introduction to Pulmonary Fibrosis What Is Pulmonary Fibrosis? Pulmonary fibrosis is ...

  10. Learn About Pulmonary Fibrosis

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    ... Events Become An Advocate Volunteer Ways To Give Pulmonary Fibrosis www.lung.org > Lung Health and Diseases > Lung ... Pulmonary Fibrosis > Introduction Share this page: Introduction to Pulmonary Fibrosis What Is Pulmonary Fibrosis? Pulmonary fibrosis is a ...

  11. Smoking-related interstitial fibrosis combined with pulmonary emphysema: computed tomography-pathologic correlative study using lobectomy specimens

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    Otani H

    2016-07-01

    Full Text Available Hideji Otani,1 Tomonori Tanaka,2 Kiyoshi Murata,1 Junya Fukuoka,2 Norihisa Nitta,1 Yukihiro Nagatani,1 Akinaga Sonoda,1 Masashi Takahashi3 1Department of Radiology, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga, 2Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Sakamoto, Nagasaki, 3Department of Radiology, Yujin-Yamazaki Hospital, Takegahana-cho, Hikone, Shiga, Japan Purpose: To evaluate the incidence and pathologic correlation of thin-section computed tomography (TSCT findings in smoking-related interstitial fibrosis (SRIF with pulmonary emphysema. Patients and methods: Our study included 172 consecutive patients who underwent TSCT and subsequent lobectomy. TSCT findings including clustered cysts with visible walls (CCVW and ground-glass attenuation with/without reticulation (GGAR were evaluated and compared in nonsmokers and smokers and among lung locations. TSCT findings, especially CCVW, were also compared with histological findings using lobectomy specimens. Results: The incidence of CCVW and GGAR was significantly higher in smokers than in nonsmokers (34.1% and 40.7%, respectively, vs 2.0% and 12.2%. CCVW and GGAR were frequently found in the lower and peripheral zones. Histologically, CCVW corresponded more often with SRIF with emphysema than usual interstitial pneumonia (UIP, 63.3% vs 30%. CCVW of irregular size and shape were seen in 19 of 20 SRIF with emphysema and in seven of nine UIP-manifested areas with similar round cysts. A less-involved subpleural parenchyma was observed more frequently in SRIF with emphysema. Conclusion: SRIF with emphysema is a more frequent pathological finding than UIP in patients with CCVW on TSCT. The irregular size and shape of CCVW and a less-involved subpleural parenchyma may be a clue suggesting the presence of SRIF with emphysema. Keywords: pulmonary emphysema, smoking, usual interstitial pneumonia, honeycombing, smoking-related interstitial

  12. Modeling pulmonary fibrosis by abnormal expression of telomerase/apoptosis/collagen V in experimental usual interstitial pneumonia

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    Parra, E.R.; Pincelli, M.S. [Departamento de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Teodoro, W.R.; Velosa, A.P.P. [Disciplina de Reumatologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Martins, V.; Rangel, M.P.; Barbas-Filho, J.V.; Capelozzi, V.L. [Departamento de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil)

    2014-06-04

    Limitations on tissue proliferation capacity determined by telomerase/apoptosis balance have been implicated in pathogenesis of idiopathic pulmonary fibrosis. In addition, collagen V shows promise as an inductor of apoptosis. We evaluated the quantitative relationship between the telomerase/apoptosis index, collagen V synthesis, and epithelial/fibroblast replication in mice exposed to butylated hydroxytoluene (BHT) at high oxygen concentration. Two groups of mice were analyzed: 20 mice received BHT, and 10 control mice received corn oil. Telomerase expression, apoptosis, collagen I, III, and V fibers, and hydroxyproline were evaluated by immunohistochemistry, in situ detection of apoptosis, electron microscopy, immunofluorescence, and histomorphometry. Electron microscopy confirmed the presence of increased alveolar epithelial cells type 1 (AEC1) in apoptosis. Immunostaining showed increased nuclear expression of telomerase in AEC type 2 (AEC2) between normal and chronic scarring areas of usual interstitial pneumonia (UIP). Control lungs and normal areas from UIP lungs showed weak green birefringence of type I and III collagens in the alveolar wall and type V collagen in the basement membrane of alveolar capillaries. The increase in collagen V was greater than collagens I and III in scarring areas of UIP. A significant direct association was found between collagen V and AEC2 apoptosis. We concluded that telomerase, collagen V fiber density, and apoptosis evaluation in experimental UIP offers the potential to control reepithelization of alveolar septa and fibroblast proliferation. Strategies aimed at preventing high rates of collagen V synthesis, or local responses to high rates of cell apoptosis, may have a significant impact in pulmonary fibrosis.

  13. [Effect of prostaglandin E1 combined with Xuebijing injection on transforming growth factor-β₁ in rats with pulmonary interstitial fibrosis].

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    Zhang, Wan-xiang; Li, Zhi-jun

    2012-12-01

    To investigate the effect of prostaglandins E1 combined with Xuebijing injection on the expression of transforming growth factor-β₁ (TGF-β₁) and tumor necrosis factor-α (TNF-α) in rats with acute pulmonary interstitial fibrosis. A rat model of pulmonary interstitial fibrosis was established by intratracheal injection of bleomycin (1 ml/kg). One hundred and eight Wistar rats were randomly divided into six groups with 18 in each group, which were normal control group, model group, hormone (methylprednisolone) treatment group, Xuebijing treatment group, prostaglandin E1 treatment group and combination treatment group (prostaglandin E1 and Xuebijing injection). Except for those in the normal control group, the rats in each group were sacrificed on the 7th, 14th and 28th day after treatment. The TGF-β₁ expression in lung tissue was measured by immunohistochemical staining. The TNF-α concentration in bronchoalveolar lavage fluid (BALF) of rat model was determined by enzyme-linked immunosorbent assay. The combination treatment group showed significantly more macrophages with TGF-β₁ expression in lung tissue at each time point, as compared with the model group, Xuebijing treatment group, methylprednisolone treatment group and prostaglandin E1 treatment group (P prostaglandin E1 treatment group (P prostaglandin E1 treatment group and combination treatment group were significantly lower than that in the model group (P Prostaglandin E1 combined with Xuebijing injection may significantly inhibit TGF-β₁ expression in the lung tissue of rats with acute pulmonary interstitial fibrosis, which reduces alveolar inflammatory response.

  14. Combined Pulmonary Fibrosis and Emphysema Syndrome: A New Phenotype within the Spectrum of Smoking-Related Interstitial Lung Disease

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    Karina Portillo

    2012-01-01

    Full Text Available Combined pulmonary fibrosis and emphysema (CPFE is a recently defined syndrome, in which centrilobular and/or paraseptal emphysemas in upper lung zones coexist with pulmonary fibrosis in lower lobes in individuals. These patients have a characteristic lung function profile, with unexpected subnormal dynamic and static lung volumes, contrasting with a significant reduction of carbon monoxide transfer (DLco and exercise hypoxemia. Pulmonary hypertension is highly prevalent in CPFE and is the leading determinant of death. Tobacco smoking has been proposed as the main factor in its etiology, though the pathophysiology and its natural history remain to be determined. High-resolution computed axial tomography is the mandatory tool to confirm the diagnosis. Currently, there is no consensus about its treatment since those published to date on this issue are limited to well-characterised series of cases; hence, a better understanding of this entity may help in the development of future therapeutic approaches.

  15. Idiopathic pulmonary fibrosis: treatment update.

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    O'Connell, Oisin J

    2011-11-01

    Idiopathic pulmonary fibrosis (IPF) is the most common of the idiopathic interstitial pneumonias. Despite multiple recent clinical trials, there is no strong evidence supporting a survival advantage for any agent in the management of patients with IPF. The limited effectiveness of current treatment regimes has led to a search for novel therapies including antifibrotic strategies. This article reviews the evidence supporting the treatments currently used in the management of IPF.

  16. Idiopathic pulmonary fibrosis

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    Noble Paul W

    2008-03-01

    Full Text Available Abstract Idiopathic pulmonary fibrosis (IPF is a non-neoplastic pulmonary disease that is characterized by the formation of scar tissue within the lungs in the absence of any known provocation. IPF is a rare disease which affects approximately 5 million persons worldwide. The prevalence is estimated to be slightly greater in men (20.2/100,000 than in women (13.2/100,000. The mean age at presentation is 66 years. IPF initially manifests with symptoms of exercise-induced breathless and dry coughing. Auscultation of the lungs reveals early inspiratory crackles, predominantly located in the lower posterior lung zones upon physical exam. Clubbing is found in approximately 50% of IPF patients. Cor pulmonale develops in association with end-stage disease. In that case, classic signs of right heart failure may be present. Etiology remains incompletely understood. Some environmental factors may be associated with IPF (cigarette smoking, exposure to silica and livestock. IPF is recognized on high-resolution computed tomography by peripheral, subpleural lower lobe reticular opacities in association with subpleural honeycomb changes. IPF is associated with a pathological lesion known as usual interstitial pneumonia (UIP. The UIP pattern consists of normal lung alternating with patches of dense fibrosis, taking the form of collagen sheets. The diagnosis of IPF requires correlation of the clinical setting with radiographic images and a lung biopsy. In the absence of lung biopsy, the diagnosis of IPF can be made by defined clinical criteria that were published in guidelines endorsed by several professional societies. Differential diagnosis includes other idiopathic interstitial pneumonia, connective tissue diseases (systemic sclerosis, polymyositis, rheumatoid arthritis, forme fruste of autoimmune disorders, chronic hypersensitivity pneumonitis and other environmental (sometimes occupational exposures. IPF is typically progressive and leads to significant

  17. Protein S is protective in pulmonary fibrosis.

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    Urawa, M; Kobayashi, T; D'Alessandro-Gabazza, C N; Fujimoto, H; Toda, M; Roeen, Z; Hinneh, J A; Yasuma, T; Takei, Y; Taguchi, O; Gabazza, E C

    2016-08-01

    Essentials Epithelial cell apoptosis is critical in the pathogenesis of idiopathic pulmonary fibrosis. Protein S, a circulating anticoagulant, inhibited apoptosis of lung epithelial cells. Overexpression of protein S in lung cells reduced bleomycin-induced pulmonary fibrosis. Intranasal therapy with exogenous protein S ameliorated bleomycin-induced pulmonary fibrosis. Background Pulmonary fibrosis is the terminal stage of interstitial lung diseases, some of them being incurable and of unknown etiology. Apoptosis plays a critical role in lung fibrogenesis. Protein S is a plasma anticoagulant with potent antiapoptotic activity. The role of protein S in pulmonary fibrosis is unknown. Objectives To evaluate the clinical relevance of protein S and its protective role in pulmonary fibrosis. Methods and Results The circulating level of protein S was measured in patients with pulmonary fibrosis and controls by the use of enzyme immunoassays. Pulmonary fibrosis was induced with bleomycin in transgenic mice overexpressing human protein S and wild-type mice, and exogenous protein S or vehicle was administered to wild-type mice; fibrosis was then compared in both models. Patients with pulmonary fibrosis had reduced circulating levels of protein S as compared with controls. Inflammatory changes, the levels of profibrotic cytokines, fibrosis score, hydroxyproline content in the lungs and oxygen desaturation were significantly reduced in protein S-transgenic mice as compared with wild-type mice. Wild-type mice treated with exogenous protein S showed significant decreases in the levels of inflammatory and profibrotic markers and fibrosis in the lungs as compared with untreated control mice. After bleomycin infusion, mice overexpressing human protein S showed significantly low caspase-3 activity, enhanced expression of antiapoptotic molecules and enhanced Akt and Axl kinase phosphorylation as compared with wild-type counterparts. Protein S also inhibited apoptosis of alveolar

  18. Imaging pulmonary fibrosis

    International Nuclear Information System (INIS)

    Brauner, M.W.; Rety, F.; Naccache, J.M.; Girard, F.; Valeyre, D.F.

    2001-01-01

    Localized fibrosis of the lung is usually scar tissue while diffuse pulmonary fibrosis is more often a sign of active disease. Chronic infiltrative lung disease may be classified into four categories: idiopathic pneumonitis, collagen diseases, granulomatosis (sarcoidosis), and caused by known diseases (pneumoconiosis, hypersensitivity pneumonitis, drug-induced lung disease, radiation). (authors)

  19. Pathogenesis of Idiopathic Pulmonary Fibrosis

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    Wolters, Paul J.; Collard, Harold R.; Jones, Kirk D.

    2014-01-01

    Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease associated with aging that is characterized by the histopathological pattern of usual interstitial pneumonia. Although an understanding of the pathogenesis of IPF is incomplete, recent advances delineating specific clinical and pathologic features of IPF have led to better definition of the molecular pathways that are pathologically activated in the disease. In this review we highlight several of these advances, with a focus on genetic predisposition to IPF and how genetic changes, which occur primarily in epithelial cells, lead to activation of profibrotic pathways in epithelial cells. We then discuss the pathologic changes within IPF fibroblasts and the extracellular matrix, and we conclude with a summary of how these profibrotic pathways may be interrelated. PMID:24050627

  20. Effect of mixing scanner types and reconstruction kernels on the characterization of lung parenchymal pathologies: emphysema, interstitial pulmonary fibrosis and normal non-smokers

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    Xu, Ye; van Beek, Edwin J.; McLennan, Geoffrey; Guo, Junfeng; Sonka, Milan; Hoffman, Eric

    2006-03-01

    In this study we utilize our texture characterization software (3-D AMFM) to characterize interstitial lung diseases (including emphysema) based on MDCT generated volumetric data using 3-dimensional texture features. We have sought to test whether the scanner and reconstruction filter (kernel) type affect the classification of lung diseases using the 3-D AMFM. We collected MDCT images in three subject groups: emphysema (n=9), interstitial pulmonary fibrosis (IPF) (n=10), and normal non-smokers (n=9). In each group, images were scanned either on a Siemens Sensation 16 or 64-slice scanner, (B50f or B30 recon. kernel) or a Philips 4-slice scanner (B recon. kernel). A total of 1516 volumes of interest (VOIs; 21x21 pixels in plane) were marked by two chest imaging experts using the Iowa Pulmonary Analysis Software Suite (PASS). We calculated 24 volumetric features. Bayesian methods were used for classification. Images from different scanners/kernels were combined in all possible combinations to test how robust the tissue classification was relative to the differences in image characteristics. We used 10-fold cross validation for testing the result. Sensitivity, specificity and accuracy were calculated. One-way Analysis of Variances (ANOVA) was used to compare the classification result between the various combinations of scanner and reconstruction kernel types. This study yielded a sensitivity of 94%, 91%, 97%, and 93% for emphysema, ground-glass, honeycombing, and normal non-smoker patterns respectively using a mixture of all three subject groups. The specificity for these characterizations was 97%, 99%, 99%, and 98%, respectively. The F test result of ANOVA shows there is no significant difference (p <0.05) between different combinations of data with respect to scanner and convolution kernel type. Since different MDCT and reconstruction kernel types did not show significant differences in regards to the classification result, this study suggests that the 3-D AMFM can

  1. The Four Corners Sign: A Specific Imaging Feature in Differentiating Systemic Sclerosis-related Interstitial Lung Disease From Idiopathic Pulmonary Fibrosis.

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    Walkoff, Lara; White, Darin B; Chung, Jonathan H; Asante, Dennis; Cox, Christian W

    2018-01-16

    Differentiating between systemic sclerosis-related interstitial lung disease (SSc-ILD) and idiopathic pulmonary fibrosis (IPF) is important because of the differences in workup, prognosis, and treatment. However, there is much overlap in the appearance of these 2 entities on high-resolution computed tomography. We propose that inflammation and/or fibrosis focally or disproportionately involving the bilateral anterolateral upper lobes and posterosuperior lower lobes ["Four Corners" Sign (FCS)] is specific for SSc-ILD. Randomized high-resolution computed tomography studies from 74 IPF and 73 SSc-ILD cases were evaluated by 2 thoracic radiologists blinded to all patient data. For each case the reviewers noted whether the FCS was present and assigned a confidence level on the basis of a 7-point Likert scale. The same process was then performed on a randomized external validation group of 42 SSc-ILD and 42 IPF cases. For Likert scores of 6 or 7 ("mostly agree" or "entirely agree" that the FCS is present, respectively) the sensitivity in SSc was 16.4% (95% confidence interval, 9.7%, 26.6%), specificity 100.0% (95% confidence interval, 95.1%, 100.0%). There was a significant association between a confidently present FCS and SSc compared with a confidently present FCS and IPF (P=0.0003). Analysis on an external validation group of 42 SSc and 42 IPF cases conferred similarly high specificity for SSc in cases characterized as FCS with high confidence. The FCS, a pattern of focal or disproportionate inflammation and/or fibrosis involving the bilateral anterolateral upper lobes and posterosuperior lower lobes, is specific for SSc-ILD when readers are confident of its presence.

  2. Genetics Home Reference: idiopathic pulmonary fibrosis

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    ... Twitter Home Health Conditions Idiopathic pulmonary fibrosis Idiopathic pulmonary fibrosis Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Idiopathic pulmonary fibrosis is a chronic, progressive lung disease. This condition ...

  3. rheumatoid arthritis associated with pulmonary fibrosis in nigerians

    African Journals Online (AJOL)

    among Africans with Rheumatoid arthritis without extra-articular features (4). Various pulmonary manifestations have been reported in the developed world, these include diffuse interstitial fibrosis, pleural effusion, nodular lung disease, pulmonary vasculitis, alveolar haemorrhage, and pneumonitis (5). Two cases seen in the ...

  4. Jaccoud's arthropathy and pulmonary fibrosis in CREST syndrome

    International Nuclear Information System (INIS)

    Spinel B, Nestor; Montenegro, Pablo; Rondon Federico; Restrepo, Jose F; Iglesias G, Antonio

    2010-01-01

    We report a case of a 48 years old patient with diagnosis of incomplete CREST syndrome (variant limited systemic sclerosis) in who we documented the presence of Jaccoud's arthropathy of the hands and pulmonary involvement by pulmonary fibrosis type usual interstitial pneumonia, with positivity for rheumatoid factor and anti-cyclic citrullinated peptide antibody.

  5. Glycyrrhizic acid alleviates bleomycin-induced pulmonary fibrosis in rats

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    Lili eGao

    2015-10-01

    Full Text Available Idiopathic pulmonary fibrosis is a progressive and lethal form of interstitial lung disease that lacks effective therapies at present. Glycyrrhizic acid (GA, a natural compound extracted from a traditional Chinese herbal medicine Glycyrrhiza glabra, was recently reported to benefit lung injury and liver fibrosis in animal models, yet whether GA has a therapeutic effect on pulmonary fibrosis is unknown. In this study, we investigated the potential therapeutic effect of GA on pulmonary fibrosis in a rat model with bleomycin (BLM-induced pulmonary fibrosis. The results indicated that GA treatment remarkably ameliorated BLM-induced pulmonary fibrosis and attenuated BLM-induced inflammation, oxidative stress, epithelial-mesenchymal transition and activation of tansforming growth factor-beta signaling pathway in the lungs. Further, we demonstrated that GA treatment inhibited proliferation of 3T6 fibroblast cells, induced cell cycle arrest and promoted apoptosis in vitro, implying that GA-mediated suppression of fibroproliferation may contribute to the anti-fibrotic effect against BLM-induced pulmonary fibrosis. In summary, our study suggests a therapeutic potential of GA in the treatment of pulmonary fibrosis.

  6. Serial changes and prognostic implications of CT findings in combined pulmonary fibrosis and emphysema: comparison with fibrotic idiopathic interstitial pneumonias alone.

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    Lee, Geewon; Kim, Ki Uk; Lee, Ji Won; Suh, Young Ju; Jeong, Yeon Joo

    2017-05-01

    Background Although fibrotic idiopathic interstitial pneumonias (IIPs) alone and those combined with pulmonary emphysema are naturally progressive diseases, the process of deterioration and outcomes are variable. Purpose To evaluate and compare serial changes of computed tomography (CT) abnormalities and prognostic predictive factors in fibrotic IIPs alone and those combined with pulmonary emphysema. Material and Methods A total of 148 patients with fibrotic IIPs alone (82 patients) and those combined with pulmonary emphysema (66 patients) were enrolled. Semi-quantitative CT analysis was used to assess the extents of CT characteristics which were evaluated on initial and follow-up CT images. Univariate and multivariate analyses were performed to assess the effects of clinical and CT variables on survival. Results Significant differences were noted between fibrotic scores, as determined using initial CT scans, in the fibrotic IIPs alone (21.22 ± 9.83) and those combined with pulmonary emphysema groups (14.70 ± 7.28) ( P lung cancer was more prevalent ( P = 0.001) in the fibrotic IIPs combined with pulmonary emphysema group. Multivariate Cox proportional hazards analysis showed changes in the extent of GGO (hazard ratio, 1.056) and the presence of lung cancer (hazard ratio, 4.631) were predictive factors of poor survivals. Conclusion Although patients with fibrotic IIPs alone and those combined with pulmonary emphysema have similar mortalities, lung cancer was more prevalent in patients with fibrotic IIPs combined with pulmonary emphysema. Furthermore, changes in the extent of GGO and the presence of lung cancer were independent prognostic factors of poor survivals.

  7. HRCT appearances of pulmonary interstitial diseases. The pathologic basis and clinical diagnostic significance

    International Nuclear Information System (INIS)

    Ma Daqing; Li Tieyi; Guan Yansheng; He Wen; Nie Yongkang

    1999-01-01

    Objective: To evaluate the CT appearances, the pathologic basis and diagnostic significance of pulmonary interstitial diseases. methods: 14 isolated lungs with interstitial diseases were obtained at autopsy and surgery. The lungs were inflated and fixed. HRCT and 1 cm thin slice soft X-ray radiograph were performed and then histologic examination was done. HRCT images of 72 cases with interstitial diseases were analysed. The HRCT appearances of 10 cases were followed up for 1.5-7.0 years. Results: According to HRCT-pathologic correlation, pulmonary interstitial diseases had the following HRCT findings: (1) Intralobular interstitial thickening (33 cases, 46%), including fine linear, reticular and radiating appearances and the interface sign. (2) Interlobular septal thickening (24 cases, 33%). (3) Thickening of bronchovesicular bundles (35 cases, 49%), with coarse, blurred or smooth bundle, and nodular shape. (4) Subpleural lines (31 cases, 43%). (5) Ground-glass opacity (22 cases, 31%) with peripheral, diffuse or locular distribution. (6) Honeycombing (27 cases, 38%), having sizes: 5 mm. Of the 10 cases with follow-up, 2 cases became normal on CT and 8 cases progressing to honeycombed lung. Conclusions: The HRCT findings of pulmonary interstitial diseases represent abnormalities of axial, peripheral and septal interstitium. Interstitial fibrosis of the lung can be differentiated from that without fibrosis by HRCT. Ground-glass opacity, intralobular interstitial thickening and subpleural lines are preliminary findings of pulmonary interstitial fibrosis

  8. The Role of Catalase in Pulmonary Fibrosis

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    Takigawa Tomoko

    2010-12-01

    Full Text Available Abstract Background Catalase is preferentially expressed in bronchiolar and alveolar epithelial cells, and acts as an endogenous antioxidant enzyme in normal lungs. We thus postulated epithelial damage would be associated with a functional deficiency of catalase during the development of lung fibrosis. Methods The present study evaluates the expression of catalase mRNA and protein in human interstitial pneumonias and in mouse bleomycin-induced lung injury. We examined the degree of bleomycin-induced inflammation and fibrosis in the mice with lowered catalase activity. Results In humans, catalase was decreased at the levels of activity, protein content and mRNA expression in fibrotic lungs (n = 12 compared to control lungs (n = 10. Immunohistochemistry revealed a decrease in catalase in bronchiolar epithelium and abnormal re-epithelialization in fibrotic areas. In C57BL/6J mice, catalase activity was suppressed along with downregulation of catalase mRNA in whole lung homogenates after bleomycin administration. In acatalasemic mice, neutrophilic inflammation was prolonged until 14 days, and there was a higher degree of lung fibrosis in association with a higher level of transforming growth factor-β expression and total collagen content following bleomycin treatment compared to wild-type mice. Conclusions Taken together, these findings demonstrate diminished catalase expression and activity in human pulmonary fibrosis and suggest the protective role of catalase against bleomycin-induced inflammation and subsequent fibrosis.

  9. Familial Pulmonary Fibrosis

    Science.gov (United States)

    ... associated interstitial lung disease (RB-ILD); and cryptogenic organizing pneumonia (COP). Cigarette smoking is a major risk factor for developing IIP, even in families with FPF. Clinical Trials For more than 100 ...

  10. Cough in idiopathic pulmonary fibrosis

    NARCIS (Netherlands)

    M.J.G. Van Manen (Mirjam); S.S. Birring (Surinder S.); C. Vancheri (Carlo); V. Cottin (Vincent); Renzoni, E.A. (Elisabetta A.); Russell, A.-M. (Anne-Marie); M.S. Wijsenbeek (Marlies)

    2016-01-01

    textabstractMany patients with idiopathic pulmonary fibrosis (IPF) complain of chronic refractory cough. Chronic cough is a distressing and disabling symptom with a major impact on quality of life. During recent years, progress has been made in gaining insight into the pathogenesis of cough in IPF,

  11. Autophagy in idiopathic pulmonary fibrosis.

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    Avignat S Patel

    Full Text Available Autophagy is a basic cellular homeostatic process important to cell fate decisions under conditions of stress. Dysregulation of autophagy impacts numerous human diseases including cancer and chronic obstructive lung disease. This study investigates the role of autophagy in idiopathic pulmonary fibrosis.Human lung tissues from patients with IPF were analyzed for autophagy markers and modulating proteins using western blotting, confocal microscopy and transmission electron microscopy. To study the effects of TGF-β(1 on autophagy, human lung fibroblasts were monitored by fluorescence microscopy and western blotting. In vivo experiments were done using the bleomycin-induced fibrosis mouse model.Lung tissues from IPF patients demonstrate evidence of decreased autophagic activity as assessed by LC3, p62 protein expression and immunofluorescence, and numbers of autophagosomes. TGF-β(1 inhibits autophagy in fibroblasts in vitro at least in part via activation of mTORC1; expression of TIGAR is also increased in response to TGF-β(1. In the bleomycin model of pulmonary fibrosis, rapamycin treatment is antifibrotic, and rapamycin also decreases expression of á-smooth muscle actin and fibronectin by fibroblasts in vitro. Inhibition of key regulators of autophagy, LC3 and beclin-1, leads to the opposite effect on fibroblast expression of á-smooth muscle actin and fibronectin.Autophagy is not induced in pulmonary fibrosis despite activation of pathways known to promote autophagy. Impairment of autophagy by TGF-β(1 may represent a mechanism for the promotion of fibrogenesis in IPF.

  12. Pulmonary complications of cystic fibrosis

    International Nuclear Information System (INIS)

    Ng, M.Y.; Flight, W.; Smith, E.

    2014-01-01

    The life expectancy of patients with cystic fibrosis (CF) has steadily increased over recent decades with a corresponding increase in the frequency of complications of the disease. Radiologists are increasingly involved with managing and identifying the pulmonary complications of CF. This article reviews the common manifestations of CF lung disease as well as updating radiologists with a number of less well-known complications of the condition. Early and accurate detection of the pulmonary effects of CF are increasingly important to prevent irreversible lung damage and give patients the greatest possibility of benefiting from the new therapies becoming available, which correct the underlying defect causing CF

  13. Lung adenocarcinoma mimicking pulmonary fibrosis-a case report

    International Nuclear Information System (INIS)

    Mehić, Bakir; Duranović Rayan, Lina; Bilalović, Nurija; Dohranović Tafro, Danina; Pilav, Ilijaz

    2016-01-01

    Lung cancer is usually presented with cough, dyspnea, pain and weight loss, which is overlapping with symptoms of other lung diseases such as pulmonary fibrosis. Pulmonary fibrosis shows characteristic reticular and nodular pattern, while lung cancers are mostly presented with infiltrative mass, thick-walled cavitations or a solitary nodule with spiculated borders. If the diagnosis is established based on clinical symptoms and CT findings, it would be a misapprehension. We report a case of lung adenocarcinoma whose symptoms as well as clinical images overlapped strongly with pulmonary fibrosis. The patient’s non-productive cough, progressive dyspnea, restrictive pattern of pulmonary function test and CT scans (showing reticular interstitial opacities) were all indicative of pulmonary fibrosis. The patient underwent a treatment consisting of corticosteroids and antibiotics, to no avail. Histopathology of the lung showed that the patient suffered from mucinous adenocarcinoma. Albeit the immunohistochemical staining was not consistent with lung adenocarcinoma, tumor’s morphological characteristics were consistent, and were used to make the definitive diagnosis. Given the fact that radiography cannot always make a clear-cut difference between pulmonary fibrosis and lung adenocarcinomas, and that clinical symptoms often overlap, histological examination should be considered as gold standard for diagnosis of lung adenocarcinoma

  14. Lung adenocarcinoma mimicking pulmonary fibrosis-a case report.

    Science.gov (United States)

    Mehić, Bakir; Duranović Rayan, Lina; Bilalović, Nurija; Dohranović Tafro, Danina; Pilav, Ilijaz

    2016-09-13

    Lung cancer is usually presented with cough, dyspnea, pain and weight loss, which is overlapping with symptoms of other lung diseases such as pulmonary fibrosis. Pulmonary fibrosis shows characteristic reticular and nodular pattern, while lung cancers are mostly presented with infiltrative mass, thick-walled cavitations or a solitary nodule with spiculated borders. If the diagnosis is established based on clinical symptoms and CT findings, it would be a misapprehension. We report a case of lung adenocarcinoma whose symptoms as well as clinical images overlapped strongly with pulmonary fibrosis. The patient's non-productive cough, progressive dyspnea, restrictive pattern of pulmonary function test and CT scans (showing reticular interstitial opacities) were all indicative of pulmonary fibrosis. The patient underwent a treatment consisting of corticosteroids and antibiotics, to no avail. Histopathology of the lung showed that the patient suffered from mucinous adenocarcinoma. Albeit the immunohistochemical staining was not consistent with lung adenocarcinoma, tumor's morphological characteristics were consistent, and were used to make the definitive diagnosis. Given the fact that radiography cannot always make a clear-cut difference between pulmonary fibrosis and lung adenocarcinomas, and that clinical symptoms often overlap, histological examination should be considered as gold standard for diagnosis of lung adenocarcinoma.

  15. Therapeutic targets in idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Kolb, Martin; Bonella, Francesco; Wollin, Lutz

    2017-10-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal interstitial lung disease. After many drugs failed in clinical trials, improvements in the understanding of the pathogenesis of IPF led to the approval of two drugs that slow the progression of the disease. However, the prognosis for patients with IPF remains poor and the search continues for drugs that inhibit the pathogenic pathways active in IPF to reduce or even halt the progression of the disease. In this article, we review the mechanisms of action of the two approved therapies for IPF (nintedanib and pirfenidone) and of the investigational compounds that are in Phase II trials and discuss the potential for combination therapy in the treatment of IPF. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Sputum eosinophilia in idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Birring, S S; Parker, D; McKenna, S; Hargadon, B; Brightling, C E; Pavord, I D; Bradding, P

    2005-02-01

    Cough is a common symptom in idiopathic pulmonary fibrosis that is difficult to treat and has a major impact on quality of life. We tested the hypothesis that the cough and increased cough reflex sensitivity seen in patients with idiopathic pulmonary fibrosis may be due to airway inflammation in a prospective, cross-sectional study. We measured the induced sputum inflammatory cell profile and cell-free supernatant inflammatory mediator concentrations in 15 patients with idiopathic pulmonary fibrosis, 17 healthy controls and 15 patients with chronic obstructive pulmonary disease. Both the geometric mean sputum differential eosinophil cell count and median eosinophilic-cationic-protein concentration were significantly higher in patients with idiopathic pulmonary fibrosis than controls (2.1% vs 0.3%; p <0.001 and 1.1 mg/ml versus 0.2 mg/ml; p=0.03 respectively). There were no significant differences in sputum eosinophil counts and eosinophilic-cationic-protein concentrations between patients with idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease. Sputum leukotriene-B4 concentrations were significantly lower in patients with idiopathic pulmonary fibrosis (p=0.03) and chronic obstructive pulmonary disease (p=0.008) compared to controls. Idiopathic pulmonary fibrosis is characterised by the presence of active eosinophilic airway inflammation raising the possibility that airway inflammation may contribute to symptoms such as cough.

  17. Normal Lung Quantification in Usual Interstitial Pneumonia Pattern: The Impact of Threshold-based Volumetric CT Analysis for the Staging of Idiopathic Pulmonary Fibrosis.

    Directory of Open Access Journals (Sweden)

    Hirotsugu Ohkubo

    Full Text Available Although several computer-aided computed tomography (CT analysis methods have been reported to objectively assess the disease severity and progression of idiopathic pulmonary fibrosis (IPF, it is unclear which method is most practical. A universal severity classification system has not yet been adopted for IPF.The purpose of this study was to test the correlation between quantitative-CT indices and lung physiology variables and to determine the ability of such indices to predict disease severity in IPF.A total of 27 IPF patients showing radiological UIP pattern on high-resolution (HR CT were retrospectively enrolled. Staging of IPF was performed according to two classification systems: the Japanese and GAP (gender, age, and physiology staging systems. CT images were assessed using a commercially available CT imaging analysis workstation, and the whole-lung mean CT value (MCT, the normally attenuated lung volume as defined from -950 HU to -701 Hounsfield unit (NL, the volume of the whole lung (WL, and the percentage of NL to WL (NL%, were calculated.CT indices (MCT, WL, and NL closely correlated with lung physiology variables. Among them, NL strongly correlated with forced vital capacity (FVC (r = 0.92, P <0.0001. NL% showed a large area under the receiver operating characteristic curve for detecting patients in the moderate or advanced stages of IPF. Multivariable logistic regression analyses showed that NL% is significantly more useful than the percentages of predicted FVC and predicted diffusing capacity of the lungs for carbon monoxide (Japanese stage II/III/IV [odds ratio, 0.73; 95% confidence intervals (CI, 0.48 to 0.92; P < 0.01]; III/IV [odds ratio. 0.80; 95% CI 0.59 to 0.96; P < 0.01]; GAP stage II/III [odds ratio, 0.79; 95% CI, 0.56 to 0.97; P < 0.05].The measurement of NL% by threshold-based volumetric CT analysis may help improve IPF staging.

  18. Spontaneous pneumothorax associated with pulmonary fibrosis in a patient with neurofibromatosis type 2

    International Nuclear Information System (INIS)

    Alcala Cerra, Gabriel; Moscote-Salazar, Luis Rafael; Lozano Tagua, Carlos Fernando; Sabogal Barrios, Ruben

    2010-01-01

    Pulmonary involvement in patients with neurofibromatosis has been repetitively reported as a very rare complication in type 1 variety. It is characterized by pulmonary interstitial disease, pulmonary fibrosis and bullaes, the last with high risk of rupture. We described a case of spontaneous pneumothorax in a patient with type 2 neurofibromatosis, as consequence of pulmonary fibrotic changes. To our knowledge this association had not been reported.

  19. Recent advances in understanding idiopathic pulmonary fibrosis

    Science.gov (United States)

    Daccord, Cécile; Maher, Toby M.

    2016-01-01

    Despite major research efforts leading to the recent approval of pirfenidone and nintedanib, the dismal prognosis of idiopathic pulmonary fibrosis (IPF) remains unchanged. The elaboration of international diagnostic criteria and disease stratification models based on clinical, physiological, radiological, and histopathological features has improved the accuracy of IPF diagnosis and prediction of mortality risk. Nevertheless, given the marked heterogeneity in clinical phenotype and the considerable overlap of IPF with other fibrotic interstitial lung diseases (ILDs), about 10% of cases of pulmonary fibrosis remain unclassifiable. Moreover, currently available tools fail to detect early IPF, predict the highly variable course of the disease, and assess response to antifibrotic drugs. Recent advances in understanding the multiple interrelated pathogenic pathways underlying IPF have identified various molecular phenotypes resulting from complex interactions among genetic, epigenetic, transcriptional, post-transcriptional, metabolic, and environmental factors. These different disease endotypes appear to confer variable susceptibility to the condition, differing risks of rapid progression, and, possibly, altered responses to therapy. The development and validation of diagnostic and prognostic biomarkers are necessary to enable a more precise and earlier diagnosis of IPF and to improve prediction of future disease behaviour. The availability of approved antifibrotic therapies together with potential new drugs currently under evaluation also highlights the need for biomarkers able to predict and assess treatment responsiveness, thereby allowing individualised treatment based on risk of progression and drug response. This approach of disease stratification and personalised medicine is already used in the routine management of many cancers and provides a potential road map for guiding clinical care in IPF. PMID:27303645

  20. The impact of emphysema in pulmonary fibrosis

    Directory of Open Access Journals (Sweden)

    Vincent Cottin

    2013-06-01

    Full Text Available Several groups have described a syndrome in which idiopathic pulmonary fibrosis (IPF coexists with pulmonary emphysema. This comes as no surprise since both diseases are associated with a history of exposure to cigarette smoke. The syndrome of combined pulmonary fibrosis and emphysema (CPFE is characterised by upper lobe emphysema and lower lobe fibrosis. Physiological testing of these patients reveals preserved lung volume indices contrasted by markedly impaired diffusion capacity. The incidence of CPFE remains unknown but several case series suggest that this subgroup may comprise up to 35% of patients with IPF. CPFE is a strong determinant of associated pulmonary hypertension (PH. In addition, CPFE has major effects on measures of physiological function, exercise capacity and prognosis, and may affect the results of pulmonary fibrosis trials. Further studies are needed to ascertain the aetiology, morbidity, mortality and management of the CPFE syndrome, with or without PH, and to evaluate novel therapeutic options in CPFE.

  1. Pulmonary fibrosis and exposure to steel welding fume.

    Science.gov (United States)

    Cosgrove, M P

    2015-12-01

    Arc welders who have been exposed to high concentrations of steel welding fume for prolonged periods of time may develop pulmonary fibrosis but the nature of the fibrotic changes has been debated over the last 80 years without any clear international consensus. To characterize the nature of the pulmonary fibrosis that develops in response to steel welding fume exposure and to provide a working hypothesis that would explain the findings of the existing research, to provide a platform for future research and to inform future occupational and clinical management of welders with pulmonary effects from welding fume. Review of the world literature on pulmonary fibrosis and welding of steel in all languages using PubMed, with further secondary search of references in the articles found in the primary search. Google and Reference Manager were used as further confirmatory search tools. Only case series and case reports were found but these provided consistent evidence that the consequence of exposure to steel welding fume at high levels for a prolonged period of time is a type of pulmonary fibrosis similar to, and possibly the same as, respiratory bronchiolitis which eventually develops into desquamative interstitial pneumonia with ongoing exposure. Steel welding fume may cause an occupational respiratory bronchiolitis which may develop into de squamative interstitial pneumonia with ongoing exposure. This concept may explain the difficulties in interpreting the wider literature on welding fume and lung function at lower exposures and may also explain the increased risk of lung cancer in welders. © The Author 2015. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  2. Interstitial lung diseases with fibrosis - the pattern at high resolution

    International Nuclear Information System (INIS)

    Jarzemska, A.; Lasek, W.; Nawrocka, E.; Meder, G.; Zapala, M.

    2003-01-01

    Surgical lung biopsy, either open thoracotomy or video-assisted thoracoscopy is recommended in the diagnosis of interstitial lung diseases (ILD). In some cases, however, the repetitive pattern of radiological features in high-resolution computed tomography is often sufficient to confirm the diagnosis in a non-invasive manner. The purpose of the study was to determine whether patients with ILD can be selected on the basis of the HRCT pattern. Thin-section CT scans were performed in 40 patients with histologically proven idiopathic interstitial pneumonia (26 patients with usual interstitial pneumonia UIP, 2 patients with desquamative interstitial pneumonia DIP, 2 patients with bronchiolitis obliterans organizing pneumonia BOOP, 2 patients with non-specific interstitial pneumonia NSIP, 11 patients with hypersensitivity pneumonitis, and 3 patients with pulmonary histiocytosis X). The location and the intensity of lesions were taken into consideration. Clinical and histopathological findings were compared. HRCT features of interstitial lung diseases such as nodules and cystic spaces in hypersensitivity pneumonitis and pulmonary histiocytosis, and ground-glass opacities in idiopathic interstitial pneumonias (IIP) were statistically significant for differential diagnosis in ILD cases. Combination of honeycombing and ground-glass opacities found in UIP and nodules found in DIP were also statistically significant features in IIP subtypes diagnosis. In some cases, HRCT patterns of hypersensitivity pneumonitis, pulmonary histiocytosis X and IPF combined with clinical findings allowed for the accurate diagnosis without resorting to lung biopsy. Within a group of idiopathic interstitial pneumonia only in usual interstitial pneumonia characteristic pattern in thin-section CT can be defined. In other subgroups some typical features can imply a diagnosis. (author)

  3. Grape seed extract ameliorates bleomycin-induced mouse pulmonary fibrosis.

    Science.gov (United States)

    Liu, Qi; Jiang, Jun-Xia; Liu, Ya-Nan; Ge, Ling-Tian; Guan, Yan; Zhao, Wei; Jia, Yong-Liang; Dong, Xin-Wei; Sun, Yun; Xie, Qiang-Min

    2017-05-05

    Pulmonary fibrosis is common in a variety of inflammatory lung diseases, such as interstitial pneumonia, chronic obstructive pulmonary disease, and silicosis. There is currently no effective clinical drug treatment. It has been reported that grape seed extracts (GSE) has extensive pharmacological effects with minimal toxicity. Although it has been found that GSE can improve the lung collagen deposition and fibrosis pathology induced by bleomycin in rat, its effects on pulmonary function, inflammation, growth factors, matrix metalloproteinases and epithelial-mesenchymal transition remain to be researched. In the present study, we studied whether GSE provided protection against bleomycin (BLM)-induced mouse pulmonary fibrosis. ICR strain mice were treated with BLM in order to establish pulmonary fibrosis models. GSE was given daily via intragastric administration for three weeks starting at one day after intratracheal instillation. GSE at 50 or 100mg/kg significantly reduced BLM-induced inflammatory cells infiltration, proinflammatory factor protein expression, and hydroxyproline in lung tissues, and improved pulmonary function in mice. Additionally, treatment with GSE also significantly impaired BLM-induced increases in lung fibrotic marker expression (collagen type I alpha 1 and fibronectin 1) and decreases in an anti-fibrotic marker (E-cadherin). Further investigation indicated that the possible molecular targets of GSE are matrix metalloproteinases-9 (MMP-9) and TGF-β1, given that treatment with GSE significantly prevented BLM-induced increases in MMP-9 and TGF-β1 expression in the lungs. Together, these results suggest that supplementation with GSE may improve the quality of life of lung fibrosis patients by inhibiting MMP-9 and TGF-β1 expression in the lungs. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Pulmonary tuberculosis in patients with idiopathic pulmonary fibrosis

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    Chung, Myung Jin; Goo, Jin Mo E-mail: jmgoo@plaza.snu.ac.kr; Im, Jung-Gi

    2004-11-01

    Objectives: Patients with idiopathic pulmonary fibrosis (IPF) have an increased risk of pulmonary tuberculosis. However, detecting pulmonary tuberculosis may be difficult due to the underlying fibrosis. The aim of this report is to describe the radiological and clinical findings of pulmonary tuberculosis in patients with idiopathic pulmonary fibrosis. Materials and methods: We reviewed 143 consecutive patients in whom IPF was diagnosed by either the histological or radio-clinical criteria. Among them, nine patients were histologically (n=2) or bacteriologically (n=7) confirmed to have active pulmonary tuberculosis. The location and patterns of pulmonary tuberculosis were examined on a thin section CT scan. Results: The most common thin section CT findings were subpleural nodules (n=6; mean diameter, 3.2 cm) and a lobar or segmental consolidation (n=3). The lesions were located most commonly in the right lower lobe (n=4). The incidence of tuberculosis in patients with idiopathic pulmonary fibrosis was more than five times higher than that of the general population. Conclusion: The atypical manifestation of pulmonary tuberculosis is common in patients with idiopathic pulmonary fibrosis, which may mimic lung cancer or bacterial pneumonia.

  5. Pulmonary tuberculosis in patients with idiopathic pulmonary fibrosis

    International Nuclear Information System (INIS)

    Chung, Myung Jin; Goo, Jin Mo; Im, Jung-Gi

    2004-01-01

    Objectives: Patients with idiopathic pulmonary fibrosis (IPF) have an increased risk of pulmonary tuberculosis. However, detecting pulmonary tuberculosis may be difficult due to the underlying fibrosis. The aim of this report is to describe the radiological and clinical findings of pulmonary tuberculosis in patients with idiopathic pulmonary fibrosis. Materials and methods: We reviewed 143 consecutive patients in whom IPF was diagnosed by either the histological or radio-clinical criteria. Among them, nine patients were histologically (n=2) or bacteriologically (n=7) confirmed to have active pulmonary tuberculosis. The location and patterns of pulmonary tuberculosis were examined on a thin section CT scan. Results: The most common thin section CT findings were subpleural nodules (n=6; mean diameter, 3.2 cm) and a lobar or segmental consolidation (n=3). The lesions were located most commonly in the right lower lobe (n=4). The incidence of tuberculosis in patients with idiopathic pulmonary fibrosis was more than five times higher than that of the general population. Conclusion: The atypical manifestation of pulmonary tuberculosis is common in patients with idiopathic pulmonary fibrosis, which may mimic lung cancer or bacterial pneumonia

  6. Chymase: a multifunctional player in pulmonary hypertension associated with lung fibrosis.

    Science.gov (United States)

    Kosanovic, Djuro; Luitel, Himal; Dahal, Bhola Kumar; Cornitescu, Teodora; Janssen, Wiebke; Danser, A H Jan; Garrelds, Ingrid M; De Mey, Jo G R; Fazzi, Gregorio; Schiffers, Paul; Iglarz, Marc; Fischli, Walter; Ghofrani, Hossein Ardeschir; Weissmann, Norbert; Grimminger, Friedrich; Seeger, Werner; Reiss, Irwin; Schermuly, Ralph Theo

    2015-10-01

    Limited literature sources implicate mast-cell mediator chymase in the pathologies of pulmonary hypertension and pulmonary fibrosis. However, there is no evidence on the contribution of chymase to the development of pulmonary hypertension associated with lung fibrosis, which is an important medical condition linked with increased mortality of patients who already suffer from a life-threatening interstitial lung disease.The aim of this study was to investigate the role of chymase in this particular pulmonary hypertension form, by using a bleomycin-induced pulmonary hypertension model.Chymase inhibition resulted in attenuation of pulmonary hypertension and pulmonary fibrosis, as evident from improved haemodynamics, decreased right ventricular remodelling/hypertrophy, pulmonary vascular remodelling and lung fibrosis. These beneficial effects were associated with a strong tendency of reduction in mast cell number and activity, and significantly diminished chymase expression levels. Mechanistically, chymase inhibition led to attenuation of transforming growth factor β1 and matrix-metalloproteinase-2 contents in the lungs. Furthermore, chymase inhibition prevented big endothelin-1-induced vasoconstriction of the pulmonary arteries.Therefore, chymase plays a role in the pathogenesis of pulmonary hypertension associated with pulmonary fibrosis and may represent a promising therapeutic target. In addition, this study may provide valuable insights on the contribution of chymase in the pulmonary hypertension context, in general, regardless of the pulmonary hypertension form. Copyright ©ERS 2015.

  7. Factors Influencing Oxidative Imbalance in Pulmonary Fibrosis: An Immunohistochemical Study

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    Simona Inghilleri

    2011-01-01

    Full Text Available Background. Idiopathic Pulmonary Fibrosis (IPF is a fatal lung disease of unknown etiology characterized by interstitial fibrosis determining irreversible distortion of pulmonary architecture. Reactive oxygen species (ROS and markers of oxidative stress play a pivotal role in human IPF pathology, possibly through induction of epithelial-mesenchymal transition (EMT. Methods. We investigated by immunohistochemistry, in UIP and COP tissue samples, the expression of most relevant markers of the molecular interplay involving RAGE, oxidant/antioxidant balance regulation, tissue nitrosylation, and mediators of EMT. Results. In both UIP and COP, the degree of RAGE expression was similarly high, while SODs and i-NOS, diffusely present in COP endoalveolar plugs, were almost absent in UIP fibroblast foci. A lower degree of tissue nitrosilation was observed in UIP than in COP. Conclusions. Fibroblast lesions of UIP and of COP share a similar degree of activation of RAGE, while antioxidant enzyme expression markedly reduced in UIP.

  8. Angiotensin II type 1 and 2 receptors and lymphatic vessels modulate lung remodeling and fibrosis in systemic sclerosis and idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Parra, Edwin Roger; Ruppert, Aline Domingos Pinto; Capelozzi, Vera Luiza

    2014-01-01

    To validate the importance of the angiotensin II receptor isotypes and the lymphatic vessels in systemic sclerosis and idiopathic pulmonary fibrosis. We examined angiotensin II type 1 and 2 receptors and lymphatic vessels in the pulmonary tissues obtained from open lung biopsies of 30 patients with systemic sclerosis and 28 patients with idiopathic pulmonary fibrosis. Their histologic patterns included cellular and fibrotic non-specific interstitial pneumonia for systemic sclerosis and usual interstitial pneumonia for idiopathic pulmonary fibrosis. We used immunohistochemistry and histomorphometry to evaluate the number of cells in the alveolar septae and the vessels stained by these markers. Survival curves were also used. We found a significantly increased percentage of septal and vessel cells immunostained for the angiotensin type 1 and 2 receptors in the systemic sclerosis and idiopathic pulmonary fibrosis patients compared with the controls. A similar percentage of angiotensin 2 receptor positive vessel cells was observed in fibrotic non-specific interstitial pneumonia and usual interstitial pneumonia. A significantly increased percentage of lymphatic vessels was present in the usual interstitial pneumonia group compared with the non-specific interstitial pneumonia and control groups. A Cox regression analysis showed a high risk of death for the patients with usual interstitial pneumonia and a high percentage of vessel cells immunostained for the angiotensin 2 receptor in the lymphatic vessels. We concluded that angiotensin II receptor expression in the lung parenchyma can potentially control organ remodeling and fibrosis, which suggests that strategies aimed at preventing high angiotensin 2 receptor expression may be used as potential therapeutic target in patients with pulmonary systemic sclerosis and idiopathic pulmonary fibrosis.

  9. Molecular and cellular mechanisms of pulmonary fibrosis

    Science.gov (United States)

    2012-01-01

    Pulmonary fibrosis is a chronic lung disease characterized by excessive accumulation of extracellular matrix (ECM) and remodeling of the lung architecture. Idiopathic pulmonary fibrosis is considered the most common and severe form of the disease, with a median survival of approximately three years and no proven effective therapy. Despite the fact that effective treatments are absent and the precise mechanisms that drive fibrosis in most patients remain incompletely understood, an extensive body of scientific literature regarding pulmonary fibrosis has accumulated over the past 35 years. In this review, we discuss three broad areas which have been explored that may be responsible for the combination of altered lung fibroblasts, loss of alveolar epithelial cells, and excessive accumulation of ECM: inflammation and immune mechanisms, oxidative stress and oxidative signaling, and procoagulant mechanisms. We discuss each of these processes separately to facilitate clarity, but certainly significant interplay will occur amongst these pathways in patients with this disease. PMID:22824096

  10. Targeting sphingosine kinase 1 attenuates bleomycin-induced pulmonary fibrosis.

    Science.gov (United States)

    Huang, Long Shuang; Berdyshev, Evgeny; Mathew, Biji; Fu, Panfeng; Gorshkova, Irina A; He, Donghong; Ma, Wenli; Noth, Imre; Ma, Shwu-Fan; Pendyala, Srikanth; Reddy, Sekhar P; Zhou, Tong; Zhang, Wei; Garzon, Steven A; Garcia, Joe G N; Natarajan, Viswanathan

    2013-04-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease, wherein transforming growth factor β (TGF-β) and sphingosine-1-phosphate (S1P) contribute to the pathogenesis of fibrosis. However, the in vivo contribution of sphingosine kinase (SphK) in fibrotic processes has not been documented. Microarray analysis of blood mononuclear cells from patients with IPF and SphK1- or SphK2-knockdown mice and SphK inhibitor were used to assess the role of SphKs in fibrogenesis. The expression of SphK1/2 negatively correlated with lung function and survival in patients with IPF. Also, the expression of SphK1 was increased in lung tissues from patients with IPF and bleomycin-challenged mice. Knockdown of SphK1, but not SphK2, increased survival and resistance to pulmonary fibrosis in bleomycin-challenged mice. Administration of SphK inhibitor reduced bleomycin-induced mortality and pulmonary fibrosis in mice. Knockdown of SphK1 or treatment with SphK inhibitor attenuated S1P generation and TGF-β secretion in a bleomycin-induced lung fibrosis mouse model that was accompanied by reduced phosphorylation of Smad2 and MAPKs in lung tissue. In vitro, bleomycin-induced expression of SphK1 in lung fibroblast was found to be TGF-β dependent. Taken together, these data indicate that SphK1 plays a critical role in the pathology of lung fibrosis and is a novel therapeutic target.

  11. Sequential occurrence of combined pulmonary fibrosis and emphysema syndrome in a non-smoker female patient.

    Science.gov (United States)

    Gupta, Pawan; Dash, Devijyoti; Mittal, Richa; Chhabra, Sunil K

    2017-05-01

    The combined pulmonary fibrosis and emphysema (CPFE) syndrome is a unique and an under-recognized disorder characterized by emphysema in the upper lobes and interstitial fibrosis in the lower lobes of the lung. It occurs predominantly in males and almost exclusively in smokers. This rare combination of a restrictive and an obstructive mechanical defect carries a poorer prognosis than either of the two components. We present a case of CPFE syndrome in a non-smoker female patient who developed lower lobe emphysema subsequent to development of interstitial fibrosis. The case was remarkable for the extreme rarity of several presenting features, namely, a lower lobe occurrence of emphysema subsequent to pre-existent interstitial fibrosis, female gender and absence of a history of smoking. © 2015 John Wiley & Sons Ltd.

  12. Ultrasound lung comets: new echographic sign of lung interstitial fibrosis in systemic sclerosis

    Directory of Open Access Journals (Sweden)

    C. Giacomelli

    2011-09-01

    Full Text Available Objective: Interstitial lung disease (ILD and pulmonary arterial hypertension (PAH are common complications of systemic sclerosis (SSc. Echocardiography evaluates PAH, and chest sonography detects even mild ILC as ultrasound lung comets (ULC, i.e. multiple comet-tails fanning out from the lung surface and originating from subpleural interlobular septa thickened by fibrosis. Aim: to assess ILaD and PAH by integrated cardiac and chest ultrasound in SSc. Methods: We enrolled 30 consecutive SSc patients (age= 54±13 years, 23 females in the Rheumatology Clinic of Pisa University. In all, we assessed systolic pulmonary arterial pressure (SPAP, from maximal velocity of tricuspid regurgitation flow, and ULC score with chest sonography (summing the number of ULC from each scanning space of anterior and posterior right and left chest, from second to fifth intercostal space. All patients underwent plasma assay for anti-topoisomerase antibodies (anti-Scl70, and antiicentromere associated with development of pulmonary involvement. Twenty-eight patients also underwent high resolution computed tomography, HRCT (from 0= no fibrosis to 3= honey combing. Results: ULC number - but not SPAP - was correlated to HRCT fibrosis and presence Scl-70 antibodies. ULC number was similar in localized or diffuse forms (16±20 vs 21±19, p=ns and was unrelated to SPAP (r=0.216, p=ns. Conclusions: Chest sonography assessment and ULC allow a complete, simple, radiation-free characterization of interstitial lung involvement in SSc - all in one setting and with the same instrument, same transducer and the same sonographer. In particular, ULC number is associated with HRCT evidence of lung fibrosis and presence of Scl-70 antibodies.

  13. Lysyl oxidases in idiopathic pulmonary fibrosis: A key participant in collagen I matrix remodelling

    NARCIS (Netherlands)

    Tjin, Gavin; Mahar, Annabelle; Kable, Eleanor; Burgess, Janette

    2015-01-01

    Introduction: The fibrotic element in Idiopathic Pulmonary Fibrosis (IPF) is a key feature and is associated with Usual Interstitial Pneumonia (UIP) pattern. Fibrillar collagen I (COL1) has second harmonic generation (SHG) properties, with signals both in the forward (F) (organized collagen) &

  14. IDENTIFICATION AND CHARACTERIZATION OF AN IDIOPATHIC PULMONARY FIBROSIS-LIKE CONDITION IN CATS

    Science.gov (United States)

    Interstitial lung diseases are a heterogeneous group of disorders due to a variety of causes. In veterinary medicine, those with a prominent fibrotic component of unknown etiology are often called idiopathic pulmonary fibrosis (IPF). In human medicine, this term is reserved for ...

  15. Gastroesophageal Reflux and Idiopathic Pulmonary Fibrosis: A Review

    Directory of Open Access Journals (Sweden)

    Ahmed Fahim

    2011-01-01

    Full Text Available The histological counterpart of idiopathic pulmonary fibrosis is usual interstitial pneumonia, in which areas of fibrosis of various ages are interspersed with normal lung. This pattern could be explained by repeated episodes of lung injury followed by abnormal wound healing responses. The cause of the initiating alveolar epithelial injury is unknown, but postulated mechanisms include immunological, microbial, or chemical injury, including aspirated gastric refluxate. Reflux is promoted by low basal pressure in the lower oesophageal sphincter and frequent relaxations, potentiated by hiatus hernia or oesophageal dysmotility. In susceptible individuals, repeated microaspiration of gastric refluxate may contribute to the pathogenesis of IPF. Microaspiration of nonacid or gaseous refluxate is poorly detected by current tests for gastroesophageal reflux which were developed for investigating oesophageal symptoms. Further studies using pharyngeal pH probes, high-resolution impedance manometry, and measurement of pepsin in the lung should clarify the impact of reflux and microaspiration in the pathogenesis of IPF.

  16. The lived experience with idiopathic pulmonary fibrosis

    DEFF Research Database (Denmark)

    Overgaard, Dorthe; Kaldan, Gudrun; Marsaa, Kristoffer

    2016-01-01

    The disease course in idiopathic pulmonary fibrosis (IPF) is variable, but patients experience a progressive decline in lung function and increased symptom burden leading to death. Little is known about the patients' experience and their needs during the disease course or about the burden on family...

  17. Pirfenidone treatment in idiopathic pulmonary fibrosis

    DEFF Research Database (Denmark)

    Salih, Goran Nadir; Shaker, Saher Burhan; Madsen, Helle Dall

    2016-01-01

    BACKGROUND: Pirfenidone was approved by the European Medicines Agency and introduced in most European countries in 2011 for treatment of idiopathic pulmonary fibrosis (IPF). OBJECTIVE: To describe the national Danish experiences of pirfenidone treatment for IPF during 30 months with respect...

  18. MicroRNA mimicry blocks pulmonary fibrosis

    Science.gov (United States)

    Montgomery, Rusty L; Yu, Guoying; Latimer, Paul A; Stack, Christianna; Robinson, Kathryn; Dalby, Christina M; Kaminski, Naftali; van Rooij, Eva

    2014-01-01

    Over the last decade, great enthusiasm has evolved for microRNA (miRNA) therapeutics. Part of the excitement stems from the fact that a miRNA often regulates numerous related mRNAs. As such, modulation of a single miRNA allows for parallel regulation of multiple genes involved in a particular disease. While many studies have shown therapeutic efficacy using miRNA inhibitors, efforts to restore or increase the function of a miRNA have been lagging behind. The miR-29 family has gained a lot of attention for its clear function in tissue fibrosis. This fibroblast-enriched miRNA family is downregulated in fibrotic diseases which induces a coordinate increase of many extracellular matrix genes. Here, we show that intravenous injection of synthetic RNA duplexes can increase miR-29 levels in vivo for several days. Moreover, therapeutic delivery of these miR-29 mimics during bleomycin-induced pulmonary fibrosis restores endogenous miR-29 function whereby decreasing collagen expression and blocking and reversing pulmonary fibrosis. Our data support the feasibility of using miRNA mimics to therapeutically increase miRNAs and indicate miR-29 to be a potent therapeutic miRNA for treating pulmonary fibrosis. PMID:25239947

  19. Airway-centered interstitial fibrosis: etiology, clinical findings and prognosis.

    Science.gov (United States)

    Kuranishi, Lilian Tiemi; Leslie, Kevin O; Ferreira, Rimarcs Gomes; Coletta, Ester Aparecida Ney; Storrer, Karin Mueller; Soares, Maria Raquel; de Castro Pereira, Carlos Alberto

    2015-05-09

    Airway-centered Interstitial Fibrosis (ACIF) is a common pathologic pattern observed in our practice. The objectives of this study are to describe the causes associated with ACIF in a large sample of patients and its effect on survival. A retrospective study in three centers of interstitial lung disease in São Paulo, between January of 1995 and December of 2012. The surgical lung biopsy specimens were reviewed by three pathologists. The clinical, functional and tomographic findings were analyzed by a standardized protocol. There were 68 cases of ACIF, most of them women. The mean age was 57 ± 12 yr. Dyspnea, cough, restrictive pattern at spirometry and oxygen desaturation at exercise were common. A reticular pattern with peribronchovascular infiltrates was found in 79% of the cases. The etiologies of ACIF were hypersensitivity pneumonitis in 29 (42.6%), gastroesophageal reflux disease in 17 (25.0%), collagen vascular disease in 4 (5.9%), a combination of them in 15 cases and idiopathic in 3 (4.4%). The median survival was 116 months (95% CI = 58.5 - 173.5). Lower values of oxygen saturation at rest, presence of cough and some histological findings--organizing tissue in the airways, fibroblastic foci and microscopic honeycombing--were predictors of worse survival. ACIF is an interstitial lung disease with a better survival when compared with IPF. The main etiologies are HP and GERD. The oxygen saturation at rest, the presence of cough and some histological findings are predictors of survival.

  20. Doxycycline Attenuated Pulmonary Fibrosis Induced by Bleomycin in Mice

    OpenAIRE

    Fujita, Masaki; Ye, Qing; Ouchi, Hiroshi; Harada, Eiji; Inoshima, Ichiro; Kuwano, Kazuyoshi; Nakanishi, Yoichi

    2006-01-01

    The administration of doxycycline prior to bleomycin in mice attenuated pulmonary fibrosis. Bronchoalveolar neutrophil influx and gelatinase activity, but not caseinolytic activity, were attenuated by doxycycline. Established fibrosis was not affected by doxycycline. Thus, doxycycline might be useful for slowing down pulmonary fibrosis by biological activity other than antibacterial activity.

  1. Simvastatin impairs the induction of pulmonary fibrosis caused by a western style diet: a preliminary study.

    Science.gov (United States)

    Kruzliak, Peter; Hare, David L; Zvonicek, Vaclav; Klimas, Jan; Zulli, Anthony

    2015-11-01

    The role of an atherogenic diet in causing pulmonary fibrosis has received little attention and simvastatin has been shown to reduce pulmonary fibrosis in animal models. To determine if an atherogenic diet can induce pulmonary fibrosis and whether simvastatin treatment is beneficial by up-regulating heat shock protein 70 and 90. New Zealand white rabbits (n = 15) were divided: Group 1 (control); Group 2 (MC) received a normal rabbit diet with 1% methionine plus 0.5% cholesterol (atherogenic diet). Group 3 received the same diet as the MC group plus 5 mg/kg/day simvastatin orally (MCS). After 4 weeks, the lungs were collected and analysed. Picrosirus red staining of lung interstitial collagen content showed that the atherogenic diet increased fibrosis 2.9-fold (P Western blot analysis showed that the atherogenic diet significantly reduced lung Hsp70 protein by 22% (P diet stimulates pulmonary fibrosis and reduces lung Hsp70/Hsp90 protein concentration. Simvastatin impairs this by mechanisms unrelated to Hsp70/Hsp90, but possibly a reduction in angiotensin II receptor or alpha adrenergic receptor pathways. These results could have implications in idiopathic pulmonary fibrosis. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  2. Fibrocytes in pulmonary fibrosis: a brief synopsis

    Directory of Open Access Journals (Sweden)

    Shyam Maharaj

    2013-12-01

    Full Text Available Fibrocytes are bone marrow-derived, circulating mesenchymal progenitor cells that play a role in several fibrotic disorders, including lung fibrosis. They are attracted to injured tissue by various chemokines. It is likely that fibrocytes play a detrimental role in tissue homeostasis and promote fibrosis, although this paradigm needs further confirmation. This would make fibrocytes a possible novel treatment target for fibrotic disorders. Fibrocytes also have some potential as a biomarker for idiopathic pulmonary fibrosis (IPF and other diseases, but the promising preliminary data from single centre studies still require independent validation. Despite several, as yet, unresolved issues, it has become clear that fibrocytes are more than an incidental finding in lung injury and repair, and may hold great promise for the future of IPF management.

  3. Comorbid Conditions in Idiopathic Pulmonary Fibrosis: Recognition and Management

    Directory of Open Access Journals (Sweden)

    Justin M. Oldham

    2017-08-01

    Full Text Available Idiopathic pulmonary fibrosis (IPF, a fibrosing interstitial pneumonia of unknown etiology, primarily affects older adults and leads to a progressive decline in lung function and quality of life. With a median survival of 3–5 years, IPF is the most common and deadly of the idiopathic interstitial pneumonias. Despite the poor survivorship, there exists substantial variation in disease progression, making accurate prognostication difficult. Lung transplantation remains the sole curative intervention in IPF, but two anti-fibrotic therapies were recently shown to slow pulmonary function decline and are now approved for the treatment of IPF in many countries around the world. While the approval of these therapies represents an important first step in combatting of this devastating disease, a comprehensive approach to diagnosing and treating patients with IPF remains critically important. Included in this comprehensive assessment is the recognition and appropriate management of comorbid conditions. Though IPF is characterized by single organ involvement, many comorbid conditions occur within other organ systems. Common cardiovascular processes include coronary artery disease and pulmonary hypertension (PH, while gastroesophageal reflux and hiatal hernia are the most commonly encountered gastrointestinal disorders. Hematologic abnormalities appear to place patients with IPF at increased risk of venous thromboembolism, while diabetes mellitus (DM and hypothyroidism are prevalent metabolic disorders. Several pulmonary comorbidities have also been linked to IPF, and include emphysema, lung cancer, and obstructive sleep apnea. While the treatment of some comorbid conditions, such as CAD, DM, and hypothyroidism is recommended irrespective of IPF, the benefit of treating others, such as gastroesophageal reflux and PH, remains unclear. In this review, we highlight common comorbid conditions encountered in IPF, discuss disease-specific diagnostic

  4. Pulmonary interstitial emphysema in neonates -reporting of 11 cases

    International Nuclear Information System (INIS)

    Alvares, Beatriz Regina; Santos Mezzacappa, Maria Aparecida dos; Marba, Sergio Tadeu Martins

    1997-01-01

    The present paper relates the radiologic and clinical aspects of pulmonary interstitial emphysema in 11 infants submitted to assisted ventilation. The radiologic diagnosis was made using the classification of Boothroyd and Barson (levels I to III). A prevalence of pulmonary interstitial emphysema of levels II and III was observed in masculine premature infants with hyaline membrane disease and intrauterine pneumonia. Mortality was high and occurred in the infants with advanced levels of the disease. The authors emphasize the importance of early radiologic diagnosis of this condition during the treatment of premature infants submitted to assisted ventilation. (author)

  5. The Canadian Registry for Pulmonary Fibrosis: Design and Rationale of a National Pulmonary Fibrosis Registry

    Directory of Open Access Journals (Sweden)

    Christopher J. Ryerson

    2016-01-01

    Full Text Available Background. The relative rarity and diversity of fibrotic interstitial lung disease (ILD have made it challenging to study these diseases in single-centre cohorts. Here we describe formation of a multicentre Canadian registry that is needed to describe the outcomes of fibrotic ILD and to enable detailed healthcare utilization analyses that will be the cornerstone for future healthcare planning. Methods. The Canadian Registry for Pulmonary Fibrosis (CARE-PF is a prospective cohort anticipated to consist of at least 2,800 patients with fibrotic ILD. CARE-PF will be used to (1 describe the natural history of fibrotic ILD, specifically determining the incidence and outcomes of acute exacerbations of ILD subtypes and (2 determine the impact of ILD and acute exacerbations of ILD on health services use and healthcare costs in the Canadian population. Consecutive patients with fibrotic ILD will be recruited from five Canadian ILD centres over a period of five years. Patients will be followed up as clinically indicated and will complete standardized questionnaires at each clinic visit. Prespecified outcomes and health services use will be measured based on self-report and linkage to provincial health administrative databases. Conclusion. CARE-PF will be among the largest prospective multicentre ILD registries in the world, providing detailed data on the natural history of fibrotic ILD and the healthcare resources used by these patients. As the largest and most comprehensive cohort of Canadian ILD patients, CARE-PF establishes a network for future clinical research and early phase clinical trials and provides a platform for translational and basic science research.

  6. Interstitial Lung Disease

    Science.gov (United States)

    ... grouped together under the label of idiopathic interstitial pneumonias, the most common and deadly of which is idiopathic pulmonary fibrosis. Risk factors Factors that may make you more susceptible to ...

  7. Endoplasmic reticulum stress in pulmonary fibrosis.

    Science.gov (United States)

    Burman, Ankita; Tanjore, Harikrishna; Blackwell, Timothy S

    2018-03-19

    Endoplasmic reticulum (ER) stress is associated with development and progression of fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). ER stress was first implicated in the pathogenesis of IPF >15 years ago with the discovery of disease-causing mutations in surfactant protein C, which result in a misfolded gene product in type II alveolar epithelial cells (AECs). ER stress and the unfolded protein response (UPR) have been linked to lung fibrosis through regulation of AEC apoptosis, epithelial-mesenchymal transition, myofibroblast differentiation, and M2 macrophage polarization. Although progress has been made in understanding the causes and consequences of ER stress in IPF and a number of chronic fibrotic disorders, further studies are needed to identify key factors that induce ER stress in important cell types and define critical down-stream processes and effector molecules that mediate ER stress-related phenotypes. This review discusses potential causes of ER stress induction in the lungs and current evidence linking ER stress to fibrosis in the context of individual cell types: AECs, fibroblasts, and macrophages. As our understanding of the relationship between ER stress and lung fibrosis continues to evolve, future studies will examine new strategies to modulate UPR pathways for therapeutic benefit. Copyright © 2017. Published by Elsevier B.V.

  8. Pulmonary function vascular index predicts prognosis in idiopathic interstitial pneumonia

    NARCIS (Netherlands)

    Corte, Tamera J.; Wort, Stephen J.; MacDonald, Peter S.; Edey, Anthony; Hansell, David M.; Renzoni, Elisabetta; Maher, Toby M.; Nicholson, Andrew G.; Bandula, Steven; Bresser, Paul; Wells, Athol U.

    2012-01-01

    Background and objective: Pulmonary hypertension (PH) is associated with increased mortality in fibrotic idiopathic interstitial pneumonia (IIP). We hypothesize that baseline KCO (diffusing capacity of carbon monoxide/alveolar volume) and 6-month decline in KCO reflect PH, thus predicting mortality

  9. Acute exacerbations and pulmonary hypertension in advanced idiopathic pulmonary fibrosis.

    LENUS (Irish Health Repository)

    Judge, Eoin P

    2012-07-01

    The aim of this study was to evaluate the risk factors for and outcomes of acute exacerbations in patients with advanced idiopathic pulmonary fibrosis (IPF), and to examine the relationship between disease severity and neovascularisation in explanted IPF lung tissue. 55 IPF patients assessed for lung transplantation were divided into acute (n=27) and non-acute exacerbation (n=28) groups. Haemodynamic data was collected at baseline, at the time of acute exacerbation and at lung transplantation. Histological analysis and CD31 immunostaining to quantify microvessel density (MVD) was performed on the explanted lung tissue of 13 transplanted patients. Acute exacerbations were associated with increased mortality (p=0.0015). Pulmonary hypertension (PH) at baseline and acute exacerbations were associated with poor survival (p<0.01). PH at baseline was associated with a significant risk of acute exacerbations (HR 2.217, p=0.041). Neovascularisation (MVD) was significantly increased in areas of cellular fibrosis and significantly decreased in areas of honeycombing. There was a significant inverse correlation between mean pulmonary artery pressure and MVD in areas of honeycombing. Acute exacerbations were associated with significantly increased mortality in patients with advanced IPF. PH was associated with the subsequent development of an acute exacerbation and with poor survival. Neovascularisation was significantly decreased in areas of honeycombing, and was significantly inversely correlated with mean pulmonary arterial pressure in areas of honeycombing.

  10. Pathological and radiological correlation in an autopsy case of combined pulmonary fibrosis and emphysema

    Directory of Open Access Journals (Sweden)

    Karata H

    2015-07-01

    Full Text Available Hiroki Karata,1 Tomonori Tanaka,1 Ryoko Egashira,2 Kazuhiro Tabata,1 Kyoko Otani,3 Ryuji Hayashi,4 Takashi Hori,5 Junya Fukuoka1 1Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; 2Department of Radiology, Faculty of Medicine, Saga University, Saga, Japan; 3Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Japan; 4Department of Internal Medicine, University of Toyama, Faculty of Medicine, Toyama, Japan; 5Laboratory of Pathology, Toyama University Hospital, Toyama, Japan Abstract: We report an educational autopsy case of combined pulmonary fibrosis and emphysema. Radiological patterns of the upper lung were considered as mostly emphysema, but pathological observation revealed significant interstitial fibrosis of usual interstitial pneumonia as a major pathology. The patient eventually developed acute exacerbation of background interstitial pneumonia. Careful radiological and pathological correlation of the current case indicates that regions with distal acinar emphysema on computed tomography image may possess histologically marked dense fibrosis of lethal interstitial pneumonia. Keywords: interstitial pneumonia, CPFE, AEF, smoking, CT

  11. Pulmonary Artery Dimensions as a Prognosticator of Transplant-Free Survival in Scleroderma Interstitial Lung Disease.

    Science.gov (United States)

    Gleason, James Benjamin; Patel, Krunal B; Hernandez, Felix; Hadeh, Anas; Highland, Kristin B; Rahaghi, Franck; Mehta, Jinesh P

    2017-08-01

    Systemic sclerosis is a chronic debilitating autoimmune disease characterized by endothelial dysfunction and multi-organ fibrosis. Interstitial lung disease, a common manifestation of SSc, is termed scleroderma-related interstitial lung disease (SSc-ILD) and along with pulmonary hypertension contributes to a majority of deaths in SSc. SSc-ILD patients frequently develop pulmonary hypertension, which prognosticates a poorer outcome. We investigated pulmonary artery dimensions as an outcome predictor in patients with SSc-ILD. A retrospective chart review abstracting data from SSc-ILD patients evaluated at a large tertiary care center was performed. HRCT imaging was reviewed and pulmonary artery (PA) and ascending aorta (Ao) diameters were measured for calculation of the PA:Ao ratio. Additionally, demographics, vital signs, spirometric parameters, comorbidities, and mean pulmonary artery pressures were collected when available. Outcome analysis with lung transplant or death events within 4 years based on pulmonary artery size as well as PA:Ao ratio was performed. 70 SSc-ILD patients were identified. Mean pulmonary artery diameter and PA:Ao ratio was 31.17 and 1.07 mm, respectively. Patients with a pulmonary artery diameter ≥32 mm had higher risk of lung transplantation or death (p < 0.001) within 4 years. Patients with a PA:Ao ratio ≥1.1 also had higher risk of lung transplantation or death (p < 0.001) within 4 years. Unadjusted outcomes analyses also identified PA:Ao ratio ≥1.1 as an independent outcome predictor (hazard ratio 3.30, p < 0.001). In SSc-ILD patients, a PA:Ao ratio ≥1.1 is associated with higher risk of lung transplant or death. These data suggest that PA:Ao dimension may be used for prognostication in SSc-ILD.

  12. Conditional Knockout of Telomerase Reverse Transcriptase in Mesenchymal Cells Impairs Mouse Pulmonary Fibrosis.

    Directory of Open Access Journals (Sweden)

    Tianju Liu

    Full Text Available Telomerase is typically expressed in cellular populations capable of extended replication, such as germ cells, tumor cells, and stem cells, but is also induced in tissue injury, repair and fibrosis. Its catalytic component, telomerase reverse transcriptase (TERT is induced in lung fibroblasts from patients with fibrotic interstitial lung disease and in rodents with bleomycin-induced pulmonary fibrosis. To evaluate the fibroblast specific role of TERT in pulmonary fibrosis, transgenic mice bearing a floxed TERT allele were generated, and then crossed with an inducible collagen α2(I-Cre mouse line to generate fibroblast specific TERT conditional knockout mice. TERT-specific deficiency in mesenchymal cells caused attenuation of pulmonary fibrosis as manifested by reduced lung hydroxyproline content, type I collagen and α-smooth muscle actin mRNA levels. The TERT-deficient mouse lung fibroblasts displayed decreased cell proliferative capacity and higher susceptibility to induced apoptosis compared with control cells. Additionally TERT deficiency was associated with heightened α-smooth muscle actin expression indicative of myofibroblast differentiation. However the impairment of cell proliferation and increased susceptibility to apoptosis would cause a reduction in the myofibroblast progenitor population necessary to mount a successful myofibroblast-dependent fibrotic response. These findings identified a key role for TERT in fibroblast proliferation and survival essential for pulmonary fibrosis.

  13. Glaucocalyxin A improves survival in bleomycin-induced pulmonary fibrosis in mice.

    Science.gov (United States)

    Yang, Fei; Cao, Yiren; Zhang, Jian; You, Tao; Zhu, Li

    2017-01-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with unclear etiology and poor prognosis. Despite numerous studies on the pathogenesis of IPF, only scant treatment options are available for the management of IPF. Glaucocalyxin A (GLA), an ent-Kaurane diterpenoid, has been demonstrated to exert anti-inflammatory, anti-neoplastic and anti-platelet activities. In this study, we evaluated the role of GLA as an anti-fibrotic agent in bleomycin-induced pulmonary fibrosis in mice and investigated the underlying mechanisms by which GLA attenuates lung fibrosis. Intraperitoneal administration of GLA (10 mg/kg) significantly reduced collagen deposition and hydroxyproline content in mouse lungs treated with bleomycin. Importantly, GLA significantly improved survival in bleomycin treated mice. In addition, GLA reduced weight loss in mice that reflects cachexia due to pulmonary fibrosis. Mechanistically, GLA alleviated the infiltration of macrophages and neutrophils in lungs, attenuated the increases of proinflammatory cytokines in lung tissue and bronchoalveolar lavage fluid, and inhibited the activation of NF-κB in fibrotic lungs induced by bleomycin. These results provide evidence that GLA can effectively ameliorate pulmonary fibrosis through the antagonism of leukocyte infiltration and proinflammatory cytokine production, suggesting that it may become a potential anti-fibrotic agent in IPF management. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Improved pulmonary function following pirfenidone treatment in a patient with progressive interstitial lung disease associated with systemic sclerosis

    Directory of Open Access Journals (Sweden)

    Zarir F Udwadia

    2015-01-01

    Full Text Available Pirfenidone is an anti-fibrotic drug which has been approved for the management of patients with Idiopathic Pulmonary Fibrosis (IPF. However, its role in interstitial lung disease (ILD due to other causes such as systemic sclerosis (SSc is not clear. We present a case of a patient with SSc associated ILD who showed a subjective as well as objective improvement in lung function with pirfenidone.

  15. Thin-section computed tomography–histopathologic comparisons of pulmonary focal interstitial fibrosis, atypical adenomatous hyperplasia, adenocarcinoma in situ, and minimally invasive adenocarcinoma with pure ground-glass opacity

    Energy Technology Data Exchange (ETDEWEB)

    Si, Ming-Jue, E-mail: smjsh@hotmail.com [Department of Radiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, No. 280, Mohe Road, Shanghai 201999 (China); Tao, Xiao-Feng, E-mail: taoxiaofeng1963@hotmail.com [Department of Radiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, No. 280, Mohe Road, Shanghai 201999 (China); Du, Guang-Ye, E-mail: 715376158@qq.com [Department of Pathology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, No. 280, Mohe Road, Shanghai 201999 (China); Cai, Ling-Ling, E-mail: caill_00@163.com [Department of Radiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, No. 280, Mohe Road, Shanghai 201999 (China); Han, Hong-Xiu, E-mail: hanhongxiu@hotmail.com [Department of Pathology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, No. 280, Mohe Road, Shanghai 201999 (China); Liang, Xi-Zi, E-mail: liangxizish@hotmail.com [Department of Pathology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, No. 280, Mohe Road, Shanghai 201999 (China); Zhao, Jiang-Min, E-mail: zhaojiangmin1962@hotmail.com [Department of Radiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, No. 280, Mohe Road, Shanghai 201999 (China)

    2016-10-15

    Objective: To retrospectively compare focal interstitial fibrosis (FIF), atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), and minimally invasive adenocarcinoma (MIA) with pure ground-glass opacity (GGO) using thin-section computed tomography (CT). Materials and methods: Sixty pathologically confirmed cases were reviewed including 7 cases of FIF, 17 of AAH, 23of AIS, and 13 of MIA. All nodules kept pure ground glass appearances before surgical resection and their last time of thin-section CT imaging data before operation were collected. Differences of patient demographics and CT features were compared among these four types of lesions. Results: FIF occurred more frequently in males and smokers while the others occurred more frequently in female nonsmokers. Nodule size was significant larger in MIA (P < 0.001, cut-off value = 7.5 mm). Nodule shape (P = 0.045), margin characteristics (P < 0.001), the presence of pleural indentation (P = 0.032), and vascular ingress (P < 0.001) were significant factors that differentiated the 4 groups. A concave margin was only demonstrated in a high proportion of FIF at 85.7% (P = 0.002). There were no significant differences (all P > 0.05) in age, malignant history, attenuation value, location, and presence of bubble-like lucency. Conclusion: A nodule size >7.5 mm increases the possibility of MIA. A concave margin could be useful for differentiation of FIF from the other malignant or pre-malignant GGO nodules. The presence of spiculation or pleural indentation may preclude the diagnosis of AAH.

  16. Ultrasound in Rheumatologic Interstitial Lung Disease: A Case Report of Nonspecific Interstitial Pneumonia in Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    A. Laria

    2015-01-01

    Full Text Available According to the American Thoracic Society (ATS/European Respiratory Society consensus classification, idiopathic interstitial pneumonias (IIPs include several clinic-radiologic-pathologic entities: idiopathic pulmonary fibrosis (IPF, usual interstitial pneumonia (UIP, nonspecific interstitial pneumonia (NSIP, cryptogenic organizing pneumonia, acute interstitial pneumonia, respiratory bronchiolitis-associated ILD, desquamative interstitial pneumonia, and lymphoid interstitial pneumonia. Ultrasound Lung Comets (ULCs are an echographic chest-sonography hallmark of pulmonary interstitial fibrosis. We describe the ultrasound (US findings in the follow-up of a NSIP’s case in rheumatoid arthritis (RA.

  17. Correlation of tomographic findings with pulmonary function parameters in nonsmoking patients with idiopathic pulmonary fibrosis

    International Nuclear Information System (INIS)

    Lopes, Agnaldo Jose; Capone, Domenico; Mogami, Roberto; Jansen, Jose Manoel .E mail: phel.lop@uol.com.br; Cunha, Daniel Leme da; Melo, Pedro Lopes de

    2007-01-01

    Objective: To correlate tomographic findings with pulmonary function parameters in patients with idiopathic pulmonary fibrosis (IPF). Methods: A cross-sectional study was carried out, in which 30 nonsmoking patients with IPF were evaluated. Using a semiquantitative scoring system, the following high-resolution computerized tomography findings were quantified: total interstitial disease (TID), reticular abnormality/honeycombing, and ground-glass opacity (GGO). The functional variables were measured by spirometry, forced oscillation technique (FOT), helium dilution method, as well as the single-breath method of measuring diffusion capacity of the lung for carbon monoxide (DLCO). Results: Of the 30 patients studied, 18 were female, and 12 were male, with a mean age of 70.9 years. We found that TID and reticular abnormality and honeycombing correlated significantly (negative correlations) with the measurements of forced vital capacity (FVC), total lung capacity (TLC), DLCO, and dynamic respiratory compliance were found, as well as that GGO correlated significantly (and positively) with residual volume/TLC. The ratio of forced expiratory flow between 25 and 75% of FVC to FVC (FEF25-75%/FVC) correlated positively with TID, reticular abnormality/honeycombing, and GGO. Conclusion: In IPF patients, the measurements of volume, diffusion, and dynamic compliance are the physiological variables which best reflect the extent of the interstitial disease on HRCT scans. (author)

  18. Correlation of tomographic findings with pulmonary function parameters in nonsmoking patients with idiopathic pulmonary fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Lopes, Agnaldo Jose; Capone, Domenico; Mogami, Roberto; Jansen, Jose Manoel [Universidade do Estado do Rio de Janeiro (UERJ), RJ (Brazil). School of Medical Sciences].E mail: phel.lop@uol.com.br; Cunha, Daniel Leme da [Universidade do Estado do Rio de Janeiro (UERJ), RJ (Brazil). Pedro Ernesto University Hospital. Dept. of Radiology and Diagnostic Imaging; Melo, Pedro Lopes de [Universidade do Estado do Rio de Janeiro (UERJ), RJ (Brazil). Inst. of Biology

    2007-11-15

    Objective: To correlate tomographic findings with pulmonary function parameters in patients with idiopathic pulmonary fibrosis (IPF). Methods: A cross-sectional study was carried out, in which 30 nonsmoking patients with IPF were evaluated. Using a semiquantitative scoring system, the following high-resolution computerized tomography findings were quantified: total interstitial disease (TID), reticular abnormality/honeycombing, and ground-glass opacity (GGO). The functional variables were measured by spirometry, forced oscillation technique (FOT), helium dilution method, as well as the single-breath method of measuring diffusion capacity of the lung for carbon monoxide (DLCO). Results: Of the 30 patients studied, 18 were female, and 12 were male, with a mean age of 70.9 years. We found that TID and reticular abnormality and honeycombing correlated significantly (negative correlations) with the measurements of forced vital capacity (FVC), total lung capacity (TLC), DLCO, and dynamic respiratory compliance were found, as well as that GGO correlated significantly (and positively) with residual volume/TLC. The ratio of forced expiratory flow between 25 and 75% of FVC to FVC (FEF25-75%/FVC) correlated positively with TID, reticular abnormality/honeycombing, and GGO. Conclusion: In IPF patients, the measurements of volume, diffusion, and dynamic compliance are the physiological variables which best reflect the extent of the interstitial disease on HRCT scans. (author)

  19. Experimental induction of pulmonary fibrosis in horses with the gammaherpesvirus equine herpesvirus 5.

    Science.gov (United States)

    Williams, Kurt J; Robinson, N Edward; Lim, Ailam; Brandenberger, Christina; Maes, Roger; Behan, Ashley; Bolin, Steven R

    2013-01-01

    Gammaherpesviruses (γHV) are implicated in the pathogenesis of pulmonary fibrosis in humans and murine models of lung fibrosis, however there is little direct experimental evidence that such viruses induce lung fibrosis in the natural host. The equine γHV EHV 5 is associated with equine multinodular pulmonary fibrosis (EMPF), a progressive fibrosing lung disease in its natural host, the horse. Experimental reproduction of EMPF has not been attempted to date. We hypothesized that inoculation of EHV 5 isolated from cases of EMPF into the lungs of clinically normal horses would induce lung fibrosis similar to EMPF. Neutralizing antibody titers were measured in the horses before and after inoculation with EHV 5. PCR and virus isolation was used to detect EHV 5 in antemortem blood and BAL samples, and in tissues collected postmortem. Nodular pulmonary fibrosis and induction of myofibroblasts occurred in EHV 5 inoculated horses. Mean lung collagen in EHV 5 inoculated horses (80 µg/mg) was significantly increased compared to control horses (26 µg/mg) (p < 0.5), as was interstitial collagen (32.6% ± 1.2% vs 23% ± 1.4%) (mean ± SEM; p < 0.001). Virus was difficult to detect in infected horses throughout the experiment, although EHV 5 antigen was detected in the lung by immunohistochemistry. We conclude that the γHV EHV 5 can induce lung fibrosis in the horse, and hypothesize that induction of fibrosis occurs while the virus is latent within the lung. This is the first example of a γHV inducing lung fibrosis in the natural host.

  20. Experimental induction of pulmonary fibrosis in horses with the gammaherpesvirus equine herpesvirus 5.

    Directory of Open Access Journals (Sweden)

    Kurt J Williams

    Full Text Available Gammaherpesviruses (γHV are implicated in the pathogenesis of pulmonary fibrosis in humans and murine models of lung fibrosis, however there is little direct experimental evidence that such viruses induce lung fibrosis in the natural host. The equine γHV EHV 5 is associated with equine multinodular pulmonary fibrosis (EMPF, a progressive fibrosing lung disease in its natural host, the horse. Experimental reproduction of EMPF has not been attempted to date. We hypothesized that inoculation of EHV 5 isolated from cases of EMPF into the lungs of clinically normal horses would induce lung fibrosis similar to EMPF. Neutralizing antibody titers were measured in the horses before and after inoculation with EHV 5. PCR and virus isolation was used to detect EHV 5 in antemortem blood and BAL samples, and in tissues collected postmortem. Nodular pulmonary fibrosis and induction of myofibroblasts occurred in EHV 5 inoculated horses. Mean lung collagen in EHV 5 inoculated horses (80 µg/mg was significantly increased compared to control horses (26 µg/mg (p < 0.5, as was interstitial collagen (32.6% ± 1.2% vs 23% ± 1.4% (mean ± SEM; p < 0.001. Virus was difficult to detect in infected horses throughout the experiment, although EHV 5 antigen was detected in the lung by immunohistochemistry. We conclude that the γHV EHV 5 can induce lung fibrosis in the horse, and hypothesize that induction of fibrosis occurs while the virus is latent within the lung. This is the first example of a γHV inducing lung fibrosis in the natural host.

  1. Calcitonin gene-related peptide down-regulates bleomycin-induced pulmonary fibrosis.

    Science.gov (United States)

    Li, Xian-Wei; Li, Xiao-Hui; Du, Jie; Li, Dai; Li, Yuan-Jian; Hu, Chang-Ping

    2016-12-01

    We have found that eIF3a plays an important role in bleomycin-induced pulmonary fibrosis, and up-regulation of eIF3a induced by TGF-β1 is mediated via the ERK1/2 pathway. Whether ERK1/2 - eIF3a signal pathway is involved in calcitonin gene-related peptide (CGRP)-mediated pathogenesis of bleomycin-induced pulmonary fibrosis remains unknown. Pulmonary fibrosis was induced by intratracheal instillation of bleomycin (5 mg/kg) in rats. Primary pulmonary fibroblasts were cultured to investigate the proliferation by BrdU incorporation method and flow cytometry. Sensory CGRP depletion by capsaicin exacerbated bleomycin-induced pulmonary fibrosis in rats, as shown by a significant disturbed alveolar structure, marked thickening of the interalveolar septa and dense interstitial infiltration by inflammatory cells and fibroblasts, accompanied with increased expression of TGF-β1, eIF3a, phosphorylated ERK1/2, α-SMA, collagen I, and collagen III. Exogenous application of CGRP significantly inhibited TGF-β1-induced proliferation and differentiation of pulmonary fibroblasts concomitantly with decreased expression of eIF3a, phosphorylated ERK1/2, α-SMA, collagen I, and collagen III. These effects of CGRP were abolished in the presence of CGRP 8-37 . These results suggest that endogenous CGRP is related to the development of pulmonary fibrosis induced by bleomycin, and the inhibitory effect of CGRP on proliferation of lung fibroblasts involves the ERK1/2 - eIF3a signaling pathway.

  2. Prominin-1/CD133+ lung epithelial progenitors protect from bleomycin-induced pulmonary fibrosis.

    Science.gov (United States)

    Germano, Davide; Blyszczuk, Przemyslaw; Valaperti, Alan; Kania, Gabriela; Dirnhofer, Stephan; Landmesser, Ulf; Lüscher, Thomas F; Hunziker, Lukas; Zulewski, Henryk; Eriksson, Urs

    2009-05-15

    The mouse model of bleomycin-induced lung injury offers an approach to study idiopathic pulmonary fibrosis, a progressive interstitial lung disease with poor prognosis. Progenitor cell-based treatment strategies might combine antiinflammatory effects and the capacity for tissue repair. To expand progenitor cells with reparative and regenerative capacities and to evaluate their protective effects on pulmonary fibrosis in vivo. Prominin-1/CD133(+) epithelial progenitor cells (PEPs) were expanded from adult mouse lungs after digestion and culture of distal airways. Lung fibrosis was induced in C57Bl/6 mice by instillation of bleomycin. Two hours later, animals were transplanted with PEPs. Inflammation and fibrosis were assessed by immunohistochemistry, bronchoalveolar lavage fluid differentials, and real-time polymerase chain reaction. PEPs expanded from mouse lungs were of bone marrow origin, coexpressed stem and hematopoietic cell markers, and differentiated in vitro into alveolar type II surfactant protein-C(+) epithelial cells. In bleomycin-challenged mice, intratracheally injected PEPs engrafted into the lungs and differentiated into type II pneumocytes. Furthermore, PEPs suppressed proinflammatory and profibrotic gene expression, prevented the recruitment of inflammatory cells, and protected bleomycin-challenged mice from pulmonary fibrosis. Mechanistically, the protective effect depended on upregulation of inducible nitric oxide synthase in PEPs and nitric oxide-mediated suppression of alveolar macrophage proliferation. Accordingly, PEPs from iNOS(-/-) but not iNOS(+/+) mice failed to protect from bleomycin-induced lung injury. The combined antiinflammatory and regenerative capacity of bone marrow-derived pulmonary epithelial progenitors offers a promising approach for development of cell-based therapeutic strategies against pulmonary fibrosis.

  3. Computed Tomography in pulmonary cystic fibrosis

    International Nuclear Information System (INIS)

    Taccone, A.; Marzoli, A.; Romano, L.; Girosi, D.

    1991-01-01

    This study was aimed at evaluating CT sensitivity in identifying the signs of pulmonary cystic fibrosis (CF). The chests of 39 patients (16 males and 23 females, mean age 19.1 years) were examined by CT: all patients had been given a clinical score according to Schwachman and Kulckzycki criteria. Thickened bronchial walls were observed in all cases, which are typical of peribronchitis. Bronchiectases were present in 87% of cases; their extent, pattern and localization were exactly shown on CT scans. Bronchoceles were seen on CT scans in 64% of patients; less frequent was the finding of atelectases and subpleural bullous emphysema. In a great number of patients (64% and 82%, respectively) pleural thickening and hilar adenopathy were demonstrated on CT scans. In conclusion, our results confirm CT as a more sensitive method than conventional radiography to identify and locate the signs of pulmonary CF. The early identification of the lesions of high prognostic value, since the early detection and treatment of bronchoceles may prevent permanent bronchiectasis

  4. Lymphatics in lymphangioleiomyomatosis and idiopathic pulmonary fibrosis

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    Souheil El-Chemaly

    2012-09-01

    Full Text Available The primary function of the lymphatic system is absorbing and transporting macromolecules and immune cells to the general circulation, thereby regulating fluid, nutrient absorption and immune cell trafficking. Lymphangiogenesis plays an important role in tissue inflammation and tumour cell dissemination. Lymphatic involvement is seen in lymphangioleiomyomatosis (LAM and idiopathic pulmonary fibrosis (IPF. LAM, a disease primarily affecting females, involves the lung (cystic destruction, kidney (angiomyolipoma and axial lymphatics (adenopathy and lymphangioleiomyoma. LAM occurs sporadically or in association with tuberous sclerosis complex (TSC. Cystic lung destruction results from proliferation of LAM cells, which are abnormal smooth muscle-like cells with mutations in the TSC1 or TSC2 gene. Lymphatic abnormalities arise from infiltration of LAM cells into the lymphatic wall, leading to damage or obstruction of lymphatic vessels. Benign appearing LAM cells possess metastatic properties and are found in the blood and other body fluids. IPF is a progressive lung disease resulting from fibroblast proliferation and collagen deposition. Lymphangiogenesis is associated with pulmonary destruction and disease severity. A macrophage subset isolated from IPF bronchoalveolar lavage fluid (BALF express lymphatic endothelial cell markers in vitro, in contrast to the same macrophage subset from normal BALF. Herein, we review lymphatic involvement in LAM and IPF.

  5. induced pulmonary fibrosis in mice via regulation of IL

    African Journals Online (AJOL)

    Keywords: Saikosapoin D, Idiopathic pulmonary fibrosis, Myeloid differentiation factor, Hydroxyproline,. Interleukin, Interferon, IL-33/ST2 pathway ... corticosteroids and immunosuppressants is considered as common strategy for IPF ... medicine in China with broad spectrum bioactivities. Previous reports indicated that SSD.

  6. Impairment of Excitation-Contraction Coupling in Right Ventricular Hypertrophied Muscle with Fibrosis Induced by Pulmonary Artery Banding

    Science.gov (United States)

    Urashima, Takashi; Shimura, Daisuke; Amemiya, Erika; Miyasaka, Genki; Yokota, Shunsuke; Fujimoto, Yoshitaka; Akaike, Toru; Inoue, Takahiro; Minamisawa, Susumu

    2017-01-01

    Interstitial myocardial fibrosis is one of the factors responsible for dysfunction of the heart. However, how interstitial fibrosis affects cardiac function and excitation-contraction coupling (E-C coupling) has not yet been clarified. We developed an animal model of right ventricular (RV) hypertrophy with fibrosis by pulmonary artery (PA) banding in rats. Two, four, and six weeks after the PA-banding operation, the tension and intracellular Ca2+ concentration of RV papillary muscles were simultaneously measured (n = 33). The PA-banding rats were clearly divided into two groups by the presence or absence of apparent interstitial fibrosis in the papillary muscles: F+ or F- group, respectively. The papillary muscle diameter and size of myocytes were almost identical between F+ and F-, although the RV free wall weight was heavier in F+ than in F-. F+ papillary muscles exhibited higher stiffness, lower active tension, and lower Ca2+ responsiveness compared with Sham and F- papillary muscles. In addition, we found that the time to peak Ca2+ had the highest correlation coefficient to percent of fibrosis among other parameters, such as RV weight and active tension of papillary muscles. The phosphorylation level of troponin I in F+ was significantly higher than that in Sham and F-, which supports the idea of lower Ca2+ responsiveness in F+. We also found that connexin 43 in F+ was sparse and disorganized in the intercalated disk area where interstitial fibrosis strongly developed. In the present study, the RV papillary muscles obtained from the PA-banding rats enabled us to directly investigate the relationship between fibrosis and cardiac dysfunction, the impairment of E-C coupling in particular. Our results suggest that interstitial fibrosis worsens cardiac function due to 1) the decrease in Ca2+ responsiveness and 2) the asynchronous activation of each cardiac myocyte in the fibrotic preparation due to sparse cell-to-cell communication. PMID:28068381

  7. Impairment of Excitation-Contraction Coupling in Right Ventricular Hypertrophied Muscle with Fibrosis Induced by Pulmonary Artery Banding.

    Directory of Open Access Journals (Sweden)

    Yoichiro Kusakari

    Full Text Available Interstitial myocardial fibrosis is one of the factors responsible for dysfunction of the heart. However, how interstitial fibrosis affects cardiac function and excitation-contraction coupling (E-C coupling has not yet been clarified. We developed an animal model of right ventricular (RV hypertrophy with fibrosis by pulmonary artery (PA banding in rats. Two, four, and six weeks after the PA-banding operation, the tension and intracellular Ca2+ concentration of RV papillary muscles were simultaneously measured (n = 33. The PA-banding rats were clearly divided into two groups by the presence or absence of apparent interstitial fibrosis in the papillary muscles: F+ or F- group, respectively. The papillary muscle diameter and size of myocytes were almost identical between F+ and F-, although the RV free wall weight was heavier in F+ than in F-. F+ papillary muscles exhibited higher stiffness, lower active tension, and lower Ca2+ responsiveness compared with Sham and F- papillary muscles. In addition, we found that the time to peak Ca2+ had the highest correlation coefficient to percent of fibrosis among other parameters, such as RV weight and active tension of papillary muscles. The phosphorylation level of troponin I in F+ was significantly higher than that in Sham and F-, which supports the idea of lower Ca2+ responsiveness in F+. We also found that connexin 43 in F+ was sparse and disorganized in the intercalated disk area where interstitial fibrosis strongly developed. In the present study, the RV papillary muscles obtained from the PA-banding rats enabled us to directly investigate the relationship between fibrosis and cardiac dysfunction, the impairment of E-C coupling in particular. Our results suggest that interstitial fibrosis worsens cardiac function due to 1 the decrease in Ca2+ responsiveness and 2 the asynchronous activation of each cardiac myocyte in the fibrotic preparation due to sparse cell-to-cell communication.

  8. WNT7B in fibroblastic foci of idiopathic pulmonary fibrosis

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    Meuten Travis

    2012-07-01

    Full Text Available Abstract Background Idiopathic pulmonary fibrosis (IPF is a devastating interstitial pneumonia causing a loss of respiratory surface area due to a proliferative fibrotic response involving hyperplastic, hypertrophic, and metaplastic epithelium, cystic honeycomb change, septal expansion, and variable inflammation. Wnt (wingless signaling glycoproteins are known to be involved in lung development and tissue repair, and are up-regulated in patients with IPF. Based on previous qRT-PCR data showing increased Wnt7B in lungs of IPF patients, a systematic, quantitative examination of its tissue site distribution was undertaken. Methods Tissue samples from the Lung Tissue Research Consortium (LTRC of 39 patients diagnosed with mild to severe IPF/usual interstitial pneumonia (UIP and 19 normal patients were examined for the immunolocalization of Wnt7B. Results In normal lung, moderate Wnt7B reactivity was confined to airway epithelium, smooth muscle of airways and vasculature, and macrophages. IPF lung showed strong Wnt7B reactivity in fibroblastic foci, dysplastic airway and alveolar epithelium, and in highly discrete subepithelial, basement membrane-associated regions. All reactive sites were sized and counted relative to specific microscopic regions. Those in the subepithelial sites were found in significantly greater numbers and larger relative area compared with the others. No reactive sites were present in normal patient controls. Conclusions The results demonstrate Wnt7B to be expressed at high concentrations in regions of active hyperplasia, metaplasia, and fibrotic change in IPF patients. In this context and its previously established biologic activities, Wnt7B would be expected to be of potential importance in the pathogenesis of IPF.

  9. Mast Cells: A Pivotal Role in Pulmonary Fibrosis

    Science.gov (United States)

    Veerappan, Arul; O'Connor, Nathan J.; Brazin, Jacqueline; Reid, Alicia C.; Jung, Albert; McGee, David; Summers, Barbara; Branch-Elliman, Dascher; Stiles, Brendon; Worgall, Stefan; Kaner, Robert J.

    2013-01-01

    Pulmonary fibrosis is characterized by an inflammatory response that includes macrophages, neutrophils, lymphocytes, and mast cells. The purpose of this study was to evaluate whether mast cells play a role in initiating pulmonary fibrosis. Pulmonary fibrosis was induced with bleomycin in mast-cell-deficient WBB6F1-W/Wv (MCD) mice and their congenic controls (WBB6F1-+/+). Mast cell deficiency protected against bleomycin-induced pulmonary fibrosis, but protection was reversed with the re-introduction of mast cells to the lungs of MCD mice. Two mast cell mediators were identified as fibrogenic: histamine and renin, via angiotensin (ANG II). Both human and rat lung fibroblasts express the histamine H1 and ANG II AT1 receptor subtypes and when activated, they promote proliferation, transforming growth factor β1 secretion, and collagen synthesis. Mast cells appear to be critical to pulmonary fibrosis. Therapeutic blockade of mast cell degranulation and/or histamine and ANG II receptors should attenuate pulmonary fibrosis. PMID:23570576

  10. Significance of connective tissue diseases features in pulmonary fibrosis

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    Vincent Cottin

    2013-09-01

    Full Text Available Interstitial lung disease (ILD can occur in any of the connective tissue diseases (CTD with varying frequency and severity, and an overall long-term prognosis that is less severe than that of idiopathic pulmonary fibrosis (IPF. Because ILD may be the presenting manifestation of CTD and/or the dominant manifestation of CTD, clinical extra-thoracic manifestations should be systematically considered in the diagnostic approach of ILD. When present, autoantibodies strongly contribute to the recognition and classification of the CTD. Patients with clinical extrathoracic manifestations of CTD and/or autoantibodies (especially with a high titer and/or the antibody is considered “highly specific” of an autoimmune condition, but who do not fit with established international CTD criteria may be called undifferentiated CTD or “lung-dominant CTD”. Although it remains to be determined which combination of symptoms and serologic tests best identify the subset of patients with clinically relevant CTD features, available evidence suggests that such patients may have distinct clinical and imaging presentation and may portend a distinct clinical course. However, autoantibodies alone when present in IPF patients do not seem to impact prognosis or management. Referral to a rheumatologist and multidisciplinary discussion may contribute to management of patients with undifferentiated CTD.

  11. C-type natriuretic peptide ameliorates pulmonary fibrosis by acting on lung fibroblasts in mice.

    Science.gov (United States)

    Kimura, Toru; Nojiri, Takashi; Hino, Jun; Hosoda, Hiroshi; Miura, Koichi; Shintani, Yasushi; Inoue, Masayoshi; Zenitani, Masahiro; Takabatake, Hiroyuki; Miyazato, Mikiya; Okumura, Meinoshin; Kangawa, Kenji

    2016-02-19

    , indicating that CNP suppresses fibroblast differentiation into myofibroblasts. Furthermore, human lung fibroblasts from patients with or without interstitial lung disease substantially expressed GC-B receptor mRNA. These data suggest that CNP ameliorates bleomycin-induced pulmonary fibrosis by suppressing TGF-β signaling and myofibroblastic differentiation in lung fibroblasts. Therefore, we propose consideration of CNP for clinical application to pulmonary fibrosis treatment.

  12. Characteristic patterns in the fibrotic lung. Comparing idiopathic pulmonary fibrosis with chronic lung allograft dysfunction.

    Science.gov (United States)

    Fernandez, Isis E; Heinzelmann, Katharina; Verleden, Stijn; Eickelberg, Oliver

    2015-03-01

    Tissue fibrosis, a major cause of death worldwide, leads to significant organ dysfunction in any organ of the human body. In the lung, fibrosis critically impairs gas exchange, tissue oxygenation, and immune function. Idiopathic pulmonary fibrosis (IPF) is the most detrimental and lethal fibrotic disease of the lung, with an estimated median survival of 50% after 3-5 years. Lung transplantation currently remains the only therapeutic alternative for IPF and other end-stage pulmonary disorders. Posttransplant lung function, however, is compromised by short- and long-term complications, most importantly chronic lung allograft dysfunction (CLAD). CLAD affects up to 50% of all transplanted lungs after 5 years, and is characterized by small airway obstruction with pronounced epithelial injury, aberrant wound healing, and subepithelial and interstitial fibrosis. Intriguingly, the mechanisms leading to the fibrotic processes in the engrafted lung exhibit striking similarities to those in IPF; therefore, antifibrotic therapies may contribute to increased graft function and survival in CLAD. In this review, we focus on these common fibrosis-related mechanisms in IPF and CLAD, comparing and contrasting clinical phenotypes, the mechanisms of fibrogenesis, and biomarkers to monitor, predict, or prognosticate disease status.

  13. Double knockout of Bax and Bak from kidney proximal tubules reduces unilateral urethral obstruction associated apoptosis and renal interstitial fibrosis.

    Science.gov (United States)

    Mei, Shuqin; Li, Lin; Wei, Qingqing; Hao, Jielu; Su, Yunchao; Mei, Changlin; Dong, Zheng

    2017-03-20

    Interstitial fibrosis, a common pathological feature of chronic kidney diseases, is often associated with apoptosis in renal tissues. To determine the associated apoptotic pathway and its role in renal interstitial fibrosis, we established a mouse model in which Bax and Bak, two critical genes in the intrinsic pathway of apoptosis, were deleted specifically from kidney proximal tubules and used this model to examine renal apoptosis and interstitial fibrosis following unilateral urethral obstruction (UUO). It was shown that double knockout of Bax and Bak from proximal tubules attenuated renal tubular cell apoptosis and suppressed renal interstitial fibrosis in UUO. The results indicate that the intrinsic pathway of apoptosis contributes significantly to the tubular apoptosis and renal interstitial fibrosis in kidney diseases.

  14. Inhibiting aerobic glycolysis suppresses renal interstitial fibroblast activation and renal fibrosis.

    Science.gov (United States)

    Ding, Hao; Jiang, Lei; Xu, Jing; Bai, Feng; Zhou, Yang; Yuan, Qi; Luo, Jing; Zen, Ke; Yang, Junwei

    2017-09-01

    Chronic kidney diseases generally lead to renal fibrosis. Despite great progress having been made in identifying molecular mediators of fibrosis, the mechanism that governs renal fibrosis remains unclear, and so far no effective therapeutic antifibrosis strategy is available. Here we demonstrated that a switch of metabolism from oxidative phosphorylation to aerobic glycolysis (Warburg effect) in renal fibroblasts was the primary feature of fibroblast activation during renal fibrosis and that suppressing renal fibroblast aerobic glycolysis could significantly reduce renal fibrosis. Both gene and protein assay showed that the expression of glycolysis enzymes was upregulated in mouse kidneys with unilateral ureter obstruction (UUO) surgery or in transforming growth factor-β1 (TGF-β1)-treated renal interstitial fibroblasts. Aerobic glycolysis flux, indicated by glucose uptake and lactate production, was increased in mouse kidney with UUO nephropathy or TGF-β1-treated renal interstitial fibroblasts and positively correlated with fibrosis process. In line with this, we found that increasing aerobic glycolysis can remarkably induce myofibroblast activation while aerobic glycolysis inhibitors shikonin and 2-deoxyglucose attenuate UUO-induced mouse renal fibrosis and TGF-β1-stimulated myofibroblast activation. Furthermore, mechanistic study indicated that shikonin inhibits renal aerobic glycolysis via reducing phosphorylation of pyruvate kinase type M2, a rate-limiting glycolytic enzyme associated with cell reliance on aerobic glycolysis. In conclusion, our findings demonstrate the critical role of aerobic glycolysis in renal fibrosis and support treatment with aerobic glycolysis inhibitors as a potential antifibrotic strategy. Copyright © 2017 the American Physiological Society.

  15. An ROC study detecting ability of idiopathic pulmonary fibrosis using digital radiography

    International Nuclear Information System (INIS)

    Chung, Eun Chul; Im, Jung Gi; Han, Man Chung; Kim, Jong Hyo

    1991-01-01

    One potential advantage of the digital radiography system is its ability to enhance image quality by various types of processing. Digital unsharp masking is one of the simplest and most useful forms of enhancing processes. The efficacy of unsharp masking in radiological diagnosis has not been investigated thoroughly. To evaluate the effects of unsharp masking in film-digital chest images, 3 observers were shown 150 test radiographs. These test radiographs consisted of 50 unprocessed images (25 normals and 25 patients with idiopathic pulmonary fibrosis with honey combing) and their 100 processed images by using 450 and 15-sized masks respectively. An ROC analysis of these data suggests that unsharp masking is more effective in detecting idiopathic pulmonary fibrosis than unprocessed image (ρ < 0.05), and so it may improve diagnostic accuracy for interstitial fibrosis. In addition, the smaller mask size (15) is more effective than the larger one (mask size 45) (ρ < 0.05). By using this analytic approach, an optimal parameter in digital chest radiography may be investigated in many other forms of pulmonary disease such as pulmonary nodule or mediastinal mass

  16. A case of Amyopathic Dermatomyositis associated with Interstitial Pulmonary Disease.

    Science.gov (United States)

    Ugan, Y; Sahin, M; Dogru, A; Bayram, D; Ceyhan, A M; Tunc, S E

    2015-01-01

    Inflammatory myopathies are a heterogeneous group of diseases with unknown etiology characterized by inflammation of the skeletal muscles and proximal muscle weakness. Dermatomyositis (DM) is an idiopathic inflammatory myopathy with characteristic cutaneous findings such as heliotrope rash, Gottron's sign, Gottron's papules, shawl sign and machinist hand. Amyopathic dermatomyositis (ADM) is a rare but well-recognized clinical subtype of DM, constituting aproximately 10-20% of patients with this disease. It generally manifests only pathognomonic skin findings without clinical and laboratory evidence of muscle involvement. In this report, we present a rare case of ADM associated with interstitial pulmonary disease.

  17. Severity of lung fibrosis affects early surgical outcomes of lung cancer among patients with combined pulmonary fibrosis and emphysema.

    Science.gov (United States)

    Mimae, Takahiro; Suzuki, Kenji; Tsuboi, Masahiro; Ikeda, Norihiko; Takamochi, Kazuya; Aokage, Keiju; Shimada, Yoshihisa; Miyata, Yoshihiro; Okada, Morihito

    2016-07-01

    Combined pulmonary fibrosis and emphysema (CPFE) is defined as upper lobe emphysema and lower lobe fibrosis, which are representative lung disorders that increase the prevalence of lung cancer. This unique disorder may affect the morbidity and mortality during the early period after surgery. The present study aimed to identify which clinicopathological features significantly affect early surgical outcomes after lung resection in nonsmall cell lung cancer (NSCLC) patients and in those with CPFE.We retrospectively assessed 2295 patients with NSCLC and found that 151 (6.6%) had CPFE. All were surgically treated between January 2008 and December 2010 at 4 institutions.The postoperative complication rates for patients with and without CPFE were 39% and 17%, respectively. The 90-day mortality rates were higher among patients with than without CPFE (7.9% vs 1%). Acute exacerbation of interstitial pneumonia was the main cause of death among 12 patients with CPFE who died within 90 days after surgery. Multivariate logistic regression analysis selected CPFE, gender, age, and clinical stage as independent predictive factors for postoperative complications, and CPFE, clinical stage, and sex for 90-day mortality. The severity of lung fibrosis on preoperative CT images was an independent predictive factor for 90-day mortality among patients with CPFE.The key predictive factor for postoperative mortality and complications of lung resection for NSCLC was CPFE. The severity of lung fibrosis was the principal predictor of early outcomes after lung surgery among patients with CPFE and NSCLC.

  18. Mineralogical microanalysis of idiopathic pulmonary fibrosis

    International Nuclear Information System (INIS)

    Monso, E.; Tura, J.M.; Marsal, M.; Morell, F.; Pujadas, J.; Morera, J.

    1990-01-01

    A mineralogical analysis of lung tissue was conducted on 25 samples from patients who had been diagnosed as having idiopathic pulmonary fibrosis (IPF). Scanning electron microscopy (SEM) at low magnification and energy-dispersive x-ray analysis (EDXA) was used. In all samples, the surface silicon/sulfur (Si/S) ratio was calculated. The Si/S ratio for 25 samples of normal lung and 6 samples of pneumoconiotic lung was also determined (upper limit of normal Si/S ratio = 0.3). The difference between the Si/S ratio in the group with IPF and group with normal lung tissue was significantly significant (p less than .007, Wilcoxon test). Six of 12 patients with a previous diagnosis of IPF and a Si/S ratio greater than 0.3 had an exposure history that could imply inhalation of silica/silicates, and the correct diagnosis for these patients is most probably pneumoconiosis. The silica/silicate deposits detected in patients with IPF, and who had a ratio and no past exposure to dusts, could be either a cause or an effect of the disease

  19. [Idiopathic pulmonary fibrosis; description of a Dutch cohort].

    Science.gov (United States)

    Barlo, Nicole P; van Moorsel, Coline H M; van den Bosch, Jules M M; van de Graaf, Ed A; Kwakkel-van Erp, Johanna M; Grutters, Jan C

    2009-01-01

    To describe the clinical presentation, diagnosis, and prognosis of a cohort of Dutch patients with idiopathic pulmonary fibrosis (IPF), a serious and rapidly progressive lung disease belonging to the idiopathic interstitial pneumonias. Retrospective study of patient records. The data from the clinical presentation, diagnosis, treatment and survival of all patients with IPF, diagnosed in the St. Antonius Hospital in Nieuwegein and University Medical Center Utrecht (UMCU), both in the Netherlands, during the period 1998-2007 were investigated. For the diagnosis, the criteria of the American Thoracic Society and the European Respiratory Society from 2002 were adhered to. The records of 113 patients satisfied the inclusion criteria. Mean age at the time of presentation was 61.9 (SD: 12.7) years and a strong male predominance was observed (90 men vs. 23 women). The most common complaints and symptoms at presentation were dyspnoea, cough, basal crepitations and clubbing of the nails. Lung function tests revealed restrictive lung function impairment and a reduced diffusing capacity. In 72% of cases the diagnosis IPF was histologically confirmed by open lung biopsy, which revealed a pattern of usual interstitial pneumonia (UIP). In 17% of patients it concerned a familial form of the disease with diagnosis at a younger age (average 52 years; SD: 14.8). The medical treatment mostly consisted of corticosteroids, which for half of the patients were administered in combination with an immunosuppressant such as azathioprine or cyclophosphamide. After screening, 28 patients were eligible for lung transplantation. Of these, 12 patients underwent a lung transplantation in the study period, 9 died and 7 are still on the waiting list. The median survival period was 3.9 years. In the cohort studied, IPF presented as a rapidly progressive disease with only a marginal response to medical treatment and a poor prognosis. It is important to differentiate IPF from other fibrotic

  20. Interleukin-22 Inhibits Bleomycin-Induced Pulmonary Fibrosis

    Directory of Open Access Journals (Sweden)

    Minrui Liang

    2013-01-01

    Full Text Available Pulmonary fibrosis is a progressive and fatal fibrotic disease of the lungs with unclear etiology. Recent insight has suggested that early injury/inflammation of alveolar epithelial cells could lead to dysregulation of tissue repair driven by multiple cytokines. Although dysregulation of interleukin- (IL- 22 is involved in various pulmonary pathophysiological processes, the role of IL-22 in fibrotic lung diseases is still unclear and needs to be further addressed. Here we investigated the effect of IL-22 on alveolar epithelial cells in the bleomycin- (BLM- induced pulmonary fibrosis. BLM-treated mice showed significantly decreased level of IL-22 in the lung. IL-22 produced γδT cells were also decreased significantly both in the tissues of lungs and spleens. Administration of recombinant human IL-22 to alveolar epithelial cell line A549 cells ameliorated epithelial to mesenchymal transition (EMT and partially reversed the impaired cell viability induced by BLM. Furthermore, blockage of IL-22 deteriorated pulmonary fibrosis, with elevated EMT marker (α-smooth muscle actin (α-SMA and overactivated Smad2. Our results indicate that IL-22 may play a protective role in the development of BLM-induced pulmonary fibrosis and may suggest IL-22 as a novel immunotherapy tool in treating pulmonary fibrosis.

  1. Mechanical induction of cough in Idiopathic Pulmonary Fibrosis

    Science.gov (United States)

    2011-01-01

    Background Patients with idiopathic pulmonary fibrosis (IPF) frequently develop a dry, irritating cough which often proves refractory to anti-tussive therapies. The precise pathogenetic mechanisms responsible for this cough are unknown. We hypothesised that changes in nerves modulating mechanical sensitivity in areas of interstitial fibrosis might lead to enhanced cough response to mechanical stimulation of the chest in IPF. Methods We studied 27 non-smoking subjects with IPF (63% male), mean (SD) age 71.7 (7) years and 30 healthy non-smokers. Quality of life (Leicester Cough Questionnaire), cough symptom scores and cough severity scores (visual analog scales) were recorded. Percussion stimulation was applied over the posterior lung base, upper anterior chest and manubrium sternum at sequential frequencies (20 Hertz (Hz), 40 Hz and 60 Hz) for up to 60 seconds and repeated twice at two minute intervals. The number of subjects achieving two and five-cough responses, total cough counts and cough latency were recorded. In separate experiments, the effect of mechanical stimulation on the pattern of breathing was determined in eight IPF subjects and five control subjects. Results In patients with IPF, we demonstrated strong correlations between subjective cough measurements, particularly the cough symptom score and Leicester Cough Questionnaire (r = -0.86; p cough reflex in 23/27 (85%) IPF subjects, but only 5/30 (17%) controls (p cough response at a lower frequency (20 Hz) posteriorly than at other positions. Highest mean cough totals were seen with stimulation at or above 40 Hz. Mechanical stimulation had no effect on respiratory rate but increased tidal volume in four (50%) subjects with IPF, particularly at higher frequencies. It was associated with increased urge to cough followed by a true cough reflex. Conclusions This study demonstrates that patients with IPF show enhanced cough reflex sensitivity to mechanical stimulation of the chest wall whilst normal

  2. Pulmonary interstitial emphysema: a case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Mauricio Kauark Amoedo

    2013-09-01

    Full Text Available Pulmonary interstitial emphysema is a rare condition that generally affects low-weight preterm infants submitted to mechanical ventilation. The prognosis is variable, depending on early diagnosis and treatment. The radiologist plays a key role in this scenario. The authors report a case of persistent pulmonary interstitial emphysema, describing the main characteristics of such entity.

  3. Pulmonary interstitial emphysema: a case report and review of the literature

    Energy Technology Data Exchange (ETDEWEB)

    Amoedo, Mauricio Kauark, E-mail: mauricioamoedo@gmail.com [Interventional Radiology, Hospital A.C. Camargo, Sao Paulo, SP (Brazil); Souza, Luciana Volpon Soares; Souza, Antonio Soares [Instituto de Radiodiagnostico Rio Preto (Ultra-X), Sao Jose do Rio Preto, SP (Brazil); Souza Junior, Arthur Soares [Faculdade de Medicina de Sao Jose do Rio Preto (Famerp), SP (Brazil); Marchiori, Edson [Universidade Federal Fluminense (UFF), Niteroi, RJ (Brazil)

    2013-09-15

    Pulmonary interstitial emphysema is a rare condition that generally affects low-weight preterm infants submitted to mechanical ventilation. The prognosis is variable, depending on early diagnosis and treatment. The radiologist plays a key role in this scenario. The authors report a case of persistent pulmonary interstitial emphysema, describing the main characteristics of such entity. (author)

  4. Smoking-related emphysema is associated with idiopathic pulmonary fibrosis and rheumatoid lung.

    Science.gov (United States)

    Antoniou, Katerina M; Walsh, Simon L; Hansell, David M; Rubens, Michael R; Marten, Katharina; Tennant, Rachel; Hansel, Trevor; Desai, Sujal R; Siafakas, Nikolaos M; du Bois, Roland M; Wells, Athol U

    2013-11-01

    A combined pulmonary fibrosis/emphysema syndrome has been proposed, but the basis for this syndrome is currently uncertain. The aim was to evaluate the prevalence of emphysema in idiopathic pulmonary fibrosis (IPF) and rheumatoid lung (rheumatoid arthritis-interstitial lung disease (RA-ILD)), and to compare the morphological features of lung fibrosis between smokers and non-smokers. Using high-resolution computed tomography, the prevalence of emphysema and the pack-year smoking histories associated with emphysema were compared between current/ex-smokers with IPF (n = 186) or RA-ILD (n = 46), and non-chronic obstructive pulmonary disease (COPD) controls (n = 103) and COPD controls (n = 34). The coarseness of fibrosis was compared between smokers and non-smokers. Emphysema, present in 66/186 (35%) patients with IPF and 22/46 (48%) smokers with RA-ILD, was associated with lower pack-year smoking histories than in control groups (P emphysema in IPF was positively linked to the pack-year smoking history (odds ratio 1.04, 95% confidence interval (CI) 1.02-1.06, P emphysema but did not differ significantly between smokers and non-smokers. In IPF and RA-ILD, a high prevalence of concurrent emphysema, in association with low pack-year smoking histories, and an association between coarser pulmonary fibrosis and a history of smoking in IPF together provide support for possible pathogenetic linkage to smoking in both diseases. © 2013 The Authors. Respirology © 2013 Asian Pacific Society of Respirology.

  5. Persistent activation of autophagy in kidney tubular cells promotes renal interstitial fibrosis during unilateral ureteral obstruction

    Science.gov (United States)

    Livingston, Man J.; Ding, Han-Fei; Huang, Shuang; Hill, Joseph A.; Yin, Xiao-Ming; Dong, Zheng

    2016-01-01

    ABSTRACT Renal fibrosis is the final, common pathway of end-stage renal disease. Whether and how autophagy contributes to renal fibrosis remains unclear. Here we first detected persistent autophagy in kidney proximal tubules in the renal fibrosis model of unilateral ureteral obstruction (UUO) in mice. UUO-associated fibrosis was suppressed by pharmacological inhibitors of autophagy and also by kidney proximal tubule-specific knockout of autophagy-related 7 (PT-Atg7 KO). Consistently, proliferation and activation of fibroblasts, as indicated by the expression of ACTA2/α-smooth muscle actin and VIM (vimentin), was inhibited in PT-Atg7 KO mice, so was the accumulation of extracellular matrix components including FN1 (fibronectin 1) and collagen fibrils. Tubular atrophy, apoptosis, nephron loss, and interstitial macrophage infiltration were all inhibited in these mice. Moreover, these mice showed a specific suppression of the expression of a profibrotic factor FGF2 (fibroblast growth factor 2). In vitro, TGFB1 (transforming growth factor β 1) induced autophagy, apoptosis, and FN1 accumulation in primary proximal tubular cells. Inhibition of autophagy suppressed FN1 accumulation and apoptosis, while enhancement of autophagy increased TGFB1-induced-cell death. These results suggest that persistent activation of autophagy in kidney proximal tubules promotes renal interstitial fibrosis during UUO. The profibrotic function of autophagy is related to the regulation on tubular cell death, interstitial inflammation, and the production of profibrotic factors. PMID:27123926

  6. TINF2 Gene Mutation in a Patient with Pulmonary Fibrosis

    Directory of Open Access Journals (Sweden)

    T. W. Hoffman

    2016-01-01

    Full Text Available Pulmonary fibrosis is a frequent manifestation of telomere syndromes. Telomere gene mutations are found in up to 25% and 3% of patients with familial disease and sporadic disease, respectively. The telomere gene TINF2 encodes an eponymous protein that is part of the shelterin complex, a complex involved in telomere protection and maintenance. A TINF2 gene mutation was recently reported in a family with pulmonary fibrosis. We identified a heterozygous Ser245Tyr mutation in the TINF2 gene of previously healthy female patient that presented with progressive cough due to pulmonary fibrosis as well as panhypogammaglobulinemia at age 52. Retrospective multidisciplinary evaluation classified her as a case of possible idiopathic pulmonary fibrosis. Telomere length-measurement indicated normal telomere length in the peripheral blood compartment. This is the first report of a TINF2 mutation in a patient with sporadic pulmonary fibrosis, which represents another association between TINF2 mutations and this disease. Furthermore, this case underlines the importance of telomere dysfunction and not telomere length alone in telomere syndromes and draws attention to hypogammaglobulinemia as a manifestation of telomere syndromes.

  7. Comparing new treatments for idiopathic pulmonary fibrosis--a network meta-analysis.

    LENUS (Irish Health Repository)

    Loveman, Emma

    2015-01-01

    The treatment landscape for idiopathic pulmonary fibrosis, a devastating lung disease, is changing. To investigate the effectiveness of treatments for idiopathic pulmonary fibrosis we undertook a systematic review, network meta-analysis and indirect comparison.

  8. Overexpression of Heme Oxygenase-1 Prevents Renal Interstitial Inflammation and Fibrosis Induced by Unilateral Ureter Obstruction.

    Directory of Open Access Journals (Sweden)

    Xiao Chen

    Full Text Available Renal fibrosis plays an important role in the onset and progression of chronic kidney diseases. Many studies have demonstrated that heme oxygenase-1 (HO-1 is involved in diverse biological processes as a cytoprotective molecule, including anti-inflammatory, anti-oxidant, anti-apoptotic, antiproliferative, and immunomodulatory effects. However, the mechanisms of HO-1 prevention in renal interstitial fibrosis remain unknown. In this study, HO-1 transgenic (TG mice were employed to investigate the effect of HO-1 on renal fibrosis using a unilateral ureter obstruction (UUO model and to explore the potential mechanisms. We found that HO-1 was adaptively upregulated in kidneys of both TG and wild type (WT mice after UUO. The levels of HO-1 mRNA and protein were increased in TG mice compared with WT mice under normal conditions. HO-1 expression was further enhanced after UUO and remained high during the entire experimental process. Renal interstitial fibrosis in the TG group was significantly attenuated compared with that in the WT group after UUO. Moreover, overexpression of HO-1 inhibited the loss of peritubular capillaries. In addition, UUO-induced activation and proliferation of myofibroblasts were suppressed by HO-1 overexpression. Furthermore, HO-1 restrained tubulointerstitial infiltration of macrophages and regulated the secretion of inflammatory cytokines in UUO mice. We also found that high expression of HO-1 inhibited reactivation of Wnt/β-catenin signaling, which could play a crucial role in attenuating renal fibrosis. In conclusion, these data suggest that HO-1 prevents renal tubulointerstitial fibrosis possibly by regulating the inflammatory response and Wnt/β-catenin signaling. This study provides evidence that augmentation of HO-1 levels may be a therapeutic strategy against renal interstitial fibrosis.

  9. Combined pulmonary fibrosis and emphysema in hypersensitivity pneumonitis.

    Science.gov (United States)

    Soumagne, Thibaud; Pana-Katatali, Héloïse; Degano, Bruno; Dalphin, Jean-Charles

    2015-12-21

    Combined pulmonary fibrosis and emphysema is a distinct syndrome reported in patients who smoke. A 72-year-old, never-smoking female dairy farmer was referred for progressive dyspnoea on exertion, basal crackles on auscultation, normal spirometry and normal lung volumes but decreased diffusing capacity of the lung for carbon monoxide, centrilobular emphysema in the upper zones of the lungs and diffuse infiltrative lung disease in the lower zones on high-resolution CT scan. Bronchoalveolar lavage differential cell count showed 35% lymphocytosis, and precipitating antibodies for Wallemia sebi, Trichoderma species and Cladosporium sphaerospermum were identified. The diagnosis of farmer's lung disease with combined pulmonary fibrosis and emphysema was retained. This case highlights for the first time that hypersensitivity pneumonitis should be suspected in the setting of combined pulmonary fibrosis and emphysema in non-smoking patients. 2015 BMJ Publishing Group Ltd.

  10. Rosiglitazone attenuates pulmonary fibrosis and radiation-induced intestinal damage

    Energy Technology Data Exchange (ETDEWEB)

    Mangoni, M.; Gerini, C.; Sottili, M.; Cassani, S.; Stefania, G.; Biti, G. [Radiotherapy Unit, Clinical Physiopathology Department, University of Florence, Firenze (Italy); Castiglione, F. [Department of Human Pathology and Oncology, University of Florence, Firenze (Italy); Vanzi, E.; Bottoncetti, A.; Pupi, A. [Nuclear Medicine Unit, Clinical Physiopathology Department, University of Florence, Firenze (Italy)

    2011-10-15

    Full text of publication follows: Purpose.-The aim of the study was to evaluate radioprotective effect of rosiglitazone (RGZ) on a murine model of late pulmonary damage and of acute intestinal damage. Methods.- Lung fibrosis: C57 mice were treated with the radiomimetic agent bleomycin, with or without rosiglitazone (5 mg/kg/day). To obtain an independent qualitative and quantitative measure for lung fibrosis we used high resolution CT, performed twice a week during the entire observation period. Hounsfield Units (HU) of section slides from the upper and lower lung region were determined. On day 31 lungs were collected for histological analysis. Acute intestinal damage: mice underwent 12 Gy total body irradiation with or without rosiglitazone. Mice were sacrificed 24 or 72 h after total body irradiation and ileum and colon were collected. Results.- Lung fibrosis: after bleomycin treatment, mice showed typical CT features of lung fibrosis, including irregular septal thickening and patchy peripheral reticular abnormalities. Accordingly, HU lung density was dramatically increased. Rosiglitazone markedly attenuated the radiological signs of fibrosis and strongly inhibited HU lung density increase (60% inhibition at the end of the observation period). Histological analysis revealed that in bleomycin-treated mice, fibrosis involved 50-55% of pulmonary parenchyma and caused an alteration of the alveolar structures in 10% of parenchyma, while in rosiglitazone-treated mice, fibrosis involved only 20-25% of pulmonary parenchyma, without alterations of the alveolar structures. Acute intestinal damage: 24 h after 12 Gy of total body irradiation intestinal mucosa showed villi shortening, mucosal thickness and crypt necrotic changes. Rosiglitazone showed a histological improvement of tissue structure, with villi and crypts normalization and oedema reduction. Conclusion.- These results demonstrate that rosiglitazone displays a protective effect on pulmonary fibrosis and radiation

  11. Role of matrix metalloproteinases in the pathophysiology of idiopathic pulmonary fibrosis

    Directory of Open Access Journals (Sweden)

    Bhattacharyya P

    2007-01-01

    Full Text Available Idiopathic pulmonary fibrosis (IPF, a progressive fibrosing lung condition is a ther-apeutic medical challenge. The etiopathogenesis of IPF is complicated and hitherto not adequately understood. However, the concept, of late, is shifting from fibrosis as a result of inflammation to a mechanism of primarily dysregulated fibrogenesis. A class of enzymes called matrix metallo proteinases (MMPs appear important in the pathogenesis of IPF. The heightened activity of MMPs are derived out of an imbalance between them (MMPs and their tissue inhibitors (TIMPs. This leads to breakdown of interstitial matrix and triggering of certain growth factors which play an important mechanistic role in the pathogenesis of IPF. Understanding of the role of MMPs in pathogenesis of IPF may open up a new horizon of therapeutic intervention of the desease.

  12. Epidemiology of Idiopathic Pulmonary Fibrosis in Northern Italy.

    Directory of Open Access Journals (Sweden)

    Sergio Harari

    Full Text Available Idiopathic pulmonary fibrosis (IPF is the most common and severe form of idiopathic interstitial pneumonia. Despite its clinical relevance, few studies have examined the epidemiology of IPF and temporal variation in disease incidence and prevalence. Aim of the study was to investigate the prevalence, incidence and trends of IPF in Lombardy, a region with nearly 10 million inhabitants, during 2005-2010.For the identification of IPF patients, we used healthcare administrative databases of Lombardy Healthcare System and adopted three algorithms: generic, broad and narrow case definition (GCD, BCD, NCD. IPF cases were identified according to diagnoses reported in inpatient and outpatient claims occurred during 2000-2010. We estimated age- and sex-adjusted annual prevalence and incidence rates from 2005 to 2010, thus allowing for a 5-year washout period.The mean annual incidence rate was estimated at 2.3 and 5.3 per 100,000 person-years using NCD and GCD, respectively. IPF incidence was higher among males, and increased with age. Trend remained stable over the years. The estimated annual prevalence rate was 35.5, 22.4, and 12.6 per 100,000 person-years using GCD, BCD and NCD, respectively, and increased with age. Moreover, we observed a positive trend over the years. Using BCD and NCD, prevalence was higher among males.The results of this study, which is one of the largest population-based survey ever conducted according to strict criteria, indicated that prevalence of IPF increased across the years while incidence remained stable, thus suggesting that survival with IPF has improved.

  13. Screening for Helicobacter pylori in Idiopathic Pulmonary Fibrosis Lung Biopsies.

    Science.gov (United States)

    Kreuter, Michael; Kirsten, Detlef; Bahmer, Thomas; Penzel, Roland; Claussen, Martin; Ehlers-Tenenbaum, Svenja; Muley, Thomas; Palmowski, Karin; Eichinger, Monika; Leider, Marta; Herth, Felix J F; Rabe, Klaus F; Bittmann, Iris; Warth, Arne

    2016-01-01

    Increasing evidence suggests a role of gastro-oesophageal reflux (GER) in idiopathic pulmonary fibrosis (IPF) pathogenesis. Recently, an association between serum Helicobacter pylori (HP) antibody positivity and more severe disease was described, but HP has not been directly analysed in lung tissue so far. To investigate the presence of HP in the lung tissue of IPF patients. Two tertiary interstitial lung disease care centre databases were screened for available lung biopsy material from IPF patients. Clinical and radiological data, including presence of GER and antiacid medication, were evaluated. HP-specific PCR was carried out on the IPF lung biopsy specimens. A total of 39 IPF patients were included, of whom 85% were male. The patients' median age was 66 years, their vital capacity was 79% predicted, and their diffusing capacity for carbon monoxide was 53% predicted. In all, 82% of the lung biopsies were surgical and 18% transbronchial. Comorbidities were GER disease in 23% (n = 9), sleep apnoea in 13% (n = 5) and hiatal hernia in 38% of the cases (n = 15). Proton pump inhibitors were prescribed at the time of biopsy in 21% of the cases (n = 9). After a median follow-up of 25 months (range 6-69), there were 1 death, 1 lung transplantation and 8 acute exacerbations without relevant differences between the GER and non-GER subgroups. HP DNA was not detected in any of the lung tissue samples. The fact that no HP DNA was detected in the lung tissues calls into question the proposed relevance of HP to the direct pathogenesis of IPF. © 2015 S. Karger AG, Basel.

  14. Assessing idiopathic pulmonary fibrosis (IPF) with bronchoscopic OCT (Conference Presentation)

    Science.gov (United States)

    Hariri, Lida P.; Adams, David C.; Colby, Thomas V.; Tager, Andrew M.; Suter, Melissa J.

    2016-03-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal form of fibrotic lung disease, with a significantly worse prognosis than other forms of pulmonary fibrosis (3-year survival rate of 50%). Distinguishing IPF from other fibrotic diseases is essential to patient care because it stratifies prognosis and therapeutic decision-making. However, making the diagnosis often requires invasive, high-risk surgical procedures to look for microscopic features not seen on chest CT, such as characteristic cystic honeycombing in the peripheral lung. Optical coherence tomography (OCT) provides rapid 3D visualization of large tissue volumes with microscopic resolutions well beyond the capabilities of CT. We aim to determine whether bronchoscopic OCT can provide a low-risk, non-surgical method for IPF diagnosis. We have developed bronchoscopic OCT catheters that access the peripheral lung and conducted in vivo peripheral lung imaging in patients, including those with pulmonary fibrosis. We also conducted bronchoscopic OCT in ex vivo lung from pulmonary fibrosis patients, including IPF, to determine if OCT could successfully visualize features of IPF through the peripheral airways. Our results demonstrate that OCT is able to visualize characteristic features of IPF through the airway, including microscopic honeycombing (fibrosis, and spatial disease heterogeneity. We also found that OCT has potential to distinguish mimickers of IPF honeycombing, such as traction bronchiectasis and emphysema, from true honeycombing. These findings support the potential of bronchoscopic OCT as a minimally-invasive method for in vivo IPF diagnosis. However, future clinical studies are needed to validate these findings.

  15. Nitric Oxide Mediates Bleomycin-Induced Angiogenesis and Pulmonary Fibrosis via Regulation of VEGF

    OpenAIRE

    Iyer, Anand Krishnan V.; Ramesh, Vani; Castro, Carlos A.; Kaushik, Vivek; Kulkarni, Yogesh M.; Wright, Clayton A.; Venkatadri, Rajkumar; Rojanasakul, Yon; Azad, Neelam

    2015-01-01

    Pulmonary fibrosis is a progressive lung disease hallmarked by increased fibroblast proliferation, amplified levels of extracellular matrix deposition and increased angiogenesis. Although dysregulation of angiogenic mediators has been implicated in pulmonary fibrosis, the specific rate-limiting angiogenic markers involved and their role in the progression of pulmonary fibrosis remains unclear. We demonstrate that bleomycin treatment induces angiogenesis, and inhibition of the central angiogen...

  16. Obaculactone protects against bleomycin-induced pulmonary fibrosis in mice.

    Science.gov (United States)

    Wang, Xingqi; Ouyang, Zijun; You, Qian; He, Shuai; Meng, Qianqian; Hu, Chunhui; Wu, Xudong; Shen, Yan; Sun, Yang; Wu, Xuefeng; Xu, Qiang

    2016-07-15

    Idiopathic pulmonary fibrosis is a progressive, degenerative and almost irreversible disease. There is hardly an effective cure for lung damage due to pulmonary fibrosis. The purpose of this study was to evaluate the role of obaculactone in an already-assessed model of idiopathic pulmonary fibrosis induced by bleomycin administration. Mice were subjected to intratracheal instillation of bleomycin, and obaculactone was given orally after bleomycin instillation daily for 23days. Treatment with obaculactone ameliorated body weight loss, lung histopathology abnormalities and pulmonary collagen deposition, with a decrease of the inflammatory cell number and the cytokine level in bronchoalveolar lavage fluid. Moreover, obaculactone inhibited the expression of icam1, vcam1, inos and cox2, and attenuated oxidative stress in bleomycin-treated lungs. Importantly, the production of collagen I and α-SMA in lung tissues as well as the levels of TGF-β1, ALK5, p-Smad2 and p-Smad3 in lung homogenates was also reduced after obaculactone treatment. Finally, the TGF-β1-induced epithelial-mesenchymal transition via Smad-dependent and Smad-independent pathways was reversed by obaculactone. Collectively, these data suggest that obaculactone may be a promising drug candidate for the treatment of idiopathic pulmonary fibrosis. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Dysregulation of Galectin-3. Implications for Hermansky-Pudlak Syndrome Pulmonary Fibrosis

    Science.gov (United States)

    Cullinane, Andrew R.; Yeager, Caroline; Dorward, Heidi; Carmona-Rivera, Carmelo; Wu, Hai Ping; Moss, Joel; O’Brien, Kevin J.; Nathan, Steven D.; Meyer, Keith C.; Rosas, Ivan O.; Helip-Wooley, Amanda; Huizing, Marjan; Gahl, William A.

    2014-01-01

    The etiology of Hermansky-Pudlak syndrome (HPS) pulmonary fibrosis (HPSPF), a progressive interstitial lung disease with high mortality, is unknown. Galectin-3 is a β-galactoside–binding lectin with profibrotic effects. The objective of this study was to investigate the involvement of galectin-3 in HPSPF. Galectin-3 was measured by ELISA, immunohistochemistry, and immunoblotting in human specimens from subjects with HPS and control subjects. Mechanisms of galectin-3 accumulation were studied by quantitative RT-PCR, Northern blot analysis, membrane biotinylation assays, and rescue of HPS1-deficient cells by transfection. Bronchoalveolar lavage galectin-3 concentrations were significantly higher in HPSPF compared with idiopathic pulmonary fibrosis or that from normal volunteers, and correlated with disease severity. Galectin-3 immunostaining was increased in HPSPF compared with idiopathic pulmonary fibrosis or normal lung tissue. Fibroblasts from subjects with HPS subtypes associated with pulmonary fibrosis had increased galectin-3 protein expression compared with cells from nonfibrotic HPS subtypes. Galectin-3 protein accumulation was associated with reduced Galectin-3 mRNA, normal Mucin 1 levels, and up-regulated microRNA-322 in HPSPF cells. Membrane biotinylation assays showed reduced galectin-3 and normal Mucin 1 expression at the plasma membrane in HPSPF cells compared with control cells, which suggests that galectin-3 is mistrafficked in these cells. Reconstitution of HPS1 cDNA into HPS1-deficient cells normalized galectin-3 protein and mRNA levels, as well as corrected galectin-3 trafficking to the membrane. Intracellular galectin-3 levels are regulated by HPS1 protein. Abnormal accumulation of galectin-3 may contribute to the pathogenesis of HPSPF. PMID:24134621

  18. Pan-PPAR agonist IVA337 is effective in experimental lung fibrosis and pulmonary hypertension.

    Science.gov (United States)

    Avouac, Jerome; Konstantinova, Irena; Guignabert, Christophe; Pezet, Sonia; Sadoine, Jeremy; Guilbert, Thomas; Cauvet, Anne; Tu, Ly; Luccarini, Jean-Michel; Junien, Jean-Louis; Broqua, Pierre; Allanore, Yannick

    2017-11-01

    To evaluate the antifibrotic effects of the pan-peroxisome proliferator-activated receptor (PPAR) agonist IVA337 in preclinical mouse models of pulmonary fibrosis and related pulmonary hypertension (PH). IVA337 has been evaluated in the mouse model of bleomycin-induced pulmonary fibrosis and in Fra-2 transgenic mice, this latter being characterised by non-specific interstitial pneumonia and severe vascular remodelling of pulmonary arteries leading to PH. Mice received two doses of IVA337 (30 mg/kg or 100 mg/kg) or vehicle administered by daily oral gavage up to 4 weeks. IVA337 demonstrated at a dose of 100 mg/kg a marked protection from the development of lung fibrosis in both mouse models compared with mice receiving 30 mg/kg of IVA337 or vehicle. Histological score was markedly reduced by 61% in the bleomycin model and by 50% in Fra-2 transgenic mice, and total lung hydroxyproline concentrations decreased by 28% and 48%, respectively, as compared with vehicle-treated mice. IVA337 at 100 mg/kg also significantly decreased levels of fibrogenic markers in lesional lungs of both mouse models. In addition, IVA337 substantially alleviated PH in Fra-2 transgenic mice by improving haemodynamic measurements and vascular remodelling. In primary human lung fibroblasts, IVA337 inhibited in a dose-dependent manner fibroblast to myofibroblasts transition induced by TGF-β and fibroblast proliferation mediated by PDGF. We demonstrate that treatment with 100 mg/kg IVA337 prevents lung fibrosis in two complementary animal models and substantially attenuates PH in the Fra-2 mouse model. These findings confirm that the pan-PPAR agonist IVA337 is an appealing therapeutic candidate for these cardiopulmonary involvements. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  19. Macrophage migration inhibitory factor in lung tissue of idiopathic pulmonary fibrosis patients.

    Science.gov (United States)

    Olivieri, Carmela; Bargagli, Elena; Inghilleri, Simona; Campo, Ilaria; Cintorino, Marcella; Rottoli, Paola

    2016-06-01

    Idiopathic pulmonary fibrosis (IPF) is a severe interstitial lung disorder characterized by a pattern of Usual Interstitial Pneumonia where the presence of fibroblastic foci is the hallmark of the disease. In the present study, we analyzed the migration inhibitory factor (MIF) expression in lung tissue of IPF patients compared with healthy controls and organizing pneumonia (OP) patients focusing into MIF potential role in fibroblastic foci development. The immunohistochemical analysis was performed in 10 IPF patients (7 male), 3 OP patients (2 male), and 3 healthy controls (all male) using the streptavidin-biotin method (Dako). In IPF samples, MIF resulted overexpressed in the areas of active fibrosis and, in particular, in the alveolar epithelium, bronchiolar epithelium, and in the peripheral zones of fibroblastic foci. Bronchiolar epithelium from organizing pneumonia patients resulted only weakly positive for MIF while no evidence of MIF expression was reported for alveolar epithelium. In the control subject group, MIF was unexpressed except for a weak presence in the bronchiolar epithelium. In conclusion, MIF is a pleiotropic cytokine involved in the pathogenesis of IPF being mainly expressed in the areas of remodeling and active fibrosis, in bronchiolar and alveolar epithelium, and in the peripheral zone of fibroblastic foci.

  20. Phosphocalcic Markers and Calcification Propensity for Assessment of Interstitial Fibrosis and Vascular Lesions in Kidney Allograft Recipients.

    Directory of Open Access Journals (Sweden)

    Lena Berchtold

    Full Text Available Renal interstitial fibrosis and arterial lesions predict loss of function in chronic kidney disease. Noninvasive estimation of interstitial fibrosis and vascular lesions is currently not available. The aim of the study was to determine whether phosphocalcic markers are associated with, and can predict, renal chronic histological changes. We included 129 kidney allograft recipients with an available transplant biopsy in a retrospective study. We analyzed the associations and predictive values of phosphocalcic markers and serum calcification propensity (T50 for chronic histological changes (interstitial fibrosis and vascular lesions. PTH, T50 and vitamin D levels were independently associated to interstitial fibrosis. PTH elevation was associated with increasing interstitial fibrosis severity (r = 0.29, p = 0.001, while T50 and vitamin D were protective (r = -0.20, p = 0.025 and r = -0.23, p = 0.009 respectively. On the contrary, fibroblast growth factor 23 (FGF23 and Klotho correlated only modestly with interstitial fibrosis (p = 0.045 whereas calcium and phosphate did not. PTH, vitamin D and T50 were predictors of extensive fibrosis (AUC: 0.73, 0.72 and 0.68 respectively, but did not add to renal function prediction. PTH, FGF23 and T50 were modestly predictive of low fibrosis (AUC: 0.63, 0.63 and 0.61 but did not add to renal function prediction. T50 decreased with increasing arterial lesions (r = -0.21, p = 0.038. The discriminative performance of T50 in predicting significant vascular lesions was modest (AUC 0.61. In summary, we demonstrated that PTH, vitamin D and T50 are associated to interstitial fibrosis and vascular lesions in kidney allograft recipients independently of renal function. Despite these associations, mineral metabolism indices do not show superiority or additive value to fibrosis prediction by eGFR and proteinuria in kidney allograft recipients, except for vascular lesions where T50 could be of relevance.

  1. Interstitial Fibrosis Restricts Osmotic Water Transport in Encapsulating Peritoneal Sclerosis

    Science.gov (United States)

    Morelle, Johann; Sow, Amadou; Hautem, Nicolas; Bouzin, Caroline; Crott, Ralph

    2015-01-01

    Encapsulating peritoneal sclerosis (EPS) is a rare but severe complication of peritoneal dialysis (PD) characterized by extensive fibrosis of the peritoneum. Changes in peritoneal water transport may precede EPS, but the mechanisms and potential predictive value of that transport defect are unknown. Among 234 patients with ESRD who initiated PD at our institution over a 20-year period, 7 subsequently developed EPS. We evaluated changes in peritoneal transport over time on PD in these 7 patients and in 28 matched controls using 3.86% glucose peritoneal equilibration tests. Compared with long-term PD controls, patients with EPS showed early loss of ultrafiltration capacity and sodium sieving before the onset of overt EPS. Multivariate analysis revealed that loss of sodium sieving was the most powerful predictor of EPS. Compared with long-term PD control and uremic peritoneum, EPS peritoneum showed thicker submesothelial fibrosis, with increased collagen density and a greater amount of thick collagen fibers. Reduced osmotic conductance strongly correlated with the degree of peritoneal fibrosis, but not with vasculopathy. Peritoneal fibrosis was paralleled by an excessive upregulation of vascular endothelial growth factor and endothelial nitric oxide synthase, but the expression of endothelial aquaporin-1 water channels was unaltered. Our findings suggest that an early and disproportionate reduction in osmotic conductance during the course of PD is an independent predictor of EPS. This functional change is linked to specific alterations of the collagen matrix in the peritoneal membrane of patients with EPS, thereby validating the serial three-pore membrane/fiber matrix and distributed models of peritoneal transport. PMID:25636412

  2. Pharmacodynamic and pharmacokinetic assessment of pulmonary rehabilitation mixture for the treatment of pulmonary fibrosis.

    Science.gov (United States)

    Zhao, Juanjuan; Ren, Yan; Qu, Yubei; Jiang, Wanglin; Lv, Changjun

    2017-06-14

    Pulmonary rehabilitation mixture (PRM), a Chinese herbal medicine formula, has been used to treat pulmonary fibrosis for decades. In this study, we systematically evaluated the pharmacodynamic and pharmacokinetic performance of PRM. The pharmacodynamic results showed that PRM could improve the condition of CoCl 2 -stimulated human type II alveolar epithelial cells, human pulmonary microvascular endothelial cells, human lung fibroblasts and pulmonary fibrosis rats induced by bleomycin, PRM treatment reduced the expression of platelet-derived growth factor, fibroblast growth factor, toll-like receptor 4, high-mobility group box protein 1 and hypoxia-inducible factor 1α. In the pharmacokinetic study, an accurate and sensitive ultra-high performance liquid chromatography tandem mass spectrometry method was developed and validated for the simultaneous determination of calycosin, calycosin-7-O-glucoside, formononetin, ononin and mangiferin of PRM in the rat plasma for the first time. The method was then successfully applied to the comparative pharmacokinetic study of PRM in normal and pulmonary fibrosis rats. The five constituents could be absorbed in the blood after the oral administration of PRM and exhibited different pharmacokinetic behaviors in normal and pulmonary fibrosis rats. In summary, PRM exhibited a satisfactory pharmacodynamic and pharmacokinetic performance, which highlights PRM as a potential multi-target oral drug for the treatment of pulmonary fibrosis.

  3. 18F-Fluorodeoxyglucose positron emission tomography pulmonary imaging in idiopathic pulmonary fibrosis is reproducible: implications for future clinical trials

    International Nuclear Information System (INIS)

    Win, Thida; Lambrou, Tryphon; Hutton, Brian F.; Kayani, Irfan; Endozo, Raymondo; Shortman, Robert I.; Groves, Ashley M.; Screaton, Nicholas J.; Porter, Joanna C.; Maher, Toby M.; Lukey, Pauline

    2012-01-01

    Noninvasive markers of disease activity in patients with idiopathic pulmonary fibrosis (IPF) are lacking. We performed this study to investigate the reproducibility of pulmonary 18 F-FDG PET/CT in patients with IPF. The study group comprised 13 patients (11 men, 2 women; mean age 71.1 ± 9.9 years) with IPF recruited for two thoracic 18 F-FDG PET/CT studies performed within 2 weeks of each other. All patients were diagnosed with IPF in consensus at multidisciplinary meetings as a result of typical clinical, high-resolution CT and pulmonary function test features. Three methods for evaluating pulmonary 18 F-FDG uptake were used. The maximal 18 F-FDG pulmonary uptake (SUVmax) in the lungs was determined using manual region-of-interest placement. An 18 F-FDG uptake intensity histogram was automatically constructed from segmented lungs to evaluate the distribution of SUVs. Finally, mean SUV was determined for volumes-of-interest in pulmonary regions with interstitial lung changes identified on CT scans. Processing included correction for tissue fraction effects. Bland-Altman analysis was performed and interclass correlation coefficients (ICC) were determined to assess the reproducibility between the first and second PET scans, as well as the level of intraobserver and interobserver agreement. The mean time between the two scans was 6.3 ± 4.3 days. The interscan ICCs for pulmonary SUVmax analysis and mean SUV corrected for tissue fraction effects were 0.90 and 0.91, respectively. Intensity histograms were different in only 1 of the 13 paired studies. Intraobserver agreement was also excellent (0.80 and 0.85, respectively). Some bias was observed between observers, suggesting that serial studies would benefit from analysis by the same observer. This study demonstrated that there is excellent short-term reproducibility in pulmonary 18 F-FDG uptake in patients with IPF. (orig.)

  4. Muc1 deficiency exacerbates pulmonary fibrosis in a mouse model of silicosis.

    Science.gov (United States)

    Kato, Kosuke; Zemskova, Marina A; Hanss, Alec D; Kim, Marianne M; Summer, Ross; Kim, Kwang Chul

    2017-11-25

    MUC1 (MUC in human and Muc in animals) is a membrane-tethered mucin expressed on the apical surface of lung epithelial cells. However, in the lungs of patients with interstitial lung disease, MUC1 is aberrantly expressed in hyperplastic alveolar type II epithelial (ATII) cells and alveolar macrophages (AM), and elevated levels of extracellular MUC1 are found in bronchoalveolar lavage (BAL) fluid and the serum of these patients. While pro-fibrotic effects of extracellular MUC1 have recently been described in cultured fibroblasts, the contribution of MUC1 to the pathobiology of pulmonary fibrosis is unknown. In this study, we hypothesized that MUC1 deficiency would reduce susceptibility to pulmonary fibrosis in a mouse model of silicosis. We employed human MUC1 transgenic mice, Muc1 deficient mice and wild-type mice on C57BL/6 background in these studies. Some mice received a one-time dose of crystalline silica instilled into their oropharynx in order to induce pulmonary fibrosis and assess the effects of Muc1 deficiency on fibrotic and inflammatory responses in the lung. As previously described in other mouse models of pulmonary fibrosis, we found that extracellular MUC1 levels were markedly increased in whole lung tissues, BALF and serum of human MUC1 transgenic mice after silica. We also detected an increase in total MUC1 levels in the lungs of these mice, indicating that production as well as release contributed to elevated levels after lung injury. Immunohistochemical staining revealed that increased MUC1 expression was mostly confined to ATII cells and AMs in areas of fibrotic remodeling, illustrating a pattern similar to the expression of MUC1 in human fibrotic lung tissues. However, contrary to our hypothesis, we found that Muc1 deficiency resulted in a worsening of fibrotic remodeling in the mouse lung as judged by an increase in number of silicotic nodules, an increase in lung collagen deposition and an increase in the severity of pulmonary inflammation

  5. TINF2 Gene Mutation in a Patient with Pulmonary Fibrosis

    NARCIS (Netherlands)

    Hoffman, T W; van der Vis, J J; van Oosterhout, M F M; van Es, H W; van Kessel, D A; Grutters, J C; van Moorsel, C H M

    2016-01-01

    Pulmonary fibrosis is a frequent manifestation of telomere syndromes. Telomere gene mutations are found in up to 25% and 3% of patients with familial disease and sporadic disease, respectively. The telomere gene TINF2 encodes an eponymous protein that is part of the shelterin complex, a complex

  6. Optimizing quality of life in patients with idiopathic pulmonary fibrosis

    NARCIS (Netherlands)

    M.J.G. Van Manen (Mirjam); J.J.M. Geelhoed (Miranda); N.C. Tak-van Jaarsveld (Nelleke); M.S. Wijsenbeek (Marlies)

    2017-01-01

    textabstractIdiopathic pulmonary fibrosis (IPF) is a devastating, progressive and ultimately fatal lung disease. The combination of poor prognosis, uncertainty of disease course and severe symptom burden heavily impacts patients' and their families' quality of life. Though new antifibrotic drugs

  7. Combined pulmonary fibrosis and emphysema: an increasingly recognized condition

    Directory of Open Access Journals (Sweden)

    Olívia Meira Dias

    2014-06-01

    Full Text Available Combined pulmonary fibrosis and emphysema (CPFE has been increasingly recognized in the literature. Patients with CPFE are usually heavy smokers or former smokers with concomitant lower lobe fibrosis and upper lobe emphysema on chest HRCT scans. They commonly present with severe breathlessness and low DLCO, despite spirometry showing relatively preserved lung volumes. Moderate to severe pulmonary arterial hypertension is common in such patients, who are also at an increased risk of developing lung cancer. Unfortunately, there is currently no effective treatment for CPFE. In this review, we discuss the current knowledge of the pathogenesis, clinical characteristics, and prognostic factors of CPFE. Given that most of the published data on CPFE are based on retrospective analysis, more studies are needed in order to address the role of emphysema and its subtypes; the progression of fibrosis/emphysema and its correlation with inflammation; treatment options; and prognosis.

  8. Periostin promotes renal cyst growth and interstitial fibrosis in polycystic kidney disease

    Science.gov (United States)

    Wallace, Darren P.; White, Corey; Savinkova, Lyudmyla; Nivens, Emily; Reif, Gail A.; Pinto, Cibele S.; Raman, Archana; Parnell, Stephen C.; Conway, Simon J.; Fields, Timothy A.

    2013-01-01

    In renal cystic diseases, sustained enlargement of fluid-filled cysts is associated with severe interstitial fibrosis and progressive loss of functioning nephrons. Periostin, a matricellular protein, is highly overexpressed in cyst-lining epithelial cells of autosomal dominant polycystic disease kidneys (ADPKD) compared to normal tubule cells. Periostin accumulates in situ within the matrix subjacent to ADPKD cysts, binds to αVβ3- and αVβ5-integrins and stimulates the integrin-linked kinase to promote cell proliferation. We knocked out periostin (Postn) in pcy/pcy mice, an orthologous model of nephronophthisis type 3, to determine whether periostin loss reduces PKD progression in a slowly progressive model of renal cystic disease. At 20 weeks of age, pcy/pcy: Postn−/− mice had a 34% reduction in kidney weight/body weight, a reduction in cyst number and total cystic area, a 69% reduction in phosphorylated S6, a downstream component of the mTOR pathway, and fewer proliferating cells in the kidneys compared to pcy/pcy: Postn+/+ mice. The pcy/pcy Postn knockout mice also had less interstitial fibrosis with improved renal function at 20 weeks and significantly longer survival (51.4 compared to 38.0 weeks). Thus, periostin adversely modifies the progression of renal cystic disease by promoting cyst epithelial cell proliferation, cyst enlargement and interstitial fibrosis, all contributing to the decline in renal function and premature death. PMID:24284511

  9. Follistatin, an Activin Antagonist, Ameliorates Renal Interstitial Fibrosis in a Rat Model of Unilateral Ureteral Obstruction

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    Akito Maeshima

    2014-01-01

    Full Text Available Activin, a member of the TGF-β superfamily, regulates cell growth and differentiation in various cell types. Activin A acts as a negative regulator of renal development as well as tubular regeneration after renal injury. However, it remains unknown whether activin A is involved in renal fibrosis. To clarify this issue, we utilized a rat model of unilateral ureteral obstruction (UUO. The expression of activin A was significantly increased in the UUO kidneys compared to that in contralateral kidneys. Activin A was detected in glomerular mesangial cells and interstitial fibroblasts in normal kidneys. In UUO kidneys, activin A was abundantly expressed by interstitial α-SMA-positive myofibroblasts. Administration of recombinant follistatin, an activin antagonist, reduced the fibrotic area in the UUO kidneys. The number of proliferating cells in the interstitium, but not in the tubules, was significantly lower in the follistatin-treated kidneys. Expression of α-SMA, deposition of type I collagen and fibronectin, and CD68-positive macrophage infiltration were significantly suppressed in the follistatin-treated kidneys. These data suggest that activin A produced by interstitial fibroblasts acts as a potent profibrotic factor during renal fibrosis. Blockade of activin A action may be a novel approach for the prevention of renal fibrosis progression.

  10. Connective tissue growth factor stimulates the proliferation, migration and differentiation of lung fibroblasts during paraquat-induced pulmonary fibrosis.

    Science.gov (United States)

    Yang, Zhizhou; Sun, Zhaorui; Liu, Hongmei; Ren, Yi; Shao, Danbing; Zhang, Wei; Lin, Jinfeng; Wolfram, Joy; Wang, Feng; Nie, Shinan

    2015-07-01

    It is well established that paraquat (PQ) poisoning can cause severe lung injury during the early stages of exposure, finally leading to irreversible pulmonary fibrosis. Connective tissue growth factor (CTGF) is an essential growth factor that is involved in tissue repair and pulmonary fibrogenesis. In the present study, the role of CTGF was examined in a rat model of pulmonary fibrosis induced by PQ poisoning. Histological examination revealed interstitial edema and extensive cellular thickening of interalveolar septa at the early stages of poisoning. At 2 weeks after PQ administration, lung tissue sections exhibited a marked thickening of the alveolar walls with an accumulation of interstitial cells with a fibroblastic appearance. Masson's trichrome staining revealed a patchy distribution of collagen deposition, indicating pulmonary fibrogenesis. Western blot analysis and immunohistochemical staining of tissue samples demonstrated that CTGF expression was significantly upregulated in the PQ-treated group. Similarly, PQ treatment of MRC-5 human lung fibroblast cells caused an increase in CTGF in a dose-dependent manner. Furthermore, the addition of CTGF to MRC-5 cells triggered cellular proliferation and migration. In addition, CTGF induced the differentiation of fibroblasts to myofibroblasts, as was evident from increased expression of α-smooth muscle actin (α-SMA) and collagen. These findings demonstrate that PQ causes increased CTGF expression, which triggers proliferation, migration and differentiation of lung fibroblasts. Therefore, CTGF may be important in PQ-induced pulmonary fibrogenesis, rendering this growth factor a potential pharmacological target for reducing lung injury.

  11. Sirtuin 7 is decreased in pulmonary fibrosis and regulates the fibrotic phenotype of lung fibroblasts.

    Science.gov (United States)

    Wyman, Anne E; Noor, Zahid; Fishelevich, Rita; Lockatell, Virginia; Shah, Nirav G; Todd, Nevins W; Atamas, Sergei P

    2017-06-01

    Pulmonary fibrosis is a severe condition with no cure and limited therapeutic options. A better understanding of its pathophysiology is needed. Recent studies have suggested that pulmonary fibrosis may be driven by accelerated aging-related mechanisms. Sirtuins (SIRTs), particularly SIRT1, SIRT3, and SIRT6, are well-known mediators of aging; however, limited data exist on the contribution of sirtuins to lung fibrosis. We assessed the mRNA and protein levels of all seven known sirtuins in primary lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated interstitial lung disease (SSc-ILD) in comparison with lung fibroblasts from healthy controls. These unbiased tests revealed a tendency for all sirtuins to be expressed at lower levels in fibroblasts from patients compared with controls, but the greatest decrease was observed with SIRT7. Similarly, SIRT7 was decreased in lung tissues of bleomycin-challenged mice. Inhibition of SIRT7 with siRNA in cultured lung fibroblasts resulted in an increase in collagen and α-smooth muscle actin (α-SMA). Reciprocally, overexpression of SIRT7 resulted in lower basal and TGF-β-induced levels of COL1A1, COL1A2, COL3A1, and α-SMA mRNAs, as well as collagen and α-SMA proteins. Induced changes in SIRT7 had no effect on endogenous TGF-β mRNA levels or latent TGF-β activation, but overexpression of SIRT7 reduced the levels of Smad3 mRNA and protein. In conclusion, the decline in SIRT7 in lung fibroblasts has a profibrotic effect, which is mediated by changes in Smad3 levels.

  12. Iron chelation by deferoxamine prevents renal interstitial fibrosis in mice with unilateral ureteral obstruction.

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    Yasumasa Ikeda

    Full Text Available Renal fibrosis plays an important role in the onset and progression of chronic kidney diseases (CKD. Although several mechanisms underlying renal fibrosis and candidate drugs for its treatment have been identified, the effect of iron chelator on renal fibrosis remains unclear. In the present study, we examined the effect of an iron chelator, deferoxamine (DFO, on renal fibrosis in mice with surgically induced unilateral ureter obstruction (UUO. Mice were divided into 4 groups: UUO with vehicle, UUO with DFO, sham with vehicle, and sham with DFO. One week after surgery, augmented renal tubulointerstitial fibrosis and the expression of collagen I, III, and IV increased in mice with UUO; these changes were suppressed by DFO treatment. Similarly, UUO-induced macrophage infiltration of renal interstitial tubules was reduced in UUO mice treated with DFO. UUO-induced expression of inflammatory cytokines and extracellular matrix proteins was abrogated by DFO treatment. DFO inhibited the activation of the transforming growth factor-β1 (TGF-β1-Smad3 pathway in UUO mice. UUO-induced NADPH oxidase activity and p22(phox expression were attenuated by DFO. In the kidneys of UUO mice, divalent metal transporter 1, ferroportin, and ferritin expression was higher and transferrin receptor expression was lower than in sham-operated mice. Increased renal iron content was observed in UUO mice, which was reduced by DFO treatment. These results suggest that iron reduction by DFO prevents renal tubulointerstitial fibrosis by regulating TGF-β-Smad signaling, oxidative stress, and inflammatory responses.

  13. Resistin-like molecule alpha1 (Fizz1 recruits lung dendritic cells without causing pulmonary fibrosis

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    Madala Satish K

    2012-06-01

    Full Text Available Abstract Background Resistin-like molecule alpha or found in inflammatory zone protein (Fizz1 is increased in pulmonary epithelial cells and also in limited amounts by other lung cells during various lung injuries and fibrosis. However, the direct role of Fizz1 produced in the pulmonary epithelium has not been determined. Methods Fizz1 Transgenic mice (CCSP/Fizz1 were generated that overexpress Fizz1 in the lung epithelium under the control of a doxycycline (Dox inducible lung epithelial cell specific promoter Scgb1a1 (Clara cell secretory protein, CCSP. Histology and FACS analysis of lung cells were used to identify the direct effects of Fizz1 in the transgenic mice (Dox treated when compared with control (CCSP/- mice. Intratracheal bleomycin sulfate or silica in saline and saline alone were used to study the role of Fizz1 during bleomycin- and silica-induced pulmonary fibrosis in CCSP/Fizz1 and CCSP/- mice. Weight change, pulmonary inflammation, and fibrosis were assessed 10 days post bleomycin or 28 days post silica challenge. Results When CCSP/Fizz1 mice were fed Dox food, elevated Fizz1 protein was detected in lung homogenates by western blot. Lungs of mice in which Fizz1 was induced in the epithelium contained increased lung cells staining for CD11c and F4/80 by FACS analysis consistent with increased dendritic cells however, no changes were observed in the percentage of interstitial macrophages compared to CCSP/- controls. No significant changes were found in the lung histology of CCSP/Fizz1 mice after up to 8 weeks of overexpression compared to CCSP/- controls. Overexpression of Fizz1 prior to challenge or following challenge with bleomycin or silica did not significantly alter airway inflammation or fibrosis compared to control mice. Conclusions The current study demonstrates that epithelial cell derived Fizz1 is sufficient to increase the bone-marrow derived dendritic cells in the lungs, but it is not sufficient to cause lung

  14. Assessing idiopathic pulmonary fibrosis (IPF) with bronchoscopic OCT (Conference Presentation)

    Science.gov (United States)

    Hariri, Lida P.; Adams, David C.; Colby, Thomas V.; Tager, Andrew M.; Suter, Melissa J.

    2016-03-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal form of fibrotic lung disease, with a 3 year survival rate of 50%. Diagnostic certainty of IPF is essential to determine the most effective therapy for patients, but often requires surgery to resect lung tissue and look for microscopic honeycombing not seen on chest computed tomography (CT). Unfortunately, surgical lung resection has high risks of associated morbidity and mortality in this patient population. We aim to determine whether bronchoscopic optical coherence tomography (OCT) can serve as a novel, low-risk paradigm for in vivo IPF diagnosis without surgery or tissue removal. OCT provides rapid 3D visualization of large tissue volumes with microscopic resolutions well beyond the capabilities of CT. We have designed bronchoscopic OCT catheters to effectively and safely access the peripheral lung, and conducted in vivo peripheral lung imaging in patients, including those with pulmonary fibrosis. We utilized these OCT catheters to perform bronchoscopic imaging in lung tissue from patients with pulmonary fibrosis to determine if bronchoscopic OCT could successfully visualize features of IPF through the peripheral airways. OCT was able to visualize characteristic features of IPF through the airway, including microscopic honeycombing (fibrosis, and spatial disease heterogeneity. These findings support the potential of bronchoscopic OCT as a minimally-invasive method for in vivo IPF diagnosis. However, future clinical studies are needed to validate these findings.

  15. Panax notoginseng Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice

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    Kuen-Daw Tsai

    2011-01-01

    Full Text Available Panax notoginseng (PN is a traditional Chinese herb experimentally proven to have anti-inflammatory effects, and it is used clinically for the treatment of atherosclerosis, cerebral infarction, and cerebral ischemia. This study aimed to determine the anti-inflammatory effects of PN against bleomycin-induced pulmonary fibrosis in mice. First, in an in vitro study, culture media containing lipopolysaccharide (LPS was used to stimulate macrophage cells (RAW 264.7 cell line. TNF-α and IL-6 levels were then determined before and after treatment with PN extract. In an animal model (C57BL/6 mice, a single dose of PN (0.5 mg/kg was administered orally on Day 2 or Day 7 postbleomycin treatment. The results showed that TNF-α and IL-6 levels increased in the culture media of LPS-stimulated macrophage cells, and this effect was significantly inhibited in a concentration-dependent manner by PN extract. Histopathologic examination revealed that PN administered on Day 7 postbleomycin treatment significantly decreased inflammatory cell infiltrates, fibrosis scores, and TNF-α, TGF-β, IL-1β, and IL-6 levels in bronchoalveolar lavage fluid when compared with PN given on Day 2 postbleomycin treatment. These results suggest that PN administered in the early fibrotic stage can attenuate pulmonary fibrosis in an animal model of idiopathic pulmonary fibrosis.

  16. Protective roles of pulmonary rehabilitation mixture in experimental pulmonary fibrosis in vitro and in vivo

    International Nuclear Information System (INIS)

    Zhang, L.; Ji, Y.X.; Jiang, W.L.; Lv, C.J.

    2015-01-01

    Abnormal high mobility group protein B1 (HMGB1) activation is involved in the pathogenesis of pulmonary fibrosis. Pulmonary rehabilitation mixture (PRM), which combines extracts from eight traditional Chinese medicines, has very good lung protection in clinical use. However, it is not known if PRM has anti-fibrotic activity. In this study, we investigated the effects of PRM on transforming growth factor-β1 (TGF-β1)-mediated and bleomycin (BLM)-induced pulmonary fibrosis in vitro and in vivo. The effects of PRM on TGF-β1-mediated epithelial-mesenchymal transition (EMT) in A549 cells, on the proliferation of human lung fibroblasts (HLF-1) in vitro, and on BLM-induced pulmonary fibrosis in vivo were investigated. PRM treatment resulted in a reduction of EMT in A549 cells that was associated with attenuating an increase of vimentin and a decrease of E-cadherin. PRM inhibited the proliferation of HLF-1 at an IC 50 of 0.51 µg/mL. PRM ameliorated BLM-induced pulmonary fibrosis in rats, with reduction of histopathological scores and collagen deposition, and a decrease in α-smooth muscle actin (α-SMA) and HMGB1 expression. An increase in receptor for advanced glycation end-product (RAGE) expression was found in BLM-instilled lungs. PRM significantly decreased EMT and prevented pulmonary fibrosis through decreasing HMGB1 and regulating RAGE in vitro and in vivo. PRM inhibited TGF-β1-induced EMT via decreased HMGB1 and vimentin and increased RAGE and E-cadherin levels. In summary, PRM prevented experimental pulmonary fibrosis by modulating the HMGB1/RAGE pathway

  17. Protective roles of pulmonary rehabilitation mixture in experimental pulmonary fibrosis in vitro and in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, L.; Ji, Y.X.; Jiang, W.L.; Lv, C.J. [School of Pharmaceutical Sciences, Binzhou Medical University, Yantai (China)

    2015-05-08

    Abnormal high mobility group protein B1 (HMGB1) activation is involved in the pathogenesis of pulmonary fibrosis. Pulmonary rehabilitation mixture (PRM), which combines extracts from eight traditional Chinese medicines, has very good lung protection in clinical use. However, it is not known if PRM has anti-fibrotic activity. In this study, we investigated the effects of PRM on transforming growth factor-β1 (TGF-β1)-mediated and bleomycin (BLM)-induced pulmonary fibrosis in vitro and in vivo. The effects of PRM on TGF-β1-mediated epithelial-mesenchymal transition (EMT) in A549 cells, on the proliferation of human lung fibroblasts (HLF-1) in vitro, and on BLM-induced pulmonary fibrosis in vivo were investigated. PRM treatment resulted in a reduction of EMT in A549 cells that was associated with attenuating an increase of vimentin and a decrease of E-cadherin. PRM inhibited the proliferation of HLF-1 at an IC{sub 50} of 0.51 µg/mL. PRM ameliorated BLM-induced pulmonary fibrosis in rats, with reduction of histopathological scores and collagen deposition, and a decrease in α-smooth muscle actin (α-SMA) and HMGB1 expression. An increase in receptor for advanced glycation end-product (RAGE) expression was found in BLM-instilled lungs. PRM significantly decreased EMT and prevented pulmonary fibrosis through decreasing HMGB1 and regulating RAGE in vitro and in vivo. PRM inhibited TGF-β1-induced EMT via decreased HMGB1 and vimentin and increased RAGE and E-cadherin levels. In summary, PRM prevented experimental pulmonary fibrosis by modulating the HMGB1/RAGE pathway.

  18. Pulmonary function outcomes for assessing cystic fibrosis care.

    Science.gov (United States)

    Wagener, Jeffrey S; Elkin, Eric P; Pasta, David J; Schechter, Michael S; Konstan, Michael W; Morgan, Wayne J

    2015-05-01

    Assessing cystic fibrosis (CF) patient quality of care requires the choice of an appropriate outcome measure. We looked systematically and in detail at pulmonary function outcomes that potentially reflect clinical practice patterns. Epidemiologic Study of Cystic Fibrosis data were used to evaluate six potential outcome variables (2002 best FVC, FEV(1), and FEF(25-75) and rate of decline for each from 2000 to 2002). We ranked CF care sites by outcome measure and then assessed any association with practice patterns and follow-up pulmonary function. Sites ranked in the top quartile had more frequent monitoring, treatment of exacerbations, and use of chronic therapies and oral corticosteroids. The follow-up rate of pulmonary function decline was not predicted by site ranking. Different pulmonary function outcomes associate slightly differently with practice patterns, although annual FEV(1) is at least as good as any other measure. Current site ranking only moderately predicts future ranking. Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

  19. Pharmacological Targeting of Protease-Activated Receptor 2 Affords Protection from Bleomycin-Induced Pulmonary Fibrosis

    NARCIS (Netherlands)

    Lin, Cong; von der Thüsen, Jan; Daalhuisen, Joost; ten Brink, Marieke; Crestani, Bruno; van der Poll, Tom; Borensztajn, Keren; Spek, C. Arnold

    2015-01-01

    Idiopathic pulmonary fibrosis is the most devastating diffuse fibrosing lung disease that remains refractory to therapy. Despite increasing evidence that protease-activated receptor 2 (PAR-2) contributes to fibrosis, its importance in pulmonary fibrosis is under debate. We addressed whether PAR-2

  20. Pharmacological targeting of protease-activated receptor 2 affords protection from bleomycin-induced pulmonary fibrosis

    NARCIS (Netherlands)

    C. Lin (Cong); J. von der Thusen (Jan); J. Daalhuisen (Joost); M. Ten Brink (Marieke); B. Crestani (Bruno); T. van der Poll (Tom); K. Borensztajn (Keren); C. Arnold Spek (C.)

    2015-01-01

    textabstractIdiopathic pulmonary fibrosis is the most devastating diffuse fibrosing lung disease that remains refractory to therapy. Despite increasing evidence that protease-activated receptor 2 (PAR-2) contributes to fibrosis, its importance in pulmonary fibrosis is under debate. We addressed

  1. Pharmacological Targeting of Protease-Activated Receptor 2 Affords Protection from Bleomycin-Induced Pulmonary Fibrosis

    Science.gov (United States)

    Lin, Cong; von der Thüsen, Jan; Daalhuisen, Joost; ten Brink, Marieke; Crestani, Bruno; van der Poll, Tom; Borensztajn, Keren; Spek, C Arnold

    2015-01-01

    Idiopathic pulmonary fibrosis is the most devastating diffuse fibrosing lung disease that remains refractory to therapy. Despite increasing evidence that protease-activated receptor 2 (PAR-2) contributes to fibrosis, its importance in pulmonary fibrosis is under debate. We addressed whether PAR-2 deficiency persistently reduces bleomycin-induced pulmonary fibrosis or merely delays disease progression and whether pharmacological PAR-2 inhibition limits experimental pulmonary fibrosis. Bleomycin was instilled intranasally into wild-type or PAR-2–deficient mice in the presence/absence of a specific PAR-2 antagonist (P2pal-18S). Pulmonary fibrosis was consistently reduced in PAR-2–deficient mice throughout the fibrotic phase, as evident from reduced Ashcroft scores (29%) and hydroxyproline levels (26%) at d 28. Moreover, P2pal-18S inhibited PAR-2–induced profibrotic responses in both murine and primary human pulmonary fibroblasts (p bleomycin-treated wild-type mice but did not further reduce fibrosis in PAR-2–deficient mice. Importantly, P2pal-18S treatment starting even 7 d after the onset of fibrosis limits pulmonary fibrosis as effectively as when treatment was started together with bleomycin instillation. Overall, PAR-2 contributes to the progression of pulmonary fibrosis, and targeting PAR-2 may be a promising therapeutic strategy for treating pulmonary fibrosis. PMID:26147947

  2. Resveratrol inhibits renal interstitial fibrosis in diabetic nephropathy by regulating AMPK/NOX4/ROS pathway.

    Science.gov (United States)

    He, Ting; Xiong, Jiachuan; Nie, Ling; Yu, Yanlin; Guan, Xu; Xu, Xinli; Xiao, Tangli; Yang, Ke; Liu, Liang; Zhang, Daohai; Huang, Yunjian; Zhang, Jingbo; Wang, Junping; Sharma, Kumar; Zhao, Jinghong

    2016-12-01

    Renal interstitial fibrosis is a major pathologic feature of diabetic nephropathy, while the pathogenesis and therapeutic interventions of diabetic renal interstitial fibrosis are not well established. In this study, we first demonstrated that high glucose could induce renal fibroblast (NRK-49F) cell proliferation and activation to myofibroblasts, accompanied by a significant increase in the intracellular levels of reactive oxygen species (ROS) derived from nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4). ROS-mediated ERK1/2 activation was found to play a crucial role in high glucose-induced fibroblast proliferation and activation. Resveratrol, like the NOX4-targeting small interfering RNA (siRNA), markedly inhibited high glucose-induced fibroblast proliferation and activation by reducing NOX4-derived ROS production. It was then revealed that the increase in the expression of NOX4 induced by high glucose was due to the inactivation of AMP-activated protein kinase (AMPK), which could be reversed by resveratrol. Further in vivo investigation demonstrated that resveratrol treatment significantly attenuated renal fibrosis in db/db mice, accompanied by an evident increase in phospho-AMPK and decrease in NOX4. In summary, our results suggest that high glucose can directly promote renal fibroblasts proliferation and activation in a ROS-dependent manner, and resveratrol is a potential therapeutic agent against diabetic renal fibrosis via regulation of AMPK/NOX4/ROS signaling. Resveratrol inhibits high glucose-induced NRK cell activation by decreasing NOX4-derived ROS. Resveratrol inhibits high glucose-induced NOX4 expression in NRK cells via activation of AMPK. ROS-activated ERK1/2 signaling is involved in high glucose-induced NRK cell activation. Resveratrol attenuated renal fibrosis in db/db mice via regulation of AMPK/NOX4/ROS signaling.

  3. Coal Mine Dust Desquamative Chronic Interstitial Pneumonia: A Precursor of Dust-Related Diffuse Fibrosis and of Emphysema

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    Tomislav M Jelic

    2017-07-01

    Full Text Available Background: Diseases associated with coal mine dust continue to affect coal miners. Elucidation of initial pathological changes as a precursor of coal dust-related diffuse fibrosis and emphysema, may have a role in treatment and prevention. Objective: To identify the precursor of dust-related diffuse fibrosis and emphysema. Methods: Birefringent silica/silicate particles were counted by standard microscope under polarized light in the alveolar macrophages and fibrous tissue in 25 consecutive autopsy cases of complicated coal worker's pneumoconiosis and in 21 patients with tobacco-related respiratory bronchiolitis. Results: Coal miners had 331 birefringent particles/high power field while smokers had 4 (p<0.001. Every coal miner had intra-alveolar macrophages with silica/silicate particles and interstitial fibrosis ranging from minimal to extreme. All coal miners, including those who never smoked, had emphysema. Fibrotic septa of centrilobular emphysema contained numerous silica/silicate particles while only a few were present in adjacent normal lung tissue. In coal miners who smoked, tobacco-associated interstitial fibrosis was replaced by fibrosis caused by silica/silicate particles. Conclusion: The presence of silica/silicate particles and anthracotic pigment-laden macrophages inside the alveoli with various degrees of interstitial fibrosis indicated a new disease: coal mine dust desquamative chronic interstitial pneumonia, a precursor of both dust-related diffuse fibrosis and emphysema. In studied coal miners, fibrosis caused by smoking is insignificant in comparison with fibrosis caused by silica/silicate particles. Counting birefringent particles in the macrophages from bronchioalveolar lavage may help detect coal mine dust desquamative chronic interstitial pneumonia, and may initiate early therapy and preventive measures.

  4. Coal Mine Dust Desquamative Chronic Interstitial Pneumonia: A Precursor of Dust-Related Diffuse Fibrosis and of Emphysema.

    Science.gov (United States)

    Jelic, Tomislav M; Estalilla, Oscar C; Sawyer-Kaplan, Phyllis R; Plata, Milton J; Powers, Jeremy T; Emmett, Mary; Kuenstner, John T

    2017-07-01

    Diseases associated with coal mine dust continue to affect coal miners. Elucidation of initial pathological changes as a precursor of coal dust-related diffuse fibrosis and emphysema, may have a role in treatment and prevention. To identify the precursor of dust-related diffuse fibrosis and emphysema. Birefringent silica/silicate particles were counted by standard microscope under polarized light in the alveolar macrophages and fibrous tissue in 25 consecutive autopsy cases of complicated coal worker's pneumoconiosis and in 21 patients with tobacco-related respiratory bronchiolitis. Coal miners had 331 birefringent particles/high power field while smokers had 4 (pcoal miner had intra-alveolar macrophages with silica/silicate particles and interstitial fibrosis ranging from minimal to extreme. All coal miners, including those who never smoked, had emphysema. Fibrotic septa of centrilobular emphysema contained numerous silica/silicate particles while only a few were present in adjacent normal lung tissue. In coal miners who smoked, tobacco-associated interstitial fibrosis was replaced by fibrosis caused by silica/silicate particles. The presence of silica/silicate particles and anthracotic pigment-laden macrophages inside the alveoli with various degrees of interstitial fibrosis indicated a new disease: coal mine dust desquamative chronic interstitial pneumonia, a precursor of both dust-related diffuse fibrosis and emphysema. In studied coal miners, fibrosis caused by smoking is insignificant in comparison with fibrosis caused by silica/silicate particles. Counting birefringent particles in the macrophages from bronchioalveolar lavage may help detect coal mine dust desquamative chronic interstitial pneumonia, and may initiate early therapy and preventive measures.

  5. Growth factors in idiopathic pulmonary fibrosis: relative roles

    Directory of Open Access Journals (Sweden)

    Allen Jeremy T

    2001-11-01

    Full Text Available Abstract Treatment of idiopathic pulmonary fibrosis patients has evolved very slowly; the fundamental approach of corticosteroids alone or in combination with other immunosuppressive agents has had little impact on long-term survival. The continued use of corticosteroids is justified because of the lack of a more effective alternative. Current research indicates that the mechanisms driving idiopathic pulmonary fibrosis reflect abnormal, dysregulated wound healing within the lung, involving increased activity and possibly exaggerated responses by a spectrum of profibrogenic growth factors. An understanding of the roles of these growth factors, and the way in which they modulate events at cellular level, could lead to more targeted therapeutic strategies, improving patients' quality of life and survival.

  6. Precision Medicine: The New Frontier in Idiopathic Pulmonary Fibrosis.

    Science.gov (United States)

    Brownell, Robert; Kaminski, Naftali; Woodruff, Prescott G; Bradford, Williamson Z; Richeldi, Luca; Martinez, Fernando J; Collard, Harold R

    2016-06-01

    Precision medicine is defined by the National Institute of Health's Precision Medicine Initiative Working Group as an approach to disease treatment that takes into account individual variability in genes, environment, and lifestyle. There has been increased interest in applying the concept of precision medicine to idiopathic pulmonary fibrosis, in particular to search for genetic and molecular biomarker-based profiles (so called endotypes) that identify mechanistically distinct disease subgroups. The relevance of precision medicine to idiopathic pulmonary fibrosis is yet to be established, but we believe that it holds great promise to provide targeted and highly effective therapies to patients. In this manuscript, we describe the field's nascent efforts in genetic/molecular endotype identification and how environmental and behavioral subgroups may also be relevant to disease management.

  7. Mice with Pulmonary Fibrosis Driven by Telomere Dysfunction

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    Juan M. Povedano

    2015-07-01

    Full Text Available Idiopathic pulmonary fibrosis (IPF is a degenerative disease of the lungs with an average survival post-diagnosis of 2–3 years. New therapeutic targets and treatments are necessary. Mutations in components of the telomere-maintenance enzyme telomerase or in proteins important for telomere protection are found in both familial and sporadic IPF cases. However, the lack of mouse models that faithfully recapitulate the human disease has hampered new advances. Here, we generate two independent mouse models that develop IPF owing to either critically short telomeres (telomerase-deficient mice or severe telomere dysfunction in the absence of telomere shortening (mice with Trf1 deletion in type II alveolar cells. We show that both mouse models develop pulmonary fibrosis through induction of telomere damage, thus providing proof of principle of the causal role of DNA damage stemming from dysfunctional telomeres in IPF development and identifying telomeres as promising targets for new treatments.

  8. Acute exacerbation of idiopathic pulmonary fibrosis triggered by Aspergillus empyema

    Directory of Open Access Journals (Sweden)

    Atsushi Suzuki

    Full Text Available Acute exacerbation (AE is a severe and life-threatening complication of idiopathic pulmonary fibrosis (IPF. In 2016, the definition and diagnostic criteria for AE-IPF were updated by an international working group. The new definition includes any acute, clinically significant respiratory deterioration (both idiopathic and triggered events characterized by evidence of new widespread alveolar abnormality in patients with IPF. There are no currently proven beneficial management strategies for idiopathic and triggered AE-IPF. This is the first report describing AE-IPF triggered by Aspergillus empyema, which was improved by a combination of corticosteroid, systemic antifungal therapy, local antifungal therapy, and additional pharmacological therapies. Future research may reveal optimal strategies for both idiopathic and triggered AE-IPF. Keywords: Idiopathic pulmonary fibrosis, Acute exacerbation, AE-IPF, Triggered AE, Aspergillus infection

  9. [Measurement of pulmonary inflammation in cystic fibrosis].

    Science.gov (United States)

    Fayon, M; Chiron, R; Abely, M

    2008-06-01

    Lung inflammation is a pivotal phenomenon in the pathogenesis of cystic fibrosis. Inflammation can be measured and quantified within a research perspective, as well as in daily clinical practice. In this review paper, the "Inflammation Task Force" of the "Société Française de Mucoviscidose" has reviewed the literature regarding the various techniques currently available (bronchoalveolar lavage, sputum analysis, nasal wash and brushing, exhaled breath condensates, carbon monoxide and nitric oxide, and systemic measurements (plasma and urine)). The interpretation of all these determinations in children and adults is also discussed.

  10. The role of macrophage derived growth factors in pulmonary fibrosis

    International Nuclear Information System (INIS)

    Pickrell, J.A.; Jarpe, M.; Benson, J.M.; Henderson, R.F.

    1988-01-01

    Factors released from rat alveolar macrophages exposed to high (95 μg/mL) concentrations of the fibrogenic agent, nickel subsulfide, were found to inhibit the proliferation of cultured lung epithelial cells and stimulate the growth of fibroblasts. Such factors, if present in the alveoli of rats exposed by inhalation to nickel subsulfide in vivo, may play a role in inhibiting re-epithelization of nickel-damaged lungs and in stimulating fibroblast proliferation, leading to pulmonary fibrosis. (author)

  11. Oxidant-mediated epithelial cell injury in idiopathic pulmonary fibrosis.

    OpenAIRE

    Cantin, A M; North, S L; Fells, G A; Hubbard, R C; Crystal, R G

    1987-01-01

    Lung inflammatory cells of patients with idiopathic pulmonary fibrosis (IPF) were evaluated for their ability to injure 51Cr-labeled AKD alveolar epithelial cells in the presence and absence of IPF alveolar epithelial lining fluid (ELF). The IPF cells were spontaneously releasing exaggerated amounts of superoxide (O.2) and hydrogen peroxide (H2O2) compared with normal (P less than 0.02). Cytotoxicity of the AKD cells was markedly increased when the IPF inflammatory cells were incubated with a...

  12. Assessing exertional dyspnea in patients with idiopathic pulmonary fibrosis

    OpenAIRE

    Swigris, JJ; Streiner, DL; Brown, KK; Belkin, A; Green, KE; Wamboldt, FS; Schwarz, M; Zisman, DA; Hunninghake, G; Chapman, J; Olman, M; Lubell, S; Morrison, LD; Steele, MP; Haram, T

    2014-01-01

    Background: Dyspnea is a hallmark symptom of idiopathic pulmonary fibrosis (IPF), and dyspnea induced physical activity limitation is a prominent driver of quality of life impairment among IPF patients. Methods: We examined response data for the 21 physical activity items (the first 21 of 24) from the University of California San Diego Shortness of Breath Questionnaire (UCSD) collected at baseline in a recently conducted IPF trial. We used Rasch analysis and hypothesis testing with convention...

  13. Matrix Metalloproteinases as Therapeutic Targets for Idiopathic Pulmonary Fibrosis

    OpenAIRE

    Craig, Vanessa J.; Zhang, Li; Hagood, James S.; Owen, Caroline A.

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is a restrictive lung disease that is associated with high morbidity and mortality. Current medical therapies are not fully effective at limiting mortality in patients with IPF, and new therapies are urgently needed. Matrix metalloproteinases (MMPs) are proteinases that, together, can degrade all components of the extracellular matrix and numerous nonmatrix proteins. MMPs and their inhibitors, tissue inhibitors of MMPs (TIMPs), have been implicated in the p...

  14. Emodin alleviates bleomycin-induced pulmonary fibrosis in rats.

    Science.gov (United States)

    Guan, Ruijuan; Zhao, Xiaomei; Wang, Xia; Song, Nana; Guo, Yuhong; Yan, Xianxia; Jiang, Liping; Cheng, Wenjing; Shen, Linlin

    2016-11-16

    Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease with few treatment options and poor prognosis. Emodin, extracted from Chinese rhubarb, was found to be able to alleviate bleomycin (BLM)-induced pulmonary fibrosis, yet the underlying mechanism remains largely unknown. This study aimed to further investigate the effects of emodin on the inflammation and fibrosis of BLM-induced pulmonary fibrosis and the mechanism involved in rats. Our results showed that emodin improved pulmonary function, reduced weight loss and prevented death in BLM-treated rats. Emodin significantly relieved lung edema and fibrotic changes, decreased collagen deposition, and suppressed the infiltration of myofibroblasts [characterized by expression of α-smooth muscle actin (α-SMA)] and inflammatory cells (mainly macrophages and lymphocytes). Moreover, emodin reduced levels of TNF-α, IL-6, TGF-β1 and heat shock protein (HSP)-47 in the lungs of BLM-treated rats. In vitro, emodin profoundly inhibited TGF-β1-induced α-SMA, collagen IV and fibronectin expression in human embryo lung fibroblasts (HELFs). Emodin also inhibited TGF-β1-induced Smad2/3 and STAT3 activation, indicating that Smad2/3 and STAT3 inactivation mediates emodin-induced effects on TGF-β1-induced myofibroblast differentiation. These results suggest that emodin can exert its anti-fibrotic effect via suppression of TGF-β1 signaling and subsequently inhibition of inflammation, HSP-47 expression, myofibroblast differentiation and extracellular matrix (ECM) deposition. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  15. Pulmonary hyalinizing granuloma and retroperitoneal fibrosis in an adolescent

    International Nuclear Information System (INIS)

    Young, Adam S.; Binkovitz, Larry A.; Adler, Brent H.; Nicol, Kathleen K.; Rennebohm, Robert M.

    2007-01-01

    We describe a 15-year-old boy who developed pulmonary hyalinizing granuloma (PHG) and retroperitoneal fibrosis (RPF). His PHG and RPF were not associated with histoplasmosis or tuberculosis and appeared to represent idiopathic autoimmune phenomena. This is the first reported case of PHG in a pediatric patient and the fourth reported co-occurrence of PHG and RPF. The use of F-18 fluorodeoxyglucose positron emission tomography in the diagnostic and follow-up evaluation of PHG is reported. (orig.)

  16. Persistence of ventilatory defect after resolution of pulmonary interstitial emphysema in a preterm baby.

    Science.gov (United States)

    Filho, Luiz Vicente Ferreira da Silva; Rossi, Felipe De Souza; Deutsch, Alice d'Agostini; Yagui, Ana Cristina Zanon; Timenetsky, Karina; Rebello, Celso de Moura

    2010-07-01

    Pulmonary interstitial emphysema is a common complication of mechanical ventilation in preterm babies. We report a case of severe unilateral pulmonary interstitial emphysema in a premature newborn, treated with high-frequency oscillatory ventilation, lateral decubitus positioning and selective intubation. After complete radiological resolution of the pulmonary emphysema in the left lung, the patient was studied by electrical impedance tomography and a marked reduction of ventilation was identified in the left lung despite radiological resolution of the cysts. This finding indicates that functional abnormalities may persist for longer periods after radiologic resolution of such lesions.

  17. Clinical Impact of Emphysema Evaluated by High-Resolution Computed Tomography on Idiopathic Pulmonary Fibrosis Diagnosed by Surgical Lung Biopsy.

    Science.gov (United States)

    Kohashi, Yasuo; Arai, Toru; Sugimoto, Chikatoshi; Tachibana, Kazunobu; Akira, Masanori; Kitaichi, Masanori; Hayashi, Seiji; Inoue, Yoshikazu

    2016-01-01

    The prognosis of combined cases of pulmonary fibrosis and emphysema is unresolved partially because radiological differentiation between usual interstitial pneumonia and nonspecific interstitial pneumonia is difficult in coexisting emphysema cases. The purpose of this study was to clarify the clinical impact of emphysema on the survival of patients with idiopathic pulmonary fibrosis (IPF). One hundred and seven patients with interstitial lung diseases were diagnosed by surgical lung biopsies between 2006 and 2012, and 47 patients were diagnosed with IPF through multidisciplinary discussion. Emphysema on high-resolution computed tomography scans was evaluated semiquantitatively by visual scoring. Eight out of the 47 IPF patients showed a higher emphysema score (>3) and were diagnosed to have IPF-emphysema. The median survival time of patients with IPF-emphysema (1,734 days) from the initial diagnosis was significantly shorter than that of patients with IPF alone (2,229 days) by Kaplan-Meier analysis (p = 0.007, log-rank test). Univariate Cox proportional hazard regression analyses revealed that a higher total emphysema score (>3.0) was a significantly poor prognostic factor in addition to Krebs von den Lungen-6, surfactant protein-D, arterial oxygen tension, percent forced vital capacity, and percent diffusing capacity of carbon monoxide (%DLCO). Multivariate Cox proportional hazard regression analyses with the stepwise method showed that higher total emphysema score (>3) and %DLCO were significantly poor prognostic factors. The prognosis of IPF-emphysema was significantly worse than that of IPF alone. © 2016 S. Karger AG, Basel.

  18. YKL-40 and mast cells are associated with detrusor fibrosis in patients diagnosed with bladder pain syndrome/interstitial cystitis according to the 2008 criteria of the European Society for the Study of Interstitial Cystitis

    DEFF Research Database (Denmark)

    Richter, Benedikte; Roslind, A.; Hesse, U.

    2010-01-01

    Aims: Bladder pain syndrome/interstitial cystitis (BPS/IC), diagnosed according to the new 2008 criteria of the European Society for the Study of Interstitial Cystitis (ESSIC), may lead to detrusor fibrosis. In some inflammatory diseases, fibrosis is related to YKL-40. The aims were to examine YKL...

  19. Hypoxia Activates Src and Promotes Endocytosis Which Decreases MMP-2 Activity and Aggravates Renal Interstitial Fibrosis.

    Science.gov (United States)

    Cheng, Zhengyuan; Liu, Lei; Wang, Zhi; Cai, Yingying; Xu, Qing; Chen, Pingsheng

    2018-02-15

    The aggravation of renal interstitial fibrosis in the advanced-stage of chronic kidney disease is related to decreased matrix metalloproteinase-2 (MMP-2) activity, which is induced by hypoxia in the kidney; however, the specific mechanism remains unclear. We previously demonstrated that inhibition of Caveolin-1, a key gene involved in endocytosis, increased MMP-2 activity in hypoxic HK-2 cells. It has been reported that activated Src (phospho-Src Tyr416) is a key molecule in multiple fibrotic pathways. However, whether Src functions on the regulation of Caveolin-1 and MMP-2 activity in hypoxic HK-2 cells remains poorly understood. To explore the underlying mechanism, a rat model of renal interstitial fibrosis was established, then we observed obvious hypoxia in fibrotic kidney tissue and the protein levels of phospho-Src and Caveolin-1 increased, while MMP-2 activity decreased. Next, we treated HK-2 cells with the phospho-Src inhibitor PP1. Compared with normal cells grown in hypoxia, in cells treated with PP1, the protein levels of phospho-Src and Caveolin-1 decreased, as did the protein levels of the MMP-2-activity-regulated molecules RECK (reversion-inducing-cysteine-rich protein with kazal motifs) and TIMP-2 (tissue inhibitor of metalloproteinase-2), while the protein level of MT1-MMP (membrane type 1-matrix metalloproteinase) increased and MMP-2 activity was enhanced. Therefore, hypoxia promotes the phosphorylation of Src and phospho-Src can enhance the endocytosis of HK-2 cells, which leads to decreased MMP-2 activity and aggravates renal interstitial fibrosis.

  20. Acupuncture Treatment for Dyspnea due to Combined Pulmonary Fibrosis and Emphysema: A Case Report.

    Science.gov (United States)

    Matsumoto-Miyazaki, Jun; Miyazaki, Nagisa; Nishiwaki, Ayuko; Endo, Junki; Ushikoshi, Hiroaki; Ohno, Yasushi; Minatoguchi, Shinya

    2015-12-01

    Combined idiopathic pulmonary fibrosis with pulmonary emphysema (CPFE) is a syndrome with a characteristic presentation of upper lobe emphysema and lower lobe fibrosis. Dyspnea on exertion (DOE) is a major symptom of CPFE. We report a patient with DOE due to CPFE who was successfully treated with acupuncture. Case report. A 72-year-old Japanese man with a 4-year history of DOE was diagnosed with CPFE 2 years previously in another hospital. He received standard Western medicine treatment, which included bronchodilators. However, his DOE did not improve. Consequently, he visited our hospital for acupuncture treatment and received acupuncture treatment once a week for 1 year. After 10 weeks of acupuncture treatment, the results of the 6-minute walk test (6-minute walking distance, 379 m; lowest oxygen saturation, 86%; modified Borg dyspnea scale score: 2 units) were better than those at baseline (352 m, 84%, 4 units, respectively). These values were sustained at both 30 weeks (470 m, 88%, 1 unit) and 60 weeks (473 m, 85%, 2 units). Serum interstitial biomarkers, Krebs von den Lungen and surfactant protein-D, decreased after commencement of acupuncture therapy. A patient with CPFE showed improvements in dyspnea scores, exercise tolerance, and serum biomarkers during a 1-year course of acupuncture treatment. Use of acupuncture might be an effective adjunct therapy in relieving DOE due to CPFE. A large, well-designed cohort study that includes patients with CPFE treated with acupuncture should be conducted.

  1. Occupational risks for idiopathic pulmonary fibrosis mortality in the United States.

    Science.gov (United States)

    Pinheiro, Germania A; Antao, Vinicius C; Wood, John M; Wassell, James T

    2008-01-01

    Metal and wood dust exposures have been identified as possible occupational risk factors for idiopathic pulmonary fibrosis (IPF). We analyzed mortality data using ICD-10 code J84.1--"Other interstitial pulmonary diseases with fibrosis," derived age-adjusted mortality rates for 1999-2003, and assessed occupational risks for 1999, by calculating proportionate mortality ratios (PMRs) and mortality odds ratios (MORs) using a matched case-control approach. We identified 84,010 IPF deaths, with an age-adjusted mortality rate of 75.7 deaths/million. Mortality rates were highest among males, whites, and those aged 85 and older. Three industry categories with potential occupational exposures recognized as risk factors for IPF were identified: "Wood buildings and mobile homes" (PMR = 4.5, 95% confidence interval (CI) 1.2-11.6 and MOR = 5.3, 95% CI 1.2-23.8), "Metal mining" (PMR = 2.4, 95% CI 1.3-4.0 and MOR = 2.2, 95% CI 1.1-4.4), and "Fabricated structural metal products" (PMR = 1.9, 95% CI 1.1-3.1 and MOR = 1.7, 95% CI 1.0-3.1). Workers in these industry categories may benefit from toxicological studies and improved surveillance for this disease.

  2. Pulmonary fibrosis, part II: state-of-the-art patient management.

    Science.gov (United States)

    Meyer, Keith C

    2017-05-01

    While many pharmacologic therapies for the treatment of idiopathic pulmonary fibrosis (IPF) have been evaluated via randomized, placebo-controlled clinical trials (RCTs) conducted over the past two decades, most therapies have been shown to be ineffective or even potentially harmful. However, a number of recently completed RCTs have shown significant efficacy for pirfenidone and nintedanib for the treatment of IPF. Areas covered: This manuscript reviews recent advances in the management of IPF and other forms of fibrosing interstitial lung disease (ILD) with an emphasis on IPF. The material upon which this discussion is based was obtained from various published texts and manuscripts identified via literature searching (e.g. PubMed). Expert commentary: Anti-fibrotic drugs are now available for clinical use and perceived as standard-of-care therapies that have the potential to blunt disease progression for many patients with IPF. However, these agents do not necessarily stop disease progression or have a significant impact on mortality, and more effective pharmacologic therapies are needed for patients with IPF. Additionally, whether anti-fibrotic agents can be effective therapies for other forms of pulmonary fibrosis, which often have radiologic and histopathologic manifestations that mimic IPF, is being evaluated in a number of RCTs.

  3. Idiopathic pulmonary fibrosis: Are any of the morphological-molecular markers useful in clinical management?

    Science.gov (United States)

    Lunardi, Francesca; Balestro, Elisabetta; Nannini, Nazarena; Vuljan, Stefania Edith; Rea, Federico; Calabrese, Fiorella

    2017-07-01

    Idiopathic pulmonary fibrosis (IPF), the most common form of chronic interstitial lung disease, is a severe progressive fibrotic disorder of unknown aetiology. The disease has a heterogeneous clinical course, with frequent poor prognosis, similar to malignant disease. Correctly diagnosing IPF has become particularly important in view of the availability of more precise therapeutic indications, thus avoiding steroid treatment and allowing new approaches with novel drugs. To date we have limited information about biomarkers predictive of progressive disease and associated complications. Efforts should be made in the future to more appropriately study lung tissue and then to extrapolate the most clinically fitting biomarkers. This approach is already used in routine management of many cancers and provides a potential road map for more appropriate clinical care of IPF. This review will mainly focus on histology and etiopathogenesis highlighting some morphological and molecular features that may influence the overall management of IPF.

  4. Idiopathic pulmonary fibrosis: a holistic approach to disease management in the antifibrotic age.

    Science.gov (United States)

    Shaw, Jonathon; Marshall, Tracey; Morris, Helen; Hayton, Conal; Chaudhuri, Nazia

    2017-11-01

    Idiopathic pulmonary fibrosis (IPF) is the most common cause of interstitial lung disease (ILD) and carries a worse prognosis than many cancers. Until recently, there were no active treatment options available for patients with IPF, meaning palliation or lung transplantation in selected patients were the only options. The management of IPF has changed dramatically over the last decade with the advent of two antifibrotic agents; pirfenidone and nintedanib. These new agents have been shown to reduce decline in lung function and pirfenidone has been shown to reduce mortality. The changing landscape of IPF diagnosis and management present a number of issues that may be encountered including management of side effects related to antifibrotic therapy. This article aims to give an overview of the holistic approach to the management of patients with IPF, including antifibrotic management, symptom management and the invaluable role of the ILD specialist nurse.

  5. Lung function imaging methods in Cystic Fibrosis pulmonary disease.

    Science.gov (United States)

    Kołodziej, Magdalena; de Veer, Michael J; Cholewa, Marian; Egan, Gary F; Thompson, Bruce R

    2017-05-17

    Monitoring of pulmonary physiology is fundamental to the clinical management of patients with Cystic Fibrosis. The current standard clinical practise uses spirometry to assess lung function which delivers a clinically relevant functional readout of total lung function, however does not supply any visible or localised information. High Resolution Computed Tomography (HRCT) is a well-established current 'gold standard' method for monitoring lung anatomical changes in Cystic Fibrosis patients. HRCT provides excellent morphological information, however, the X-ray radiation dose can become significant if multiple scans are required to monitor chronic diseases such as cystic fibrosis. X-ray phase-contrast imaging is another emerging X-ray based methodology for Cystic Fibrosis lung assessment which provides dynamic morphological and functional information, albeit with even higher X-ray doses than HRCT. Magnetic Resonance Imaging (MRI) is a non-ionising radiation imaging method that is garnering growing interest among researchers and clinicians working with Cystic Fibrosis patients. Recent advances in MRI have opened up the possibilities to observe lung function in real time to potentially allow sensitive and accurate assessment of disease progression. The use of hyperpolarized gas or non-contrast enhanced MRI can be tailored to clinical needs. While MRI offers significant promise it still suffers from poor spatial resolution and the development of an objective scoring system especially for ventilation assessment.

  6. Antibiotic adjuvant therapy for pulmonary infection in cystic fibrosis.

    Science.gov (United States)

    Hurley, Matthew N; Forrester, Douglas L; Smyth, Alan R

    2013-06-05

    Cystic fibrosis is a multi-system disease characterised by the production of thick secretions causing recurrent pulmonary infection, often with unusual bacteria. This leads to lung destruction and eventually death through respiratory failure. There are no antibiotics in development that exert a new mode of action and many of the current antibiotics are ineffective in eradicating the bacteria once chronic infection is established. Antibiotic adjuvants - therapies that act by rendering the organism more susceptible to attack by antibiotics or the host immune system, by rendering it less virulent or killing it by other means, are urgently needed. To determine if antibiotic adjuvants improve clinical and microbiological outcome of pulmonary infection in people with cystic fibrosis. We searched the Cystic Fibrosis Trials Register which is compiled from database searches, hand searches of appropriate journals and conference proceedings.Date of most recent search: 26 July 2012.We also searched MEDLINE (all years) on 23 February 2013 and ongoing trials registers on 13 February 2013. Randomised controlled trials and quasi-randomised controlled trials of a therapy exerting an antibiotic adjuvant mechanism of action compared to placebo or no therapy for people with cystic fibrosis. The authors independently assessed and extracted data from identified studies. We identified eighteen studies of which four are included that examined antibiotic adjuvant therapies, three studies are ongoing. The included studies involve the assessment of β-carotene, garlic and zinc supplementation and KB001 (a biological agent). No therapy demonstrated a significant effect upon pulmonary function, pulmonary exacerbations or quality of life. The study of zinc supplementation reports a reduction in the requirement of oral antibiotics but not of intravenous antibiotics, an effect that is difficult to understand.  We could not identify an antibiotic adjuvant therapy that could be recommended for the

  7. Atrial natriuretic peptide protects against bleomycin-induced pulmonary fibrosis via vascular endothelial cells in mice : ANP for pulmonary fibrosis.

    Science.gov (United States)

    Okamoto, Atsuko; Nojiri, Takashi; Konishi, Kazuhisa; Tokudome, Takeshi; Miura, Koichi; Hosoda, Hiroshi; Hino, Jun; Miyazato, Mikiya; Kyomoto, Yohkoh; Asai, Kazuhisa; Hirata, Kazuto; Kangawa, Kenji

    2017-01-03

    Pulmonary fibrosis is a life-threatening disease characterized by progressive dyspnea and worsening pulmonary function. Atrial natriuretic peptide (ANP), a heart-derived secretory peptide used clinically in Japan for the treatment of acute heart failure, exerts a wide range of protective effects on various organs, including the heart, blood vessels, kidneys, and lungs. Its therapeutic properties are characterized by anti-inflammatory and anti-fibrotic activities mediated by the guanylyl cyclase-A (GC-A) receptor. We hypothesized that ANP would have anti-fibrotic and anti-inflammatory effects on bleomycin (BLM)-induced pulmonary fibrosis in mice. Mice were divided into three groups: normal control, BLM with vehicle, and BLM with ANP. ANP (0.5 μg/kg/min via osmotic-pump, subcutaneously) or vehicle administration was started before BLM administration (1 mg/kg) and continued until the mice were sacrificed. At 7 or 21 days after BLM administration, fibrotic changes and infiltration of inflammatory cells in the lungs were assessed based on histological findings and analysis of bronchoalveolar lavage fluid. In addition, fibrosis and inflammation induced by BLM were evaluated in vascular endothelium-specific GC-A overexpressed mice. Finally, attenuation of transforming growth factor-β (TGF-β) signaling by ANP was studied using immortalized mouse endothelial cells stably expressing GC-A receptor. ANP significantly decreased lung fibrotic area and infiltration of inflammatory cells in lungs after BLM administration. Furthermore, similar effects of ANP were observed in vascular endothelium-specific GC-A overexpressed mice. In cultured mouse endothelial cells, ANP reduced phosphorylation of Smad2 after TGF-β stimulation. ANP exerts protective effects on BLM-induced pulmonary fibrosis via vascular endothelial cells.

  8. Recent clinical trials in idiopathic pulmonary fibrosis and the BUILD-1 study

    Directory of Open Access Journals (Sweden)

    K. K. Brown

    2008-12-01

    Full Text Available Idiopathic pulmonary fibrosis (IPF, the most common of the interstitial pneumonias, is a progressive, life-limiting disease for which there are no truly effective therapies. In patients with biopsy-confirmed IPF, median survival is still <3 yrs. Although potent immunosuppressive therapy has underpinned the treatment of IPF in recent years and remains the standard of care, there is little quality evidence to support the efficacy and safety of traditional therapeutic strategies. This has spurred the search for new treatments for IPF and has led to a series of clinical trials of new therapies, seven of which are reviewed herein. They include the Bosentan Use in Interstitial Lung Disease (BUILD-1 trial, the results of which are discussed in detail, the European Idiopathic Pulmonary Fibrosis International Group Exploring N-acetylcysteine 1 Annual (IFIGENIA trial, the interferon gamma (GIPF-001 trial and the INSPIRE trial, as well as trials of anticoagulant therapy, pirfenidone and etanercept. Treatment trials in IPF are hindered by difficulties in achieving a secure diagnosis of IPF and the lack of validated outcome measures that represent either improvement or progression of disease. These and other limitations are discussed in the present article, as well as how some of these problems might be addressed in future trials. Although few of the seven studies met their primary end-points, marginal trends either on primary end-points or statistically significant trends on exploratory end-points were a recurrent theme in most trials. In the BUILD-1 trial, for example, a trend in favour of bosentan was observed on time-to-disease progression or death.

  9. Mucoid impaction presenting as multiple pulmonary nodules in cystic fibrosis

    International Nuclear Information System (INIS)

    Carpenter, L.D.; Lambie, N.K.; Wilsher, M.L.

    1996-01-01

    Mucoid impaction has been described as a complication of asthma and more commonly in patients with allergic bronchopulmonary aspergillosis. In such cases, the impacted pools of mucus may present as discrete nodules on chest X-ray and hence simulate the appearance of metastatic malignancy. A case of mucoid impaction presenting as multiple pulmonary nodules in a patient with cystic fibrosis is described. The chest X-ray showed hyperinfiltration and scattered changes consistent with bronchiectasis. Computed tomography scan confirmed these and additional intra-pulmonary nodular densities. This report illustrates that mucus impaction as a cause of pulmonary nodules should be considered in any patient with chronic lung disease characterised by excess mucus production. 6 refs., 3 figs

  10. Antiflammin-1 attenuates bleomycin-induced pulmonary fibrosis in mice.

    Science.gov (United States)

    Liu, Wei; Wan, Jing; Han, Jian-Zhong; Li, Chen; Feng, Dan-Dan; Yue, Shao-Jie; Huang, Yan-Hong; Chen, Yi; Cheng, Qing-Mei; Li, Yang; Luo, Zi-Qiang

    2013-10-08

    Antiflammin-1 (AF-1), a derivative of uteroglobin (UG), is a synthetic nonapeptide with diverse biological functions. In the present study, we investigated whether AF-1 has a protective effect against bleomycin-induced pulmonary fibrosis. C57BL/6 mice were injected with bleomycin intratracheally to create an animal model of bleomycin-induced pulmonary fibrosis. On Day 7 and Day 28, we examined the anti-inflammatory effect and antifibrotic effect, respectively, of AF-1 on the bleomycin-treated mice. The effects of AF-1 on the transforming growth factor-beta 1 (TGF-β1)-induced proliferation of murine lung fibroblasts (NIH3T3) were examined by a bromodeoxycytidine (BrdU) incorporation assay and cell cycle analysis. Severe lung inflammation and fibrosis were observed in the bleomycin-treated mice on Day 7 and Day 28, respectively. Administration of AF-1 significantly reduced the number of neutrophils in the bronchoalveolar lavage fluid (BALF) and the levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) in the lung homogenates on Day 7. Histological examination revealed that AF-1 markedly reduced the number of infiltrating cells on Day 7 and attenuated the collagen deposition and destruction of lung architecture on Day 28. The hydroxyproline (HYP) content was significantly decreased in the AF-1-treated mice. In vitro, AF-1 inhibited the TGF-β1-induced proliferation of NIH3T3 cells, which was mediated by the UG receptor. AF-1 has anti-inflammatory and antifibrotic actions in bleomycin-induced lung injury. We propose that the antifibrotic effect of AF-1 might be related to its suppression of fibroblast growth in bleomycin-treated lungs and that AF-1 has potential as a new therapeutic tool for pulmonary fibrosis.

  11. Fibrosis of Two: Epithelial Cell-Fibroblast Interactions in Pulmonary Fibrosis

    Science.gov (United States)

    Sakai, Norihiko; Tager, Andrew M.

    2013-01-01

    Idiopathic pulmonary fibrosis (IPF) is characterized by the progressive and ultimately fatal accumulation of fibroblasts and extracellular matrix in the lung that distorts its architecture and compromises its function. IPF is now thought to result from wound-healing processes that, although initiated to protect the host from injurious environmental stimuli, lead to pathological fibrosis due to these processes becoming aberrant or over-exuberant. Although the environmental stimuli that trigger IPF remain to be identified, recent evidence suggests that they initially injure the alveolar epithelium. Repetitive cycles of epithelial injury and resultant alveolar epithelial cell death provoke the migration, proliferation, activation and myofibroblast differentiation of fibroblasts, causing the accumulation of these cells and the extracellular matrix that they synthesize. In turn, these activated fibroblasts induce further alveolar epithelial cell injury and death, thereby creating a vicious cycle of pro-fibrotic epithelial cell-fibroblast interactions. Though other cell types certainly make important contributions, we focus here on the “pas de deux” (steps of two), or perhaps more appropriate to IPF pathogenesis, the “folie à deux” (madness of two) of epithelial cells and fibroblasts that drives the progression of pulmonary fibrosis. We describe the signaling molecules that mediate the interactions of these cell types in their “fibrosis of two”, including transforming growth factor-β, connective tissue growth factor, sonic hedgehog, prostaglandin E2, angiotensin II and reactive oxygen species. PMID:23499992

  12. Bronchoscopic Lung Cryobiopsy Increases Diagnostic Confidence in the Multidisciplinary Diagnosis of Idiopathic Pulmonary Fibrosis.

    Science.gov (United States)

    Tomassetti, Sara; Wells, Athol U; Costabel, Ulrich; Cavazza, Alberto; Colby, Thomas V; Rossi, Giulio; Sverzellati, Nicola; Carloni, Angelo; Carretta, Elisa; Buccioli, Matteo; Tantalocco, Paola; Ravaglia, Claudia; Gurioli, Christian; Dubini, Alessandra; Piciucchi, Sara; Ryu, Jay H; Poletti, Venerino

    2016-04-01

    Surgical lung biopsy is often required for a confident multidisciplinary diagnosis of idiopathic pulmonary fibrosis (IPF). Alternative, less-invasive biopsy methods, such as bronchoscopic lung cryobiopsy (BLC), are highly desirable. To address the impact of BLC on diagnostic confidence in the multidisciplinary diagnosis of IPF. In this cross-sectional study we selected 117 patients with fibrotic interstitial lung disease without a typical usual interstitial pneumonia pattern on high-resolution computed tomography. All cases underwent lung biopsies: 58 were BLC, and 59 were surgical lung biopsy (SLB). Two clinicians, two radiologists, and two pathologists sequentially reviewed clinical-radiologic findings and biopsy results, recording at each step in the process their diagnostic impressions and confidence levels. We observed a major increase in diagnostic confidence after the addition of BLC, similar to SLB (from 29 to 63%, P = 0.0003 and from 30 to 65%, P = 0.0016 of high confidence IPF diagnosis, in the BLC group and SLB group, respectively). The overall interobserver agreement in IPF diagnosis was similar for both approaches (BLC overall kappa, 0.96; SLB overall kappa, 0.93). IPF was the most frequent diagnosis (50 and 39% in the BLC and SLB group, respectively; P = 0.23). After the addition of histopathologic information, 17% of cases in the BLC group and 19% of cases in the SLB group, mostly idiopathic nonspecific interstitial pneumonia and hypersensitivity pneumonitis, were reclassified as IPF. BLC is a new biopsy method that has a meaningful impact on diagnostic confidence in the multidisciplinary diagnosis of interstitial lung disease and may prove useful in the diagnosis of IPF. This study provides a robust rationale for future studies investigating the diagnostic accuracy of BLC compared with SLB.

  13. Eplerenone-Mediated Aldosterone Blockade Prevents Renal Fibrosis by Reducing Renal Inflammation, Interstitial Cell Proliferation and Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Hui Chen

    2013-11-01

    Full Text Available Background/Aims: Prolonged elevation of serum aldosterone leads to renal fibrosis. Inflammation also plays a role in the pathogenesis of renal disease. We used a rat model of interstitial renal fibrosis to test the hypothesis that eplerenone-mediated aldosterone blockade prevents renal fibrosis due to its anti-inflammatory and anti-proliferative effects. Methods: Eplerenone (a selective aldosterone blocker or vehicle (control, was given to male Wistar rats (50 mg/kg, twice daily for 7 days before unilateral ureteral obstruction (UUO and for an additional 28 days after surgery. Body weight, blood pressure, renal histo-morphology, immune-staining for macrophages, monocyte chemotactic protein-1, proliferating cell nuclear antigen, α-smooth muscle actin, and serum and urine markers of renal function and oxidative stress were determined for both groups on 7, 14, and 28 days after surgery. Results: Epleronone had no effect on body weight or blood pressure. However, eplerenone inhibited the development of renal fibrosis, inflammation (macrophage and monocyte infiltration, interstitial cell proliferation, and activation of interstitial cells (α-SMA expression. Epleronone also reduced oxidative stress. Conclusion: The anti-fibrotic effect of eplerenone appears to be unrelated to its effect on blood pressure. Eplerenone inhibits renal inflammation, interstitial cell proliferation, phenotypic changes of interstitial cells, and reduces oxidative stress.

  14. Regenerative medicine in the treatment of idiopathic pulmonary fibrosis: current position

    Directory of Open Access Journals (Sweden)

    Álvarez D

    2015-04-01

    Full Text Available Diana Álvarez,1,2 Melanie Levine,1 Mauricio Rojas1–3 1Dorothy P and Richard P Simmons Center for Interstitial Lung Disease, 2Pulmonary, Allergy, and Critical Care Medicine, 3McGowan Institute for Regenerative Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Abstract: Idiopathic pulmonary fibrosis (IPF is a progressive, irreversible disease of the lung that has no lasting option for therapy other than transplantation. It is characterized by replacement of the normal lung tissue by fibrotic scarring, honeycombing, and increased levels of myofibroblasts. The underlying causes of IPF are still largely unknown. The focus of the current review is the possible use of stem cell therapy, specifically mesenchymal stem cells (MSCs, a multipotent stromal cell population, which have demonstrated promising data in multiple animal models of pulmonary fibrosis (PF. The most studied source of MSCs is the bone marrow, although they can be found also in the adipose tissue and umbilical cord, as well as in the placenta. MSCs have immunomodulatory and tissue-protective properties that allow them to manipulate the local environment of the injured tissue, ameliorating the inflammation and promoting repair. Because IPF primarily affects older patients, the issue of aging is intrinsically linked to many aspects of the disease, including the age of the stem cells. Animal models have shown the success of MSC therapy in mitigating the fibrotic effects of bleomycin-induced PF. However, bleomycin, the most commonly used model for PF, is imperfect in mimicking IPF as it presents in humans, as the duration of the illness is not parallel or reversible, and honeycombing is not produced. Furthermore, the time of MSC dosage has proven to be critical in determining whether the cells will ultimately have a positive or negative effect on disease progression, since it has been demonstrated that the maximal beneficial effect of MSCs occurs during the early

  15. Rapamycin attenuates bleomycin-induced pulmonary fibrosis in rats and the expression of metalloproteinase-9 and tissue inhibitors of metalloproteinase-1 in lung tissue.

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    Jin, Xiaoguang; Dai, Huaping; Ding, Ke; Xu, Xuefeng; Pang, Baosen; Wang, Chen

    2014-01-01

    Idiopathic pulmonary fibrosis (IPF) is the most common and devastating form of interstitial lung disease (ILD) in the clinic. There is no effective therapy except for lung transplantation. Rapamycin is an immunosuppressive drug with potent antifibrotic activity. The purpose of this study was to examine the effects of rapamycin on bleomycin-induced pulmonary fibrosis in rats and the relation to the expression of metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1). Sprague-Dawley rats were treated with intratracheal injection of 0.3 ml of bleomycin (5 mg/kg) in sterile 0.9% saline to make the pulmonary fibrosis model. Rapamycin was given at a dose of 0.5 mg/kg per gavage, beginning one day before bleomycin instillation and once daily until animal sacrifice. Ten rats in each group were sacrificed at 3, 7, 14, 28 and 56 days after bleomycin administration. Alveolitis and pulmonary fibrosis were semi-quantitatively assessed after HE staining and Masson staining under an Olympus BX40 microscope with an IDA-2000 Image Analysis System. Type I and III collagen fibers were identified by Picro-sirius-polarization. Hydroxyproline content in lung tissue was quantified by a colorimetric-based spectrophotometric assay, MMP-9 and TIMP-1 were detected by immunohistochemistry and by realtime quantitative reverse transcriptase polymerase chain reaction (RT-PCR). Bleomycin induced alveolitis and pulmonary fibrosis of rats was inhibited by rapamycin. Significant inhibition of alveolitis and hydroxyproline product were demonstrated when daily administration of rapamycin lasted for at least 14 days. The inhibitory efficacy on pulmonary fibrosis was unremarkable until rapamycin treatment lasted for at least 28 days (P pulmonary fibrosis, which is associated with decreased expression of MMP-9 and TIMP-1.

  16. Modulation of pulmonary fibrosis by IL-13Rα2.

    Science.gov (United States)

    Lumsden, Robert V; Worrell, Julie C; Boylan, Denise; Walsh, Sinead M; Cramton, Jennifer; Counihan, Ian; O'Beirne, Sarah; Medina, Maria Fe; Gauldie, Jack; Fabre, Aurelie; Donnelly, Seamas C; Kane, Rosemary; Keane, Michael P

    2015-04-01

    Pulmonary fibrosis is a progressive and fatal disease that involves the remodeling of the distal airspace and the lung parenchyma, which results in compromised gas exchange. The median survival time once diagnosed is less than three years. Interleukin (IL)-13 has been shown to play a role in a number of inflammatory and fibrotic diseases. IL-13 modulates its effector functions via a complex receptor system that includes the IL-4 receptor (R) α, IL-13Rα1, and the IL-13Rα2. IL-13Rα1 binds IL-13 with low affinity, yet, when it forms a complex with IL-4α, it binds with much higher affinity, inducing the effector functions of IL-13. IL-13Rα2 binds IL-13 with high affinity but has a short cytoplasmic tail and has been shown to act as a nonsignaling decoy receptor. Transfection of fibroblasts and epithelial cells with IL-13Rα2 inhibited the IL-13 induction of soluble collagen, TGF-β, and CCL17. Adenoviral overexpression of IL-13Rα2 in the lung reduced bleomycin-induced fibrosis. Our work shows that overexpression of IL-13Rα2 inhibits the IL-13 induction of fibrotic markers in vitro and inhibits bleomycin-induced pulmonary fibrosis. In summary our study highlights the antifibrotic nature of IL-13Ra2. Copyright © 2015 the American Physiological Society.

  17. Hsp90 regulation of fibroblast activation in pulmonary fibrosis

    Science.gov (United States)

    Sontake, Vishwaraj; Wang, Yunguan; Kasam, Rajesh K.; Sinner, Debora; Reddy, Geereddy B.; Naren, Anjaparavanda P.; McCormack, Francis X.; Jegga, Anil G.; Madala, Satish K.

    2017-01-01

    Idiopathic pulmonary fibrosis (IPF) is a severe fibrotic lung disease associated with fibroblast activation that includes excessive proliferation, tissue invasiveness, myofibroblast transformation, and extracellular matrix (ECM) production. To identify inhibitors that can attenuate fibroblast activation, we queried IPF gene signatures against a library of small-molecule-induced gene-expression profiles and identified Hsp90 inhibitors as potential therapeutic agents that can suppress fibroblast activation in IPF. Although Hsp90 is a molecular chaperone that regulates multiple processes involved in fibroblast activation, it has not been previously proposed as a molecular target in IPF. Here, we found elevated Hsp90 staining in lung biopsies of patients with IPF. Notably, fibroblasts isolated from fibrotic lesions showed heightened Hsp90 ATPase activity compared with normal fibroblasts. 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), a small-molecule inhibitor of Hsp90 ATPase activity, attenuated fibroblast activation and also TGF-β–driven effects on fibroblast to myofibroblast transformation. The loss of the Hsp90AB, but not the Hsp90AA isoform, resulted in reduced fibroblast proliferation, myofibroblast transformation, and ECM production. Finally, in vivo therapy with 17-AAG attenuated progression of established and ongoing fibrosis in a mouse model of pulmonary fibrosis, suggesting that targeting Hsp90 represents an effective strategy for the treatment of fibrotic lung disease. PMID:28239659

  18. FDG-PET/CT in the prediction of pulmonary function improvement in nonspecific interstitial pneumonia. A Pilot Study

    Energy Technology Data Exchange (ETDEWEB)

    Jacquelin, V. [AP-HP, Hosp. Avicenne, Department of Nuclear Medicine, Bobigny (France); Mekinian, A. [AP-HP, Hosp. Saint-Antoine, Department of Internal Medicine and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris (France); Brillet, P.Y. [AP-HP, Hosp. Avicenne, Department of Radiology, Bobigny (France); Univ. Paris 13, Sorbonne Paris Cité, Bobigny (France); Nunes, H. [AP-HP, Hosp. Avicenne, Department of Pneumology, Bobigny (France); Univ. Paris 13, Sorbonne Paris Cité, Bobigny (France); Fain, O. [AP-HP, Hosp. Saint-Antoine, Department of Internal Medicine and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris (France); Valeyre, D. [AP-HP, Hosp. Avicenne, Department of Pneumology, Bobigny (France); Univ. Paris 13, Sorbonne Paris Cité, Bobigny (France); Soussan, M., E-mail: michael.soussan@aphp.fr [AP-HP, Hosp. Avicenne, Department of Nuclear Medicine, Bobigny (France); Univ. Paris 13, Sorbonne Paris Cité, Bobigny (France)

    2016-12-15

    Purpose: Our study aimed to analyse the characteristics of nonspecific interstitial pneumonia (NSIP) using FDG-PET/CT (PET) and to evaluate its ability to predict the therapeutic response. Procedures: Eighteen NSIP patients were included. Maximum standardized uptake value (SUV{sub max}), FDG uptake extent (in percentage of lung volume), high resolution CT scan (HRCT) elementary lesions, and HRCT fibrosis score were recorded. The predictive value of the parameters for lung function improvement was evaluated using logistic regression and Receiver Operating Characteristic (ROC) curve analysis (n = 13/18). Results: All patients had an increased pulmonary FDG uptake (median SUV{sub max} = 3.1 [2–7.6]), with a median extent of 19% [6–67]. Consolidations, ground-glass opacities, honeycombing and reticulations showed uptake in 90%, 89%, 85% and 76%, respectively. FDG uptake extent was associated with improvement of pulmonary function under treatment (increase in forced vital capacity > 10%, p = 0.03), whereas SUV{sub max} and HRCT fibrosis score were not (p > 0.5). For FDG uptake extent, ROC analysis showed an area under the curve at 0.85 ± 0.11 and sensitivity/specificity was 88%/80% for a threshold fixed at 21%. Conclusions: Increased FDG uptake was observed in all NSIP patients, both in inflammatory and fibrotic HRCT lesions. The quantification of FDG uptake extent might be useful to predict functional improvement under treatment.

  19. FDG-PET/CT in the prediction of pulmonary function improvement in nonspecific interstitial pneumonia. A Pilot Study

    International Nuclear Information System (INIS)

    Jacquelin, V.; Mekinian, A.; Brillet, P.Y.; Nunes, H.; Fain, O.; Valeyre, D.; Soussan, M.

    2016-01-01

    Purpose: Our study aimed to analyse the characteristics of nonspecific interstitial pneumonia (NSIP) using FDG-PET/CT (PET) and to evaluate its ability to predict the therapeutic response. Procedures: Eighteen NSIP patients were included. Maximum standardized uptake value (SUV max ), FDG uptake extent (in percentage of lung volume), high resolution CT scan (HRCT) elementary lesions, and HRCT fibrosis score were recorded. The predictive value of the parameters for lung function improvement was evaluated using logistic regression and Receiver Operating Characteristic (ROC) curve analysis (n = 13/18). Results: All patients had an increased pulmonary FDG uptake (median SUV max = 3.1 [2–7.6]), with a median extent of 19% [6–67]. Consolidations, ground-glass opacities, honeycombing and reticulations showed uptake in 90%, 89%, 85% and 76%, respectively. FDG uptake extent was associated with improvement of pulmonary function under treatment (increase in forced vital capacity > 10%, p = 0.03), whereas SUV max and HRCT fibrosis score were not (p > 0.5). For FDG uptake extent, ROC analysis showed an area under the curve at 0.85 ± 0.11 and sensitivity/specificity was 88%/80% for a threshold fixed at 21%. Conclusions: Increased FDG uptake was observed in all NSIP patients, both in inflammatory and fibrotic HRCT lesions. The quantification of FDG uptake extent might be useful to predict functional improvement under treatment.

  20. Localized persistent pulmonary interstitial emphysema in a preterm infant in the absence of mechanical ventilation

    International Nuclear Information System (INIS)

    Berk, David R.; Varich, Laura J.

    2005-01-01

    Localized persistent pulmonary interstitial emphysema has rarely been reported in preterm infants in the absence of utilization of mechanical ventilation or continuous positive airway pressure. The relative rarity of this condition might preclude rendering of the correct diagnosis, making patients susceptible to unnecessary surgery and increased morbidity and mortality associated with such intervention. We present a preterm infant who developed respiratory distress and radiographic findings of pulmonary interstitial emphysema on the first day after birth, prior to receiving continuous positive airway pressure or mechanical ventilation. It is important for radiologists to consider localized persistent pulmonary interstitial emphysema in the differential diagnosis of cystic lung lesions in preterm infants, even in the absence of mechanical ventilation. In cases where there is uncertainty, CT imaging can be useful in making the correct diagnosis. (orig.)

  1. Localized persistent pulmonary interstitial emphysema in a preterm infant in the absence of mechanical ventilation

    Energy Technology Data Exchange (ETDEWEB)

    Berk, David R. [Stanford University School of Medicine, Division of Pediatric Radiology, CA (United States); Lucile Packard Children' s Hospital, Stanford, CA (United States); Varich, Laura J. [Stanford University School of Medicine, Division of Pediatric Radiology, CA (United States); Stanford University School of Medicine, Department of Radiology, CA (United States); Lucile Packard Children' s Hospital, Stanford, CA (United States)

    2005-12-01

    Localized persistent pulmonary interstitial emphysema has rarely been reported in preterm infants in the absence of utilization of mechanical ventilation or continuous positive airway pressure. The relative rarity of this condition might preclude rendering of the correct diagnosis, making patients susceptible to unnecessary surgery and increased morbidity and mortality associated with such intervention. We present a preterm infant who developed respiratory distress and radiographic findings of pulmonary interstitial emphysema on the first day after birth, prior to receiving continuous positive airway pressure or mechanical ventilation. It is important for radiologists to consider localized persistent pulmonary interstitial emphysema in the differential diagnosis of cystic lung lesions in preterm infants, even in the absence of mechanical ventilation. In cases where there is uncertainty, CT imaging can be useful in making the correct diagnosis. (orig.)

  2. Didecyldimethylammonium chloride induces pulmonary inflammation and fibrosis in mice.

    Science.gov (United States)

    Ohnuma, Aya; Yoshida, Toshinori; Tajima, Haruka; Fukuyama, Tomoki; Hayashi, Koichi; Yamaguchi, Satoru; Ohtsuka, Ryoichi; Sasaki, Junya; Fukumori, Junko; Tomita, Mariko; Kojima, Sayuri; Takahashi, Naofumi; Takeuchi, Yukiko; Kuwahara, Maki; Takeda, Makio; Kosaka, Tadashi; Nakashima, Nobuaki; Harada, Takanori

    2010-11-01

    Didecyldimethylammonium chloride (DDAC) is used worldwide as a germicide, in antiseptics, and as a wood preservative, and can cause adverse pulmonary disease in humans. However, the pulmonary toxicity of DDAC has not yet been thoroughly investigated. Mice were intratracheally instilled with DDAC to the lung and the bronchoalveolar lavage (BAL) fluid and lung tissues were collected to assess dose- and time-related pulmonary injury. Exposure to 1500 μg/kg of DDAC caused severe morbidity with pulmonary congestive oedema. When the BAL fluid from survivors was examined on day 3 after treatment, exposure to 150 μg/kg of DDAC caused weakly induced inflammation, and exposure to 15μg/kg did not cause any visible effects. Next, we observed pulmonary changes that occurred up to day 20 after 150 μg/kg of DDAC exposure. Pulmonary inflammation peaked on day 7 and was confirmed by expression of interleukin-6, monocyte chemotactic protein-1, macrophage inflammatory protein (MIP)-1α, MIP-1β, and regulated upon activation, normal T-cell expressed and secreted in the BAL fluid; these changes were accompanied by altered gene expression of their chemokine (C-C motif) receptor (Ccr) 1, Ccr2, Ccr3, and Ccr5. Cytotoxicity evoked by DDAC was related to the inflammatory changes and was confirmed by an in vitro study using isolated mouse lung fibroblasts. The inflammatory phase was accompanied or followed by pulmonary remodeling, i.e., fibrosis, which was evident in the mRNA expression of type I procollagen. These results suggest that administering DDAC by intratracheal instillation causes pulmonary injury in mice, and occupational exposure to DDAC might be a potential hazard to human health. Copyright © 2009 Elsevier GmbH. All rights reserved.

  3. Short-Term Pulmonary Function Trends Are Predictive of Mortality in Interstitial Lung Disease Associated With Systemic Sclerosis.

    Science.gov (United States)

    Goh, Nicole S; Hoyles, Rachel K; Denton, Christopher P; Hansell, David M; Renzoni, Elisabetta A; Maher, Toby M; Nicholson, Andrew G; Wells, Athol U

    2017-08-01

    To determine the prognostic value of pulmonary function test (PFT) trends at 1 and 2 years in interstitial lung disease (ILD) associated with systemic sclerosis (SSc). The prognostic significance of PFT trends at 1 year (n = 162) and 2 years (n = 140) was examined against 15-year survival in patients with SSc-associated ILD. PFT trends, expressed as continuous change and as categorical change in separate analyses, were examined against mortality in univariate and multivariate models. SSc-associated ILD was defined at presentation as either limited lung fibrosis or extensive lung fibrosis, using the United Kingdom Raynaud's and Scleroderma Association severity staging system. One-year PFT trends were predictive of mortality only in patients with extensive lung fibrosis: categorical change in the forced vital capacity (FVC), alone or in combination with categorical change in the diffusing capacity for carbon monoxide (DLco), had greater prognostic significance than continuous change in the FVC or trends in other PFT variables. Taking into account both prognostic value and sensitivity to change, the optimal definition of progression for trial purposes was an FVC and DLco composite end point, consisting of either an FVC decline from baseline of ≥10% or an FVC decline of 5-9% in association with a DLco decline of ≥15%. At 2 years, gas transfer trends had the greatest prognostic significance, in the whole cohort and in those with limited lung fibrosis. However, in patients with extensive lung fibrosis, the above-defined FVC and DLco composite end point was the strongest prognostic determinant. Larger changes in the FVC:DLco ratio than in the carbon monoxide transfer coefficient were required to achieve prognostic significance. Based on linkages to long-term outcomes, these findings provide support for use of routine spirometry and gas transfer monitoring in patients with SSc-associated ILD, with further evaluation of a composite FVC and DLco end point

  4. Effects of leflunomide on inflamation and fibrosis in bleomycine induced pulmonary fibrosis in wistar albino rats.

    Science.gov (United States)

    Kayhan, Servet; Guzel, Aygul; Duran, Latif; Tutuncu, Serife; Guzel, Ahmet; Gunaydın, Mithat; Salis, Osman; Okuyucu, Ali; Selcuk, Mustafa Yasin

    2013-10-01

    Pulmonary fibrosis is a rare and progressive lung disease with a high mortality rate. The treatment regimens still fail to recover the disease. Leflunomide (LEF) is an immunomodulatory agent with antiproliferative activity that is used for the treatment of rheumatoid arthritis. The purpose of the study is to investigate the potential therapeutic efficacy of LEF in bleomycin (BLM) induced pulmonary fibrosis. A total of 21 male, adult wistar albino rats were used. The animals were divided into three groups as control, BLM and BLM plus LEF groups (n=7). In BLM group, mice were treated with intratracheal instillation of BLM (2.5 U/kg). Control group received the same volume of saline instead of BLM. In LEF group, in addition to BLM, LEF (10 mg/kg, daily) was administrated by oral gavage. The effect of LEF on pulmonary inflammation and fibrosis was studied by measurements of serum clara cell protein-16 (CC-16), thiobarbituric acid reactive substance levels (TBARS), superoxide dismutase (SOD) and advanced oxidation protein products (AOPP) levels and lung tissue contents of IL-6, TNF-α and NF-κB by immunhistochemical examinations. LEF significantly increased the level of CC-16 and decreased the level of AOPP (P=0.042 and P=0.003 respectively). Lung tissue contents of IL-6, TNF-α and NF-κB significantly decreased in LEF group compared to BLM group by immunhistochemical examinations (P<0.001). LEF reduces oxidative stress factors, alveolar inflammation and attenuates lung injury and fibrosis.

  5. Effects of Dietary Salt Restriction on Renal Progression and Interstitial Fibrosis in Adriamycin Nephrosis

    Directory of Open Access Journals (Sweden)

    Joon-Sung Park

    2014-07-01

    Full Text Available Background/Aims: Although high salt intake is thought to accelerate renal progression in proteinuric kidney disease, it is not known whether strict dietary salt restriction could delay renal inflammation and interstitial fibrosis. Here, we sought to answer this question in a rat model of adriamycin-induced nephrotic syndrome. Methods: Adriamycin was administered via the femoral vein in a single bolus (7.5 mg/kg, and the rats were put on a sodium-deficient rodent diet. Rats with intact kidneys were studied for 5 weeks (experiment 1, and uninephrectomized rats were studied for 6 weeks (experiment 2. Results: In experiment 1, restricting salt intake improved renal tubulointerstitial histopathology in adriamycin-treated rats. Immunohistochemical and immunoblot results additionally showed that restricting dietary salt lowered adriamycin-induced expression of osteopontin, collagen III, and fibronectin. In experiment 2, salt restriction improved adriamycin-induced azotemia, although it did not affect proteinuria or blood pressure. Dietary salt restriction also reduced adriamycin-induced infiltration of ED1-positive cells and the upregulated expression of osteopontin and a-SMA. Masson's trichrome and Sirius red staining revealed that salt restriction slowed Adriamycin-induced progression of renal interstitial fibrosis. Finally, qPCR revealed that adriamycin-induced expression of TNF-a, IκB-a, gp91phox, p47phox, and p67phox mRNA was blocked by salt restriction. Conclusion: Our findings demonstrate that strict dietary salt restriction delays the progress of renal inflammation and fibrosis in proteinuric kidney disease, most likely via relieving the reactive oxygen species-mediated NF-κB activation.

  6. Pulmonary Artery Occlusion and Mediastinal Fibrosis in a Patient on Dopamine Agonist Treatment for Hyperprolactinemia

    DEFF Research Database (Denmark)

    Su, Junjing; Simonsen, Ulf; Carlsen, Jørn

    2017-01-01

    Unusual forms of pulmonary hypertension include pulmonary hypertension related to mediastinal fibrosis and the use of serotonergic drugs. Here, we describe a patient with diffuse mediastinal fibrosis and pulmonary hypertension while she was on dopamine agonist therapy. A young woman, who...... and ventilation/perfusion (V/Q) scintigraphy, chronic thromboembolic pulmonary hypertension (CTEPH) was initially considered the most plausible diagnosis. However, during an attempted pulmonary endarterectomy, loose fibrous tissues were observed in the mediastinum and cryosection of the right pulmonary artery...... showed fibrosis and chronic inflammation. Subsequent investigations revealed that diffuse mediastinal fibrosis with concurrent pulmonary hypertension, and not CTEPH, was the most likely diagnosis and cabergoline and bromocriptine may have triggered the fibrotic changes. Both drugs are ergot...

  7. Intravenous antibiotics for pulmonary exacerbations in people with cystic fibrosis.

    Science.gov (United States)

    Hurley, Matthew N; Prayle, Andrew P; Flume, Patrick

    2015-07-30

    Cystic fibrosis is a multi-system disease characterised by the production of thick secretions causing recurrent pulmonary infection, often with unusual bacteria. Intravenous antibiotics are commonly used in the treatment of acute deteriorations in symptoms (pulmonary exacerbations); however, recently the assumption that exacerbations are due to increases in bacterial burden has been questioned. To establish if intravenous antibiotics for the treatment of pulmonary exacerbations in people with cystic fibrosis improve short- and long-term clinical outcomes. We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews and ongoing trials registers.Date of last search of Cochrane trials register: 27 July 2015. Randomised controlled trials and the first treatment cycle of cross-over studies comparing intravenous antibiotics (given alone or in an antibiotic combination) with placebo, inhaled or oral antibiotics for people with cystic fibrosis experiencing a pulmonary exacerbation. The authors assessed studies for eligibility and risk of bias and extracted data. We included 40 studies involving 1717 participants. The quality of the included studies was largely poor and, with a few exceptions, these comprised of mainly small, inadequately reported studies.When comparing treatment with a single antibiotic to a combined antibiotic regimen, those participants receiving a combination of antibiotics experienced a greater improvement in lung function when considered as a whole group across a number of different measurements of lung function, but with very low quality evidence. When limited to the four placebo-controlled studies (n = 214), no difference was observed, again with very low quality evidence. With regard to the review's remaining primary outcomes, there was no effect upon time to next exacerbation and

  8. A new direction in the pathogenesis of idiopathic pulmonary fibrosis?

    Directory of Open Access Journals (Sweden)

    Kolb Martin

    2002-01-01

    Full Text Available Abstract A recent review article suggested that idiopathic pulmonary fibrosis (IPF is a disease that is associated more with abnormal wound healing than with inflammation. Data derived from transgenic and gene transfer rodent models suggest that lung inflammation may be a necessary but insufficient component of IPF, and that at some point in the natural history of the disease IPF becomes no longer dependent on the inflammatory response for propagation. Altered microenvironment and involvement of epithelial cell/mesenchymal cell interaction are the most likely contributors to the pathogenesis of this chronic progressive disorder.

  9. GHK Peptide Inhibits Bleomycin-Induced Pulmonary Fibrosis in Mice by Suppressing TGFβ1/Smad-Mediated Epithelial-to-Mesenchymal Transition

    Directory of Open Access Journals (Sweden)

    Xiao-Ming Zhou

    2017-12-01

    Full Text Available Objective: Idiopathic pulmonary fibrosis is an irreversible and progressive fibrotic lung disease that leads to declines in pulmonary function and, eventually, respiratory failure and has no effective treatment. Gly-His-Lys (GHK is a tripeptide involved in the processes of tissue regeneration and wound healing and has significant inhibitory effects on transforming growth factor (TGF-β1 secretion. The effect of GHK on fibrogenesis in pulmonary fibrosis and the exact underlying mechanism have not been studied previously. Thus, this study investigated the effects of GHK on bleomycin (BLM-induced fibrosis and identified the pathway that is potentially responsible for these effects.Methods: Intratracheal injections of 3 mg/kg BLM were administered to induce pulmonary fibrosis in C57BL/6 mice. GHK was administered intraperitoneally at doses of 2.6, 26, and 260 μg/ml/day every other day from the 4th to the 21st day after BLM instillation. Three weeks after BLM instillation, pulmonary injury and pulmonary fibrosis was evaluated by the hematoxylin-eosin (HE and Masson’s trichrome (MT staining. Chronic inflammation index was used for the histological assessments by two pathologists blindly to each other. Tumor necrosis factor (TNF-α and IL-6 levels in BALF and myeloperoxidase (MPO activity in lung extracts were measured. For the pulmonary fibrosis evaluation, the fibrosis index calculated based on MT staining, collagen deposition and active TGF-β1 expression detected by ELISA, and the expression of TGF-β1, α-smooth muscle actin (SMA, fibronectin, MMP-9, and TIMP-1 by western blotting. The epithelial mesenchymal transition index, E-cadherin, and vimentin was also detected by western blot. The statistical analysis was performed by one-way ANOVA and the comparison between different groups were performed.Results: Treatment with GHK at all three doses reduced inflammatory cell infiltration and interstitial thickness and attenuated BLM-induced pulmonary

  10. Surgical Outcomes of Lung Cancer Patients with Combined Pulmonary Fibrosis and Emphysema and Those with Idiopathic Pulmonary Fibrosis without Emphysema.

    Science.gov (United States)

    Sato, Seijiro; Koike, Terumoto; Hashimoto, Takehisa; Ishikawa, Hiroyuki; Okada, Akira; Watanabe, Takehiro; Tsuchida, Masanori

    2016-08-23

    Combined pulmonary fibrosis and emphysema (CPFE) is a unique disorder. The aim of this study was to compare the surgical outcomes of lung cancer patients with CPFE and those with idiopathic pulmonary fibrosis (IPF) without emphysema. A total of 1548 patients who underwent surgery for primary lung cancer between January 2001 and December 2012 were retrospectively reviewed. Of the 1548 patients, 55 (3.6%) had CPFE on computed tomography (CT), and 45 (2.9%) had IPF without emphysema. The overall and disease-free 5-year survival rates for patients with CPFE were not significantly worse than those for patients with IPF without emphysema (24.9% vs. 36.8%, p = 0.814; 39.8% vs. 39.3%, p = 0.653, respectively). Overall, 21 (38.1%) patients with CPFE and nine patients (20.0%) with IPF without emphysema developed postoperative cardiopulmonary complications. Patients with CPFE had significantly more postoperative cardiopulmonary complications involving pulmonary air leakage for >6 days, hypoxemia, and arrhythmia than patients with IPF without emphysema (p = 0.048). There was no significant difference in survival after surgical treatment between CPFE patients and IPF patients without emphysema, but CPFE patients had significantly higher morbidity than IPF patients without emphysema.

  11. Volúmenes pulmonares normales en pacientes con fibrosis pulmonar idiopática y enfisema Normal lung volumes in patients with idiopathic pulmonary fibrosis and emphysema

    Directory of Open Access Journals (Sweden)

    Juan Pablo Casas

    2008-08-01

    pattern with hyperinflation results in emphysema by loss of elastic recoil, expiratory collapse of the peripheral airways and air trapping. Previous reports suggest that when both diseases coexist, pulmonary volumes are compensated and a smaller than expected reduction or even normal lung volumes can be found. We report 4 male patients of 64, 60, 73 and 70 years, all with heavy cigarette smoking history and progressive breathlessness. Three of them had severe limitation in their quality of life. All four showed advanced lung interstitial involvement, at high resolution CT scan, fibrotic changes predominantly in the subpleural areas of lower lung fields and concomitant emphysema in the upper lobes. Emphysema and pulmonary fibrosis was confirmed by open lung biopsy in one patient. The four patients showed normal spirometry and lung volumes with severe compromise of gas exchange and poor exercise tolerance evaluated by 6 minute walk test. Severe pulmonary arterial hypertension was also confirmed in three patients. Normal lung volumes does not exclude diagnosis of idiopathic pulmonary fibrosis in patients with concomitant emphysema. The relatively preserved lung volumes may underestimate the severity of idiopathic pulmonary fibrosis and attenuate its effects on lung function parameters.

  12. Protease-activated receptor (PAR)-2 is required for PAR-1 signalling in pulmonary fibrosis

    NARCIS (Netherlands)

    Lin, Cong; von der Thüsen, Jan; Daalhuisen, Joost; ten Brink, Marieke; Crestani, Bruno; van der Poll, Tom; Borensztajn, Keren; Spek, C. Arnold

    2015-01-01

    Idiopathic pulmonary fibrosis is the most devastating diffuse fibrosing lung disease of unknown aetiology. Compelling evidence suggests that both protease-activated receptor (PAR)-1 and PAR-2 participate in the development of pulmonary fibrosis. Previous studies have shown that bleomycin-induced

  13. MMP-7 is a predictive biomarker of disease progression in patients with idiopathic pulmonary fibrosis

    Directory of Open Access Journals (Sweden)

    Yasmina Bauer

    2017-03-01

    Full Text Available Idiopathic pulmonary fibrosis (IPF is a progressive interstitial lung disease with poor prognosis, which is characterised by destruction of normal lung architecture and excessive deposition of lung extracellular matrix. The heterogeneity of disease progression in patients with IPF poses significant obstacles to patient care and prevents efficient development of novel therapeutic interventions. Blood biomarkers, reflecting pathobiological processes in the lung, could provide objective evidence of the underlying disease. Longitudinally collected serum samples from the Bosentan Use in Interstitial Lung Disease (BUILD-3 trial were used to measure four biomarkers (metalloproteinase-7 (MMP-7, Fas death receptor ligand, osteopontin and procollagen type I C-peptide, to assess their potential prognostic capabilities and to follow changes during disease progression in patients with IPF. In baseline BUILD-3 samples, only MMP-7 showed clearly elevated protein levels compared with samples from healthy controls, and further investigations demonstrated that MMP-7 levels also increased over time. Baseline levels of MMP-7 were able to predict patients who had higher risk of worsening and, notably, baseline levels of MMP-7 could predict changes in FVC as early as month 4. MMP-7 shows potential to be a reliable predictor of lung function decline and disease progression.

  14. Idiopathic pulmonary fibrosis in BRIC countries: the cases of Brazil, Russia, India, and China.

    Science.gov (United States)

    Richeldi, Luca; Rubin, Adalberto Sperb; Avdeev, Sergey; Udwadia, Zarir F; Xu, Zuo Jun

    2015-09-24

    Idiopathic pulmonary fibrosis (IPF), the prototype of interstitial lung diseases, has the worst prognosis and is the only interstitial lung disease for which approved pharmacological treatments are available. Despite being considered a rare disease, IPF patients pose major challenges to both physicians and healthcare systems. It is estimated that a large number of IPF patients reside in BRIC countries (Brazil, Russia, India, and China) given their overall total population of approximately 3 billion inhabitants. Nevertheless, the limited availability of chest imaging in BRIC countries is considered a chief obstacle to diagnosis, since high-resolution computed tomography of the chest is the key diagnostic test for IPF. Further, obtaining reliable lung function tests and providing treatment access is difficult in the more rural areas of these countries. However, IPF might represent an opportunity for BRIC countries: the exponentially increasing demand for the enrollment of IPF patients in clinical trials of new drugs is predicted to face a shortage of patients - BRIC countries may thus play a crucial role in advancing towards a cure for IPF.

  15. Identification of Disease Relevant Post Translational Modifications of Proteins in Pulmonary Fibrosis as Novel Biochemical Marker Targets

    DEFF Research Database (Denmark)

    Kristensen, Jacob Hull

    Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung disease and is associated with a heterogeneous occurrence of fibrosis but the cause of the disease is still unknown. There is no cure and the two most promising drug candidates (pirfenidone and nintedanib) only provide limited......AB was selected as the best candidate for the quantification of NE-specific degradation of elastin and ELISA assay development was conducted resulting in the EL-NE assay. The assay was specific towards NE-degraded elastin and the EL-NE neo-epitope with limited reactivity towards intact elastin. Secondly, we...... developed biomarkers for matrix MMP-7 degradation of elastin. The screening and assay development was conducted using similar methodology to EL-NE. The ELM7 mAB was selected as the best candidate for the quantification of MMP-7-specific degradation of elastin. The assay was specific towards MMP-7-degraded...

  16. Smoking-related interstitial lung diseases

    International Nuclear Information System (INIS)

    Marten, K.

    2007-01-01

    The most important smoking-related interstitial lung diseases (ILD) are respiratory bronchiolitis, respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, and Langerhans' cell histiocytosis. Although traditionally considered to be discrete entities, smoking-related ILDs often coexist, thus accounting for the sometimes complex patterns encountered on high-resolution computed tomography (HRCT). Further studies are needed to elucidate the causative role of smoking in the development of pulmonary fibrosis

  17. The Chinese Herbal Medicine Formula mKG Suppresses Pulmonary Fibrosis of Mice Induced by Bleomycin

    Directory of Open Access Journals (Sweden)

    Ying Gao

    2016-02-01

    Full Text Available Pulmonary fibrosis (PF is a serious progressive lung disease and it originates from inflammation-induced parenchymal injury with excessive extracellular matrix deposition to result in the destruction of the normal lung architecture. Modified Kushen Gancao Formula (mKG, derived from traditional Chinese herbal medicine, has a prominent anti-inflammatory effect. The present study is to explore the inhibitory effects of mKG on bleomycin (BLM-induced pulmonary fibrosis in mice. mKG significantly decreased pulmonary alveolitis, fibrosis scores, and interleukin-6 (IL-6, interleukin-17 (IL-17, transforming growth factor-β (TGF-β and hydroxyproline (HYP levels in lung tissue of mice compared with BLM treatment. It markedly alleviated the increase of HYP content in the lung tissues and pathologic changes of pulmonary fibrosis caused by BLM instillation. In conclusion, mKG has an anti-fibrotic effect and might be employed as a therapeutic candidate agent for attenuating pulmonary fibrosis.

  18. The effect of AT1 receptor blockade on bax and bcl-2 expression in bleomycin-induced pulmonary fibrosis

    Directory of Open Access Journals (Sweden)

    L Safaeian

    2009-03-01

    Full Text Available ABSTRACT Background and the purpose of the study: Recent studies have indicated the role of apoptosis and angiotensin in the pathogenesis of bleomycin induced-pulmonary fibrosis. Losartan, an angiotensin type 1 receptor (AT1R antagonist, has ameliorated apoptosis and fibrosis from bleomycin. In this study, alterations in the expression of apoptosis-regulatory genes (bcl-2 and bax were investigated in different cells of lung tissue of mice treated with bleomycin in the presence of losartan. Methods: Losartan (10 mg/kg, i.p. was given to mice two days before administration of bleomycin (3 U/kg and throughout the test period. After two weeks, lung tissues of mice were evaluated for fibrosis by biochemical measurement of collagen deposition and semiquantitative analysis of pathological changes of the lung. The expression of bcl-2 and bax was assessed by immunohistochemical assay using biotin-streptavidin staining method on paraffin-embedded lung tissues. Results and major conclusion: Pre-treatment with losartan significantly (P < 0.05 reduced the increase in lung collagen content and also inhibited the histological changes induced by bleomycin. Immunohistochemical studies showed that losartan significantly (P < 0.05 reduced the bax/bcl-2 expression ratio in the alveolar epithelial cells, lymphocytes, macrophages and interstitial myofibroblasts. Losartan also inhibited the bcl-2 upregulation which was educed by bleomycin in neutrophils. By reduction of bax/bcl-2 ratio as a determinant of susceptibility of a cell to apoptosis, losartan exerted protective effects on the alveolar epithelial cells that may be important in the amelioration of pulmonary fibrosis. These results may help to better understanding of the role of angiotensin II and apoptosis in pulmonary fibrosis.

  19. Influence of radiological emphysema on lung function test in idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Bodlet, Aline; Maury, Gisèle; Jamart, Jacques; Dahlqvist, Caroline

    2013-11-01

    Idiopathic pulmonary fibrosis (IPF) is one of the most frequent interstitial lung disease. Emphysema can be associated with IPF as described in the «Combined pulmonary fibrosis and emphysema» syndrome. The primary endpoint of this retrospective cohort study was to evaluate the impact of the association of IPF and emphysema on lung function tests parameters (FVC, TLC, FEV1, FEV1/FVC and DLCO). The secondary endpoint was to assess the impact of the associated radiological emphysema on lung function parameters used in the du Bois prognostic score recently developed by Ron du Bois et al. We retrospectively reviewed the medical files of 98 patients with lung fibrosis who were followed in our University Hospital with access to pharmacological studies and lung transplantation from 1981 to 2011. Fifty six patients were considered for analysis. The collected data included gender, age, smoking history and respiratory hospitalizations. We also analysed their pulmonary functional parameters along with radiological characteristics, in particular the presence of emphysema which was assessed on thoracic high resolution CT scan. The du Bois score was retrospectively calculated from these data. TLC and FVC at diagnosis were significantly higher in the IPF-E group compared to the IPF group (respectively 86.6 ± 17.2% pv versus 72.0 ± 15.0% pv; p: 0.004 and 86.8 ± 18.4% pv versus 72.6 ± 20.6% pv; p: 0.020). The [Formula: see text] used in the calculation of the du Bois prognostic score was significantly higher in the IPF-E group. By cons, [Formula: see text] was not statistically different between the two groups. Radiological emphysema associated with IPF had an impact on pulmonary function tests. Despite this difference, the du Bois score was not statistically different between these two groups. Nevertheless, after one year of follow up, the patients with emphysema were in a subclass with a lower mortality rate than those without emphysema. Copyright © 2013 Elsevier

  20. Nonspecific interstitial pneumonitis: a common cause of pulmonary disease in the acquired immunodeficiency syndrome

    International Nuclear Information System (INIS)

    Suffredini, A.F.; Ognibene, F.P.; Lack, E.E.

    1987-01-01

    During a 4.4-year period, nonspecific interstitial pneumonitis was seen in 41 of 110 (38%) patients with the acquired immunodeficiency syndrome and accounted for 32% (48/152) of all episodes of clinical pneumonitis. Diffuse alveolar damage was typically a feature of nonspecific interstitial pneumonitis, but neither lung biopsy nor bronchoalveolar lavage detected a pathogen. Of these 41 patients, 13 had no associated pulmonary tumor and had not been exposed to pulmonary toxins, whereas 28 patients had either concurrent pulmonary Kaposi sarcoma, previous experimental therapies, or a history of pneumocystis pneumonia or drug abuse. Of these 41, 23 had normal chest radiographs. The clinical features of patients with nonspecific interstitial pneumonitis were similar to those of patients with pneumocystis pneumonia, although histologic findings showed less severe alveolar damage in patients with nonspecific interstitial pneumonitis (p less than 0.001). Pathologic evaluation and clinical follow-up suggest that many clinical episodes of pneumonitis in patients with the acquired immunodeficiency syndrome are due to nonspecific interstitial pneumonitis of unknown cause

  1. Correlation between HRCT and pulmonary functional tests in cystic fibrosis

    International Nuclear Information System (INIS)

    Mastellari, Paola; Biggi, Simona; Lombardi, Alfonsa; Zompatori, Maurizio; Grzincich, Gianluigi; Pisi, Giovanna; Spaggiari, Cinzia

    2005-01-01

    Purpose. To compare the HRCT score by Oikonottlou and air trapping in expiratory scans with pulmonary functional tests and evaluate which radiological criteria are more useful to predict clinical impairment. Materials and methods. From January to September 2003, pulmonary HRCT study was performed in 37 patients (23 males), aged between 7 and 41 years, with cystic fibrosis. In the same day of CT examination they also received a complete functional evaluation. HRCT studies were evaluated by three radiologists blinded to the clinical data and were correlated with the lung function tests. Results. We obtained a high correlation (p=0.01) for two of the HRCT signs: extent of mucus plugging and mosaic perfusion pattern and all function tests. Discussion. Previous studies have demonstrated good correlation between lung function tests, in particular with FEV1 and HRCT signs. Our study differed from previous ones in that we analysed the correlation between lung function tests and with both single and combined CT criteria. Conclusion. Our results suggest that a simplified HRCT store could be useful to evaluate patients with cystic fibrosis [it

  2. Saffron Protection against Bleomycin-Induced Pulmonary Fibrosis in Rats

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    Mehrzad Bahtouee

    2017-11-01

    Full Text Available Background: Bleomycin-induced lung fibrosis has been accepted as an animal model for fibrosis in rats. The aim of this study was to evaluate the effects of saffron aqueous extract on this disorder paving the way for more investigation in treating idiopathic pulmonary fibrosis in human. Methods: Male Wistar rats (250–300 gr were instilled a single dose of bleomycin (5 mg/kg via intratracheal tube (n=6 in 2015. Sham group received normal saline. Saffron aqueous extract (50 mg/kg and 100 mg/kg were given orally in two different treated groups with bleomycin for 28 days. Lung Indices was calculated at the end of this experiment. Lung segments fixed in 10% formaldehyde were used for pathological preparation with Hematoxylin & Eosin and trichrome staining. Results: The body weight was decreased and lung Indices increased in bleomycin group (P<0.5. Bleomycin administration increased myeloperoxidase, malondialdehyde and finally TNF-α in lung tissue homogenates (P<0.05 compared with sham group. The fibrotic process and thickening of alveolar septa in treated rats with bleomycin were increased by H&E and Masson Trichrome staining. Saffron treatment (50 and 100 mg/kg attenuated the increase in MDA (264.43±10.4 nmol/g by the higher dose versus 378.4±18.1nmol/g, MPO (0.19±0.03 and 0.13± 0.04 IU/ml versus 0.39.2±0.05 IU/ml and TNF-α level (18.42±3.7 ng/ml and14.31±3.6 ng /ml versus 35.32±4.2 in lung homogenates compared to bleomycin group (P<0.05. It decreased collagen accumulation and alveolar destructive patterns in pulmonary fibrosis. Conclusion: This study introduces saffron as novel anti-fibrotic agent against bleomycin-induced fibrosis due to histological examinations and preventive effects on destructive enzyme release in rats.

  3. Pulmonary delivery of docosahexaenoic acid mitigates bleomycin-induced pulmonary fibrosis

    Science.gov (United States)

    2014-01-01

    Background Pulmonary fibrosis is an untreatable, fatal disease characterized by excess deposition of extracellular matrix and inflammation. Although the etiology of pulmonary fibrosis is unknown, recent studies have implicated dysregulated immune responses and wound healing. Since n-3 polyunsaturated fatty acids (n-3 PUFAs) may beneficially modulate immune responses in a variety of inflammatory disorders, we investigated the therapeutic role of docosahexaenoic acid (DHA), a single n-3 PUFA, in lung fibrosis. Methods Intratracheal DHA or PBS was administered to mouse lungs 4 days prior to intratracheal bleomycin treatment. Body weight and survival were monitored for 21 days. Bronchoalveolar fluid (BALF) and lung inflammatory cells, cytokines, eicosanoids, histology and lung function were determined on serial days (0, 3, 7, 14, 21) after bleomycin injury. Results Intratracheal administration of DHA mitigated bleomycin-induced lung injury. Mice pretreated with DHA had significantly less weight loss and mortality after bleomycin injury. The lungs from DHA-pretreated mice had markedly less fibrosis. DHA pretreatment also protected the mice from the functional changes associated with bleomycin injury. Bleomycin-induced cellular inflammation in BALF and lung tissue was blunted by DHA pretreatment. These advantageous effects of DHA pretreatment were associated with decreased IL-6, LTB4, PGE2 and increased IL-10. Conclusions Our findings demonstrate that intratracheal administration of DHA, a single PUFA, protected mice from the development of bleomycin-induced pulmonary inflammation and fibrosis. These results suggest that further investigations regarding the role of n-3 polyunsaturated fatty acids in fibrotic lung injury and repair are needed. PMID:24742272

  4. Quantitative pulmonary gallium scanning in interstitial lung disease

    International Nuclear Information System (INIS)

    Ramsay, S.C.; Yeates, M.G.; Burke, W.M.J.; Morgan, G.W.; Breit, S.N.; Bryant, D.H.

    1992-01-01

    The mechanisms responsible for gallium uptake in chronic, non-infective, diffuse lung disease are not completely understood. This study attempted to clarify some of them. A lung/liver gallium index was calculated in 113 subjects, some normal and some with various interstitial lung diseases, predominantly those associated with connective tissue disease. The mean gallium index was significantly higher in the groups with active interstitial lung disease (5.7) and non-infective bronchiolitis (4.1) compared with non-smoking normals (3.0; P<0.05). To investigate the mechanisms responsible for gallium uptake, the gallium index was correlated with bronchoalveolar lavage findings, respiratory function tests and clinical features. Significant correlations (P<0.05) were found with age in non-smoking normals; lavage macrophages in smoking normals; age but no other parameter in bronchiolitis; lavage lymphocytes, lavage albumin and improvement in diffusion capacity for carbon monoxide in those with active interstitial lung disease. It is concluded that in normal smokers gallium uptake may be due to a macrophage-mediated process. Gallium uptake in active interstitial lung disease associated with connective tissue disease appears to be an immunological process in which transport and retention of gallium is associated with that of albumin. (orig.)

  5. Metformin Reduces Bleomycin-induced Pulmonary Fibrosis in Mice.

    Science.gov (United States)

    Choi, Sun Mi; Jang, An Hee; Kim, Hyojin; Lee, Kyu Hwa; Kim, Young Whan

    2016-09-01

    Metformin has anti-inflammatory and anti-fibrotic effects. We investigated whether metformin has an inhibitory effect on bleomycin (BLM)-induced pulmonary fibrosis in a murine model. A total of 62 mice were divided into 5 groups: control, metformin (100 mg/kg), BLM, and BLM with metformin (50 mg/kg or 100 mg/kg). Metformin was administered to the mice orally once a day from day 1. We sacrificed half of the mice on day 10 and collected the bronchoalveolar lavage fluid (BALF) from their left lungs. The remaining mice were sacrificed and analyzed on day 21. The right lungs were harvested for histological analyses. The messenger RNA (mRNA) levels of epithelial-mesenchymal transition markers were determined via analysis of the harvested lungs on day 21. The mice treated with BLM and metformin (50 mg/kg or 100 mg/kg) showed significantly lower levels of inflammatory cells in the BALF compared with the BLM-only mice on days 10 and 21. The histological examination revealed that the metformin treatment led to a greater reduction in inflammation than the treatment with BLM alone. The mRNA levels of collagen, collagen-1, procollagen, fibronectin, and transforming growth factor-β in the metformin-treated mice were lower than those in the BLM-only mice on day 21, although statistical significance was observed only in the case of procollagen due to the small number of live mice in the BLM-only group. Additionally, treatment with metformin reduced fibrosis to a greater extent than treatment with BLM alone. Metformin suppresses the inflammatory and fibrotic processes of BLM-induced pulmonary fibrosis in a murine model.

  6. Pulmonary manifestations in scleroderma: A review | Genga | African ...

    African Journals Online (AJOL)

    The most common symptoms are dry cough and dyspnea on exertion. The high morbidity and mortality seen in SSc is generally attributed to the two major pulmonary manifestations of the disease: interstitial pulmonary fibrosis, or interstitial lung disease, and pulmonary arterial hypertension. Exertional dyspnea and dry ...

  7. Volatile Organic Compounds in Exhaled Breath of Idiopathic Pulmonary Fibrosis for Discrimination from Healthy Subjects.

    Science.gov (United States)

    Yamada, Yu-Ichi; Yamada, Gen; Otsuka, Mitsuo; Nishikiori, Hirotaka; Ikeda, Kimiyuki; Umeda, Yasuaki; Ohnishi, Hirofumi; Kuronuma, Koji; Chiba, Hirofumi; Baumbach, Jörg Ingo; Takahashi, Hiroki

    2017-04-01

    Purpose Human breath analysis is proposed with increasing frequency as a useful tool in clinical application. We performed this study to find the characteristic volatile organic compounds (VOCs) in the exhaled breath of patients with idiopathic pulmonary fibrosis (IPF) for discrimination from healthy subjects. Methods VOCs in the exhaled breath of 40 IPF patients and 55 healthy controls were measured using a multi-capillary column and ion mobility spectrometer. The patients were examined by pulmonary function tests, blood gas analysis, and serum biomarkers of interstitial pneumonia. Results We detected 85 VOC peaks in the exhaled breath of IPF patients and controls. IPF patients showed 5 significant VOC peaks; p-cymene, acetoin, isoprene, ethylbenzene, and an unknown compound. The VOC peak of p-cymene was significantly lower (p VOC peaks of acetoin, isoprene, ethylbenzene, and the unknown compound were significantly higher (p VOC peaks with clinical parameters, negative correlations with VC (r =-0.393, p = 0.013), %VC (r =-0.569, p VOCs in the exhaled breath of IPF patients. Among them, the VOC peaks of p-cymene were related to the clinical parameters of IPF. These VOCs may be useful biomarkers of IPF.

  8. A comparison of published multidimensional indices to predict outcome in idiopathic pulmonary fibrosis

    Directory of Open Access Journals (Sweden)

    Charles Sharp

    2017-03-01

    Full Text Available Idiopathic pulmonary fibrosis (IPF has an unpredictable course and prognostic factors are incompletely understood. We aimed to identify prognostic factors, including multidimensional indices from a significant IPF cohort at the Bristol Interstitial Lung Disease Centre in the UK. Patients diagnosed with IPF between 2007 and 2014 were identified. Longitudinal pulmonary physiology and exercise testing results were collated, with all-cause mortality used as the primary outcome. Factors influencing overall, 12- and 24-month survival were identified using Cox proportional hazards modelling and receiver operating characteristic curve analysis. We found in this real-world cohort of 167 patients, diffusing capacity for carbon monoxide (DLCO and initiation of long-term oxygen were independent markers of poor prognosis. Exercise testing results predicted 12-month mortality as well as DLCO, but did not perform as well for overall survival. The Composite Physiological Index was the best performing multidimensional index, but did not outperform DLCO. Our data confirmed that patients who experienced a fall in forced vital capacity (FVC >10% had significantly worse survival after that point (p=0.024. Our data from longitudinal follow-up in IPF show that DLCO is the best individual prognostic marker, outperforming FVC. Exercise testing is important in predicting early poor outcome. Regular and complete review should be conducted to ensure appropriate care is delivered in a timely fashion.

  9. Vildagliptin ameliorates pulmonary fibrosis in lipopolysaccharide-induced lung injury by inhibiting endothelial-to-mesenchymal transition.

    Science.gov (United States)

    Suzuki, Toshio; Tada, Yuji; Gladson, Santhi; Nishimura, Rintaro; Shimomura, Iwao; Karasawa, Satoshi; Tatsumi, Koichiro; West, James

    2017-10-16

    Pulmonary fibrosis is a late manifestation of acute respiratory distress syndrome (ARDS). Sepsis is a major cause of ARDS, and its pathogenesis includes endotoxin-induced vascular injury. Recently, endothelial-to-mesenchymal transition (EndMT) was shown to play an important role in pulmonary fibrosis. On the other hand, dipeptidyl peptidase (DPP)-4 was reported to improve vascular dysfunction in an experimental sepsis model, although whether DPP-4 affects EndMT and fibrosis initiation during lipopolysaccharide (LPS)-induced lung injury is unclear. The aim of this study was to investigate the anti-EndMT effects of the DPP-4 inhibitor vildagliptin in pulmonary fibrosis after systemic endotoxemic injury. A septic lung injury model was established by intraperitoneal injection of lipopolysaccharide (LPS) in eight-week-old male mice (5 mg/kg for five consecutive days). The mice were then treated with vehicle or vildagliptin (intraperitoneally, 10 mg/kg, once daily for 14 consecutive days from 1 day before the first administration of LPS.). Flow cytometry, immunohistochemical staining, and quantitative polymerase chain reaction (qPCR) analysis was used to assess cell dynamics and EndMT function in lung samples from the mice. Lung tissue samples from treated mice revealed obvious inflammatory reactions and typical interstitial fibrosis 2 days and 28 days after LPS challenge. Quantitative flow cytometric analysis showed that the number of pulmonary vascular endothelial cells (PVECs) expressing alpha-smooth muscle actin (α-SMA) or S100 calcium-binding protein A4 (S100A4) increased 28 days after LPS challenge. Similar increases in expression were also confirmed by qPCR of mRNA from isolated PVECs. EndMT cells had higher proliferative activity and migration activity than mesenchymal cells. All of these changes were alleviated by intraperitoneal injection of vildagliptin. Interestingly, vildagliptin and linagliptin significantly attenuated EndMT in the absence of immune

  10. Recent advances in understanding idiopathic pulmonary fibrosis [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Cécile Daccord

    2016-05-01

    Full Text Available Despite major research efforts leading to the recent approval of pirfenidone and nintedanib, the dismal prognosis of idiopathic pulmonary fibrosis (IPF remains unchanged. The elaboration of international diagnostic criteria and disease stratification models based on clinical, physiological, radiological, and histopathological features has improved the accuracy of IPF diagnosis and prediction of mortality risk. Nevertheless, given the marked heterogeneity in clinical phenotype and the considerable overlap of IPF with other fibrotic interstitial lung diseases (ILDs, about 10% of cases of pulmonary fibrosis remain unclassifiable. Moreover, currently available tools fail to detect early IPF, predict the highly variable course of the disease, and assess response to antifibrotic drugs.   Recent advances in understanding the multiple interrelated pathogenic pathways underlying IPF have identified various molecular phenotypes resulting from complex interactions among genetic, epigenetic, transcriptional, post-transcriptional, metabolic, and environmental factors. These different disease endotypes appear to confer variable susceptibility to the condition, differing risks of rapid progression, and, possibly, altered responses to therapy. The development and validation of diagnostic and prognostic biomarkers are necessary to enable a more precise and earlier diagnosis of IPF and to improve prediction of future disease behaviour. The availability of approved antifibrotic therapies together with potential new drugs currently under evaluation also highlights the need for biomarkers able to predict and assess treatment responsiveness, thereby allowing individualised treatment based on risk of progression and drug response. This approach of disease stratification and personalised medicine is already used in the routine management of many cancers and provides a potential road map for guiding clinical care in IPF.

  11. Translation to Spanish and Validation of the Specific Saint George's Questionnaire for Idiopathic Pulmonary Fibrosis.

    Science.gov (United States)

    Capparelli, Ignacio; Fernandez, Martín; Saadia Otero, Marcela; Steimberg, Jimena; Brassesco, María; Campobasso, Ana; Palacios, Sandra; Caro, Fabian; Alberti, María Laura; Rabinovich, Roberto A; Paulin, Francisco

    2018-02-01

    Interstitial lung disease (ILD) is associated with low exercise tolerance, dyspnea, and decreased health-related quality of life (HRQL). Idiopathic pulmonary fibrosis (IPF) is one of the most prevalent in the group. A specific version of the Saint George's questionnaire (SGRQ-I) has been developed to quantify the HRQL of IPF patients. However, this tool is not currently validated in the Spanish language. The objective was to translate into Spanish and validate the specific Saint George's Respiratory Questionnaire for idiopathic pulmonary fibrosis (SGRQ-I). The repeatability, internal consistency and construct validity of the SGRQ-I in Spanish were analyzed after a backtranslation process. In total, 23 outpatients with IPF completed the translated SGRQ-I twice, 7 days apart. Repeatability was studied, revealing good concordance in test-retest with an ICC (interclass correlation coefficient) of 0.96 (P<.001). Internal consistency was good for different questionnaire items (Cronbach's alpha of 0.9 including and 0.81 excluding the total value) (P<.001). The total score of the questionnaire showed good correlation with forced vital capacity FVC% (r=-0.44; P=.033), diffusing capacity of the lungs for carbon monoxide (DL CO %) (r=-0.55; P=.011), partial pressure of oxygen in arterial blood PaO 2 (r=-0.44; P=.036), Medical Research Council Dyspnea scale (r=-0.65; P<.001), and number of steps taken in 24hours (r=-0.47; P=.024). The Spanish version of SGRQ-Ideveloped by our group shows good internal consistency, reproducibility and validity, so it can be used for the evaluation of quality of life (QOL) in IPF patients. Copyright © 2017 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.

  12. New perspectives on management of idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Puglisi, Silvia; Torrisi, Sebastiano Emanuele; Vindigni, Virginia; Giuliano, Riccardo; Palmucci, Stefano; Mulè, Massimiliano; Vancheri, Carlo

    2016-03-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive parenchymal lung disease characterized by a median survival of 3-5 years following diagnosis. The diagnosis is based on clinical, radiological and histopathological evaluation. Therefore, a multidisciplinary team is needed to reach the correct diagnosis. For a long time, supportive care and lung transplantation in selected cases, have been considered the only possible treatments for IPF. In the last decade many studies have investigated IPF pathogenesis, leading to an improved knowledge of the mechanisms underlying the disease and to the approval of two new drugs for IPF treatment (pirfenidone and nintedanib). The therapeutic approach of IPF cannot be limited to the administration of antifibrotic drugs, but it is necessary for improving the quality of life of patients and for facilitating, as far as possible, the performance of normal daily activities and relationships. IPF patients are also afflicted by disease-related complications such as gastroesophageal reflux, pulmonary hypertension, acute exacerbations and an increased risk of developing lung cancer. The clinician who treats IPF patients, should also treat these possible complications to slow disease progression, thus maintaining the possibility of a pulmonary transplantation.

  13. High endogenous activated protein C levels attenuates bleomycin-induced pulmonary fibrosis.

    Science.gov (United States)

    Lin, Cong; von der Thüsen, Jan; Isermann, Berend; Weiler, Hartmut; van der Poll, Tom; Borensztajn, Keren; Spek, Chris A

    2016-11-01

    Coagulation activation accompanied by reduced anticoagulant activity is a key characteristic of patients with idiopathic pulmonary fibrosis (IPF). Although the importance of coagulation activation in IPF is well studied, the potential relevance of endogenous anticoagulant activity in IPF progression remains elusive. We assess the importance of the endogenous anticoagulant protein C pathway on disease progression during bleomycin-induced pulmonary fibrosis. Wild-type mice and mice with high endogenous activated protein C APC levels (APC high ) were subjected to bleomycin-induced pulmonary fibrosis. Fibrosis was assesses by hydroxyproline and histochemical analysis. Macrophage recruitment was assessed immunohistochemically. In vitro, macrophage migration was analysed by transwell migration assays. Fourteen days after bleomycin instillation, APC high mice developed pulmonary fibrosis to a similar degree as wild-type mice. Interestingly, Aschcroft scores as well as lung hydroxyproline levels were significantly lower in APC high mice than in wild-type mice on day 28. The reduction in fibrosis in APC high mice was accompanied by reduced macrophage numbers in their lungs and subsequent in vitro experiments showed that APC inhibits thrombin-dependent macrophage migration. Our data suggest that high endogenous APC levels inhibit the progression of bleomycin-induced pulmonary fibrosis and that APC modifies pulmonary fibrosis by limiting thrombin-dependent macrophage recruitment. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  14. The diffuse interstitial lung disease - with emphasis in the idiopathic interstitial pneumonias

    International Nuclear Information System (INIS)

    Bustillo P, Jose G; Pacheco, Pedro M; Matiz, Carlos; Ojeda, Paulina; Carrillo B, Jorge A.

    2003-01-01

    The term diffuse interstitial lung disease, it refers to those diseases that commit the interstice basically, the space between the membrane basal epithelial and endothelial, although the damage can also commit the outlying air spaces and the vessels; the supplement is centered in the diffuse interstitial lung illness of unknown cause; well-known as idiopathic interstitial pneumonias, making emphasis in the more frequents, the pulmonary fibrosis idiopathic or cryptogenic fibrosant alveolitis

  15. DNaseI Protects against Paraquat-Induced Acute Lung Injury and Pulmonary Fibrosis Mediated by Mitochondrial DNA

    Directory of Open Access Journals (Sweden)

    Guo Li

    2015-01-01

    Full Text Available Background. Paraquat (PQ poisoning is a lethal toxicological challenge that served as a disease model of acute lung injury and pulmonary fibrosis, but the mechanism is undetermined and no effective treatment has been discovered. Methods and Findings. We demonstrated that PQ injures mitochondria and leads to mtDNA release. The mtDNA mediated PBMC recruitment and stimulated the alveolar epithelial cell production of TGF-β1 in vitro. The levels of mtDNA in circulation and bronchial alveolar lavage fluid (BALF were elevated in a mouse of PQ-induced lung injury. DNaseI could protect PQ-induced lung injury and significantly improved survival. Acute lung injury markers, such as TNFα, IL-1β, and IL-6, and marker of fibrosis, collagen I, were downregulated in parallel with the elimination of mtDNA by DNaseI. These data indicate a possible mechanism for PQ-induced, mtDNA-mediated lung injury, which may be shared by other causes of lung injury, as suggested by the same protective effect of DNaseI in bleomycin-induced lung injury model. Interestingly, increased mtDNA in the BALF of patients with amyopathic dermatomyositis-interstitial lung disease can be appreciated. Conclusions. DNaseI targeting mtDNA may be a promising approach for the treatment of PQ-induced acute lung injury and pulmonary fibrosis that merits fast tracking through clinical trials.

  16. Loss of Matrix Metalloproteinase-13 Attenuates Murine Radiation-Induced Pulmonary Fibrosis

    International Nuclear Information System (INIS)

    Flechsig, Paul; Hartenstein, Bettina; Teurich, Sybille; Dadrich, Monika; Hauser, Kai; Abdollahi, Amir; Groene, Hermann-Josef; Angel, Peter; Huber, Peter E.

    2010-01-01

    Purpose: Pulmonary fibrosis is a disorder of the lungs with limited treatment options. Matrix metalloproteinases (MMPs) constitute a family of proteases that degrade extracellular matrix with roles in fibrosis. Here we studied the role of MMP13 in a radiation-induced lung fibrosis model using a MMP13 knockout mouse. Methods and Materials: We investigated the role of MMP13 in lung fibrosis by investigating the effects of MMP13 deficiency in C57Bl/6 mice after 20-Gy thoracic irradiation (6-MV Linac). The morphologic results in histology were correlated with qualitative and quantitative results of volume computed tomography (VCT), magnetic resonance imaging (MRI), and clinical outcome. Results: We found that MMP13 deficient mice developed less pulmonary fibrosis than their wildtype counterparts, showed attenuated acute pulmonary inflammation (days after irradiation), and a reduction of inflammation during the later fibrogenic phase (5-6 months after irradiation). The reduced fibrosis in MMP13 deficient mice was evident in histology with reduced thickening of alveolar septi and reduced remodeling of the lung architecture in good correlation with reduced features of lung fibrosis in qualitative and quantitative VCT and MRI studies. The partial resistance of MMP13-deficient mice to fibrosis was associated with a tendency towards a prolonged mouse survival. Conclusions: Our data indicate that MMP13 has a role in the development of radiation-induced pulmonary fibrosis. Further, our findings suggest that MMP13 constitutes a potential drug target to attenuate radiation-induced lung fibrosis.

  17. Deficiency of developmental endothelial locus-1 (Del-1) aggravates bleomycin-induced pulmonary fibrosis in mice.

    Science.gov (United States)

    Kang, Yoon-Young; Kim, Dong-Young; Lee, Seung-Hwan; Choi, Eun Young

    2014-03-07

    Pulmonary fibrosis is a lung disease wherein lung parenchyma is gradually and irreversibly replaced with collagen. The molecular pathogenesis of pulmonary fibrosis is not fully understood and the only effective treatment available is lung transplantation. To test if Del-1, an endogenous anti-inflammatory molecule, may be implicated in the development of pulmonary fibrosis, we induced pulmonary fibrosis in wild type (WT) and Del-1(-/-) mice by intratracheal administration of bleomycin. Del-1 expression in the lung was decreased in the WT mice treated with bleomycin compared to control mice. In addition, bleomycin-induced pulmonary fibrosis increased collagen deposition and TGF-β production in the lung of Del-1(-/-) mice. Finally, Del-1(-/-) mice treated with bleomycin displayed higher weight loss and greater mortality than did WT mice identically treated. These findings suggest that Del-1 may negatively regulate development of pulmonary fibrosis. Further delineation of a role for Del-1 in the development of pulmonary fibrosis will broaden our understanding of the molecular pathogenesis of this disease and hopefully help develop potential therapeutics. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Development and time-course of bleomycin-induced pulmonary fibrosis in NMRI mice

    Directory of Open Access Journals (Sweden)

    Jafarian-Dehkordi A.

    2007-04-01

    Full Text Available Bleomycin-induced pulmonary fibrosis is a widely used experimental model for human lung fibrosis. The severity of fibrosis varies among different strains of mice and investigation on different strains and finding the mechanisms of variation is important in understanding the pathogenesis of human lung fibrosis. In the present study, NMRI mice were used to investigate the severity and also time-course of bleomycin-induced pulmonary fibrosis in comparison with C57BL/6 mice. After single dose administration of intratracheal bleomycin, the fibrotic response was studied by biochemical measurement of collagen deposition and semiquantitative analysis of pathological lung changes. NMRI mice developed lung fibrosis from 1 to 4 week after bleomycin instillation, with significant increases in lung collagen content and significant morphological changes (P < 0.05. These findings indicate that NMRI mice might be suitable as an experimental model of bleomycin-induced lung fibrosis.

  19. Mesenchymal Stromal Cells in Animal Bleomycin Pulmonary Fibrosis Models: A Systematic Review.

    Science.gov (United States)

    Srour, Nadim; Thébaud, Bernard

    2015-12-01

    Idiopathic pulmonary fibrosis is an inexorably progressive lung disease with few available treatments. New therapeutic options are needed. Stem cells have generated much enthusiasm for the treatment of several conditions, including lung diseases. Human trials of mesenchymal stromal cell (MSC) therapy for pulmonary fibrosis are under way. To shed light on the potential usefulness of MSCs for human disease, we aimed to systematically review the preclinical literature to determine if MSCs are beneficial in animal bleomycin pulmonary fibrosis models. The MEDLINE and Embase databases were searched for original studies of stem cell therapy in animal bleomycin models of pulmonary fibrosis. Studies using embryonic stem cells or induced pluripotent stem cells were excluded. Seventeen studies were selected, all of which used MSCs in rodents. MSC therapy led to an improvement in bleomycin-induced lung collagen deposition in animal lungs and in the pulmonary fibrosis Ashcroft score in most studies. MSC therapy improved histopathology in almost all studies in which it was evaluated qualitatively. Furthermore, MSC therapy was found to improve 14-day survival in animals with bleomycin-induced pulmonary fibrosis. Bronchoalveolar lavage total and neutrophil counts, as well as transforming growth factor-β levels, were also reduced by MSCs. MSCs are beneficial in rodent bleomycin pulmonary fibrosis models. Since most studies examined the initial inflammatory phase rather than the chronic fibrotic phase, preclinical data offer better support for human trials of MSCs in acute exacerbations of pulmonary fibrosis rather than the chronic phase of the disease. There has been increased interest in mesenchymal stromal cell therapy for lung diseases. A few small clinical trials are under way in idiopathic pulmonary fibrosis. Preclinical evidence was assessed in a systematic review, as is often done for clinical studies. The existing studies offer better support for efficacy in the initial

  20. Morphologic and molecular study of lung cancers associated with idiopathic pulmonary fibrosis and other pulmonary fibroses.

    Science.gov (United States)

    Guyard, Alice; Danel, Claire; Théou-Anton, Nathalie; Debray, Marie-Pierre; Gibault, Laure; Mordant, Pierre; Castier, Yves; Crestani, Bruno; Zalcman, Gérard; Blons, Hélène; Cazes, Aurélie

    2017-06-15

    Primitive lung cancers developed on lung fibroses are both diagnostic and therapeutic challenges. Their incidence may increase with new more efficient lung fibrosis treatments. Our aim was to describe a cohort of lung cancers associated with idiopathic pulmonary fibrosis (IPF) and other lung fibrotic disorders (non-IPF), and to characterize their molecular alterations using immunohistochemistry and next-generation sequencing (NGS). Thirty-one cancer samples were collected from 2001 to 2016 in two French reference centers for pulmonary fibrosis - 18 for IPF group and 13 for non-IPF group. NGS was performed using an ampliseq panel to analyze hotspots and targeted regions in 22 cancer-associated genes. ALK, ROS1 and PD-L1 expressions were assessed by immunohistochemistry. Squamous cell carcinoma was the most frequent histologic subtype in the IPF group (44%), adenocarcinoma was the most frequent subtype in the non-IPF group (62%). Forty-one mutations in 13 genes and one EGFR amplification were identified in 25 samples. Two samples had no mutation in the selected panel. Mutations were identified in TP53 (n = 20), MET (n = 4), BRAF (n = 3), FGFR3, PIK3CA, PTEN, STK11 (n = 2), SMAD4, CTNNB1, DDR2, ERBB4, FBXW7 and KRAS (n = 1) genes. No ALK and ROS1 expressions were identified. PD-L1 was expressed in 10 cases (62%) with only one (6%) case >50%. This extensive characterization of lung fibrosis-associated cancers evidenced molecular alterations which could represent either potential therapeutic targets either clues to the pathophysiology of these particular tumors. These findings support the relevance of large molecular characterization of every lung fibrosis-associated cancer.

  1. Pirfenidone safety and adverse event management in idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Lancaster, Lisa H; de Andrade, Joao A; Zibrak, Joseph D; Padilla, Maria L; Albera, Carlo; Nathan, Steven D; Wijsenbeek, Marlies S; Stauffer, John L; Kirchgaessler, Klaus-Uwe; Costabel, Ulrich

    2017-12-31

    Pirfenidone is one of two approved therapies for the treatment of idiopathic pulmonary fibrosis (IPF). Randomised controlled clinical trials and subsequent post hoc analyses have demonstrated that pirfenidone reduces lung function decline, decreases mortality and improves progression-free survival. Long-term extension trials, registries and real-world studies have also shown similar treatment effects with pirfenidone. However, for patients with IPF to obtain the maximum benefits of pirfenidone treatment, the potential adverse events (AEs) associated with pirfenidone need to be managed. This review highlights the well-known and established safety profile of pirfenidone based on randomised controlled clinical trials and real-world data. Key strategies for preventing and managing the most common pirfenidone-related AEs are described, with the goal of maximising adherence to pirfenidone with minimal AEs. Copyright ©ERS 2017.

  2. Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

    Science.gov (United States)

    Mora, Ana L.; Rojas, Mauricio

    2017-01-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic age-related lung disease with high mortality that is characterized by abnormal scarring of the lung parenchyma. There has been a recent attempt to define the age-associated changes predisposing individuals to develop IPF. Age-related perturbations that are increasingly found in epithelial cells and fibroblasts from IPF lungs compared with age-matched cells from normal lungs include defective autophagy, telomere attrition, altered proteostasis, and cell senescence. These divergent processes seem to converge in mitochondrial dysfunction and metabolic distress, which potentiate maladaptation to stress and susceptibility to age-related diseases such as IPF. Therapeutic approaches that target aging processes may be beneficial for halting the progression of disease and improving quality of life in IPF patients. PMID:28145905

  3. Matrix metalloproteinases as therapeutic targets for idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Craig, Vanessa J; Zhang, Li; Hagood, James S; Owen, Caroline A

    2015-11-01

    Idiopathic pulmonary fibrosis (IPF) is a restrictive lung disease that is associated with high morbidity and mortality. Current medical therapies are not fully effective at limiting mortality in patients with IPF, and new therapies are urgently needed. Matrix metalloproteinases (MMPs) are proteinases that, together, can degrade all components of the extracellular matrix and numerous nonmatrix proteins. MMPs and their inhibitors, tissue inhibitors of MMPs (TIMPs), have been implicated in the pathogenesis of IPF based upon the results of clinical studies reporting elevated levels of MMPs (including MMP-1, MMP-7, MMP-8, and MMP-9) in IPF blood and/or lung samples. Surprisingly, studies of gene-targeted mice in murine models of pulmonary fibrosis (PF) have demonstrated that most MMPs promote (rather than inhibit) the development of PF and have identified diverse mechanisms involved. These mechanisms include MMPs: (1) promoting epithelial-to-mesenchymal transition (MMP-3 and MMP-7); (2) increasing lung levels or activity of profibrotic mediators or reducing lung levels of antifibrotic mediators (MMP-3, MMP-7, and MMP-8); (3) promoting abnormal epithelial cell migration and other aberrant repair processes (MMP-3 and MMP-9); (4) inducing the switching of lung macrophage phenotypes from M1 to M2 types (MMP-10 and MMP-28); and (5) promoting fibrocyte migration (MMP-8). Two MMPs, MMP-13 and MMP-19, have antifibrotic activities in murine models of PF, and two MMPs, MMP-1 and MMP-10, have the potential to limit fibrotic responses to injury. Herein, we review what is known about the contributions of MMPs and TIMPs to the pathogenesis of IPF and discuss their potential as therapeutic targets for IPF.

  4. Determinants of pulmonary fibrosis and lipidosis in the silica model.

    Science.gov (United States)

    Heppleston, A. G.

    1986-01-01

    The conditions which might favour development of the fibrotic or the lipid component of the pulmonary reaction to inhaled quartz were examined in rats. Smaller particle size and freedom from surface contamination by amorphous silica or iron oxide, status of the animals whether specific pathogen-free or conventional, and the resistance of cell membranes to damage appeared to bear on fibrogenesis. Increased membrane stability by treatment with polyvinylpyridine-N-oxide abolished not only the fibrosis but also the response of type II cells and hence lipidosis. The rate and intensity of quartz deposition may also affect the response, a low concentration inhaled over a long period favouring nodulation. No other manipulations, environmental or pharmacological, succeeded in inhibiting lipidosis to the benefit of fibrosis. Guinea pigs, however, behaved differently, their reaction being characterized by massive alveolar accumulation of dust-bearing macrophages and type II cell hyperplasia but not by lipidosis. The species variation is unexplained but macrophage predominance may represent a phase that later transforms to lipidosis. The experimental findings may have implications for forms of pneumoconiosis other than silicosis. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:3026427

  5. Naja naja atra venom ameliorates pulmonary fibrosis by inhibiting inflammatory response and oxidative stress.

    Science.gov (United States)

    Cui, Kui; Kou, Jian-Qun; Gu, Jin-Hua; Han, Rong; Wang, Guanghui; Zhen, Xuechu; Qin, Zheng-Hong

    2014-12-02

    Naja naja atra venom (NNAV) displays diverse pharmacological actions including analgesia, anti-inflammation and immune regulation.In this study, we investigated the effects of NNAV on pulmonary fibrosis and its mechanisms of action. To determine if Naja naja atra venom (NNAV) can produce beneficial effects on pulmonary fibrosis, two marine models of pulmonary fibrosis were produced with bleomycin (BLM) and lipopolysaccharide (LPS). NNAV (30, 90, 270 μg/kg) was orally administered once a day started five days before BLM and LPS until to the end of experiment. The effects of NNAV treatment on pulmonary injury were evaluated with arterial blood gas analysis, hydroxyproline (HYP) content assessment and HE/Masson staining. The effects of NNAV treatment on inflammatory related cytokines, fibrosis related TGF-β/Smad signaling pathway and oxidative stress were examined. The results showed that NNAV improved the lung gas-exchange function and attenuated the fibrotic lesions in lung. NNAV decreased IL-1β and TNF-α levels in serum in both pulmonary fibrosis models. NNAV inhibited the activation of NF-κB in LPS-induced and TGF-β/Smad pathway in BLM-induced pulmonary fibrosis. Additionally, NNAV also increased the levels of SOD and GSH and reduced the levels of MDA in BLM-induced pulmonary fibrosis model. The present study indicates that NNAV attenuates LPS- and BLM-induced lung fibrosis. Its mechanisms of action are associated with inhibiting inflammatory response and oxidative stress. The study suggests that NNAV might be a potential therapeutic drug for treatment of pulmonary fibrosis.

  6. Pleuroparenchymal fibroelastosis: a rare interstitial lung disease

    Science.gov (United States)

    English, John C; Mayo, John R; Levy, Robert; Yee, John; Leslie, Kevin O

    2015-01-01

    Pleuroparenchymal fibroelastosis (PPFE) is a newly described form of interstitial lung disease that originates in the upper lung zones and typically progresses to involve the entire lung. The disease may be idiopathic but is often associated with other pre- or coexisting conditions. Pneumothorax is a common complication and can occur at presentation or at other times during the course of the disease. Pathologically, interstitial fibrosis takes the form of a dense consolidation with some preservation of alveolar septal outlines and demonstrates a distinctly abrupt interface with residual normal lung. Unrecognized cases of PPFE may be incorrectly diagnosed as sarcoidosis, atypical idiopathic pulmonary fibrosis, or other unclassifiable interstitial pneumonias. PMID:26090119

  7. Idiopathic Pulmonary Fibrosis: The Association between the Adaptive Multiple Features Method and Fibrosis Outcomes.

    Science.gov (United States)

    Salisbury, Margaret L; Lynch, David A; van Beek, Edwin J R; Kazerooni, Ella A; Guo, Junfeng; Xia, Meng; Murray, Susan; Anstrom, Kevin J; Yow, Eric; Martinez, Fernando J; Hoffman, Eric A; Flaherty, Kevin R

    2017-04-01

    Adaptive multiple features method (AMFM) lung texture analysis software recognizes high-resolution computed tomography (HRCT) patterns. To evaluate AMFM and visual quantification of HRCT patterns and their relationship with disease progression in idiopathic pulmonary fibrosis. Patients with idiopathic pulmonary fibrosis in a clinical trial of prednisone, azathioprine, and N-acetylcysteine underwent HRCT at study start and finish. Proportion of lung occupied by ground glass, ground glass-reticular (GGR), honeycombing, emphysema, and normal lung densities were measured by AMFM and three radiologists, documenting baseline disease extent and postbaseline change. Disease progression includes composite mortality, hospitalization, and 10% FVC decline. Agreement between visual and AMFM measurements was moderate for GGR (Pearson's correlation r = 0.60, P < 0.0001; mean difference = -0.03 with 95% limits of agreement of -0.19 to 0.14). Baseline extent of GGR was independently associated with disease progression when adjusting for baseline Gender-Age-Physiology stage and smoking status (hazard ratio per 10% visual GGR increase = 1.98, 95% confidence interval [CI] = 1.20-3.28, P = 0.008; and hazard ratio per 10% AMFM GGR increase = 1.36, 95% CI = 1.01-1.84, P = 0.04). Postbaseline visual and AMFM GGR trajectories were correlated with postbaseline FVC trajectory (r = -0.30, 95% CI = -0.46 to -0.11, P = 0.002; and r = -0.25, 95% CI = -0.42 to -0.06, P = 0.01, respectively). More extensive baseline visual and AMFM fibrosis (as measured by GGR densities) is independently associated with elevated hazard for disease progression. Postbaseline change in AMFM-measured and visually measured GGR densities are modestly correlated with change in FVC. AMFM-measured fibrosis is an automated adjunct to existing prognostic markers and may allow for study enrichment with subjects at increased disease progression risk.

  8. CYFRA 21.1 in bronchoalveolar lavage of idiopathic pulmonary fibrosis patients.

    Science.gov (United States)

    Vercauteren, Inge M; Verleden, Stijn E; McDonough, John E; Vandermeulen, Elly; Ruttens, David; Lammertyn, Elise J; Bellon, Hannelore; De Dycker, Els; Dooms, Christophe; Yserbyt, Jonas; Verleden, Geert M; Vanaudenaerde, Bart M; Wuyts, Wim A

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is one of the most aggressive forms of interstitial lung diseases, however, clinically relevant biomarkers of diagnosis or prognosis are lacking. In this study, we investigated the levels of a fragment of Cytokeratin 19 (CYFRA 21.1) in bronchoalveolar lavage (BAL) of IPF patients at time of diagnosis. We further evaluated associations between CYFRA 21.1, pulmonary function evolution, mortality, and BAL cell count. Using the Lumipulse® G1200, CYFRA 21.1 was measured in BAL samples of 81 IPF patients and 9 controls. Based upon the median detected level (1.2 ng/mL) of CYFRA 21.1 in IPF patients, they were subdivided into an IPF CYFRA 21.1 low group (≤ 1.2 ng/mL) and IPF CYFRA 21.1 high group (> 1.2 ng/mL). The CYFRA 21.1 levels were significantly higher in BAL of IPF patients compared to controls (P = .0015).Worse survival was observed, but no changes in pulmonary function, for IPF patients with high CYFRA 21.1 levels versus patients with low CYFRA 21.1 levels [P = .030, HR: 0.41, (0.18-0.92)[. The CYFRA 21.1 level correlated with both neutrophils (%: R = 0.60, P < .0001; #: R = 0.47, P < .0001) and eosinophils (%: R = 0.38, P = .0005; #: R = 0.30, P < .0072). CYFRA 21.1 is increased in BAL of IPF patients. IPF patients with a high CYFRA 21.1 concentration have a worse survival. CYFRA 21.1 levels correlate with eosinophils and neutrophils. Further studies are warranted in using CYFRA 21.1 as a biomarker for IPF prognosis.

  9. Inhibiting Skp2 E3 Ligase Suppresses Bleomycin-Induced Pulmonary Fibrosis

    Directory of Open Access Journals (Sweden)

    Masashi Mikamo

    2018-02-01

    Full Text Available Idiopathic pulmonary fibrosis (IPF is a progressive disease with poor prognosis and no curative therapies. SCF-Skp2 E3 ligase is a target for cancer therapy, but there have been no reports about Skp2 as a target for IPF. Here we demonstrate that Skp2 is a promising therapeutic target for IPF. We examined whether disrupting Skp2 suppressed pulmonary fibrosis in a bleomycin (BLM-induced mouse model and found that pulmonary fibrosis was significantly suppressed in Skp2-deficient mice compared with controls. The pulmonary accumulation of fibrotic markers such as collagen type 1 and fibronectin in BLM-infused mice was decreased in Skp2-deficient mice. Moreover, the number of bronchoalveolar lavage fluid cells accompanied with pulmonary fibrosis was significantly diminished. Levels of the Skp2 target p27 were significantly decreased by BLM-administration in wild-type mice, but recovered in Skp2−/− mice. In vimentin-positive mesenchymal fibroblasts, the decrease of p27-positive cells and increase of Ki67-positive cells by BLM-administration was suppressed by Skp2-deficency. As these results suggested that inhibiting Skp2 might be effective for BLM-induced pulmonary fibrosis, we next performed a treatment experiment using the Skp2 inhibitor SZL-P1-41. As expected, BLM-induced pulmonary fibrosis was significantly inhibited by SZL-P1-41. Moreover, p27 levels were increased by the SZL-P1-41 treatment, suggesting p27 may be an important Skp2 target for BLM-induced pulmonary fibrosis. Our study suggests that Skp2 is a potential molecular target for human pulmonary fibrosis including IPF.

  10. Systolic and diastolic myocardial mechanics in hypertrophic cardiomyopathy and their link to the extent of hypertrophy, replacement fibrosis and interstitial fibrosis.

    Science.gov (United States)

    Nucifora, Gaetano; Muser, Daniele; Gianfagna, Pasquale; Morocutti, Giorgio; Proclemer, Alessandro

    2015-12-01

    Aim of the present study was to investigate the relations between myocardial mechanics and the extent of hypertrophy and fibrosis in hypertrophic cardiomyopathy (HCM). Forty-five consecutive patients with HCM and 15 subjects without structural heart disease were included. Cardiac magnetic resonance with late gadolinium enhancement (LGE) imaging was performed to evaluate biventricular function, LV mass index and presence/extent of LGE, expression of replacement fibrosis. Myocardial T1 relaxation, a surrogate of interstitial fibrosis, was measured from Look-Locker sequence. Feature-tracking analysis was applied to LV basal, mid and apical short-axis images to assess systolic and diastolic global LV circumferential strain (CS) and strain rate (CSr). Peak systolic CS and CSr were significantly higher among HCM patients as compared to control subjects (p = 0.015 and p = 0.007, respectively). The ratio of peak CSr during early filling to peak systolic CSr was significantly lower among HCM patients (p = 0.002). At multivariate linear regression analysis, LV mass index (p < 0.001) and %LV LGE (p = 0.011) were significantly and independently related to peak systolic CS; LV mass index (p < 0.001) and %LV LGE (p = 0.023) were significantly and independently related to peak systolic CSr; %LV LGE (p = 0.021) and T1 ratio (p = 0.006) were significantly and independently related to the ratio of peak CSr during early filling to peak systolic CSr. LV systolic mechanics are enhanced and LV diastolic mechanics are impaired in HCM. Extent of hypertrophy and replacement fibrosis influence the LV systolic mechanics while extent of replacement fibrosis and interstitial fibrosis influence the LV diastolic mechanics.

  11. Glycosaminoglycan synthesis in amiodarone-induced pulmonary fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Farinas, E.M.

    1986-01-01

    Glycosaminoglycans (GAG) have previously been demonstrated to be synthesized in greater than normal amounts following a single intratracheal insufflation of bleomycin in hamsters. This suggests that GAG may play a role in the propagation of pulmonary fibrotic reactions. To further test this hypothesis, GAG synthesis was studied in a new hamster model of interstitial lung injury, induced by the cardiac drug, aminodarone. Animals received a single intratracheal instillation of 1.25 mg aminodarone. At 4, 9, and 21 days post-insufflation, the animals were sacrificed, their lungs removed, and 1 mm fragments placed in explant culture for 6 hours at 37/sup 0/C in the presence of /sup 35/S-sulfate. The labeled GAG were isolated and measured for /sup 35/S incorporation. The author then isolated the hexosamine portions of the respective GAGs, Heparan Sulfate (HEP S), Chondroitin-6-Sulfate (Ch-6-S) and Chondroitin-4-Sulfate and Dermatan Sulfate (CH-4-S and DS) using the enzyme ABC and paper chromatography. They also studied the GAG content and distribution in hamster lung fibroblasts incorporated with /sup 35/S for 48 hours and subjected to either 0, 0.01 mg, 0.1 mg, or 1 mg of aminodarone. GAG synthesis is increased at an early stage following the induction of lung injury by aminodarone and remains elevated for a 3 week period. The change in GAG distribution boards elevated CH-4-S and DS may be characteristic of interstitial diseases in general. The GAGs that are synthesized by fibroblasts may be responsible for the increased CH-4-S and DS synthesis.

  12. Progression of Common Variable Immunodeficiency Interstitial Lung Disease Accompanies Distinct Pulmonary and Laboratory Findings.

    Science.gov (United States)

    Maglione, Paul J; Overbey, Jessica R; Cunningham-Rundles, Charlotte

    2015-01-01

    Common variable immunodeficiency may be complicated by interstitial lung disease, which leads to worsened morbidity and mortality in some. Although immunomodulatory treatment has efficacy, choice of patient, duration of treatment, and long-term follow-up are not available. Interstitial lung disease appears stable in certain instances, so it is not known whether all patients will develop progressive disease or require immunomodulatory therapy. This study aims to determine if all common variable immunodeficiency patients with interstitial lung disease have physiological worsening, and if clinical and/or laboratory parameters may correlate with disease progression. A retrospective review of medical records at Mount Sinai Medical Center in New York was conducted for referred patients with common variable immunodeficiency, CT scan-confirmed interstitial lung disease, and periodic pulmonary function testing covering 20 or more months before immunomodulatory therapy. Fifteen patients were identified from the retrospective review and included in this study. Of the 15 patients with common variable immunodeficiency, 9 had physiological worsening of interstitial lung disease adapted from consensus guidelines, associated with significant reductions in forced expiratory volume in 1 second, forced vital capacity, and diffusion capacity of the lung for carbon monoxide. Those with progressive lung disease also had significantly lower mean immunoglobulin G levels, greater increases and highest levels of serum immunoglobulin M (IgM), and more significant thrombocytopenia. Interstitial lung disease resulted in physiological worsening in many, but not all subjects, and was associated with suboptimal immunoglobulin G replacement. Those with worsening pulmonary function tests, elevated IgM, and severe thrombocytopenic episodes appear to be at highest risk for progressive disease. Such patients may benefit from immunomodulatory treatment. Copyright © 2015 American Academy of Allergy

  13. High endogenous activated protein C levels attenuates bleomycin-induced pulmonary fibrosis

    NARCIS (Netherlands)

    Lin, Cong; von der Thüsen, Jan; Isermann, Berend; Weiler, Hartmut; van der Poll, Tom; Borensztajn, Keren; Spek, Chris A.

    2016-01-01

    Coagulation activation accompanied by reduced anticoagulant activity is a key characteristic of patients with idiopathic pulmonary fibrosis (IPF). Although the importance of coagulation activation in IPF is well studied, the potential relevance of endogenous anticoagulant activity in IPF progression

  14. Targeting protease activated receptor-1 with P1pal-12 limits bleomycin-induced pulmonary fibrosis

    NARCIS (Netherlands)

    Lin, Cong; Duitman, Janwillem; Daalhuisen, Joost; ten Brink, Marieke; von der Thüsen, Jan; van der Poll, Tom; Borensztajn, Keren; Spek, C. Arnold

    2014-01-01

    Idiopathic pulmonary fibrosis is the most devastating fibrotic diffuse parenchymal lung disease which remains refractory to pharmacological therapies. Therefore, novel treatments are urgently required. Protease-activated receptor (PAR)-1 is a G-protein-coupled receptor that mediates critical

  15. Pulmonary fibrosis in response to environmental cues and molecular targets involved in its pathogenesis.

    Science.gov (United States)

    Yoshida, Toshinori; Ohnuma, Aya; Horiuchi, Haruka; Harada, Takanori

    2011-03-01

    Chronic lung injury resulting from a variety of different causes is frequently associated with the develop ment of pulmonary fibrosis in humans. Although the etiology of pulmonary fibrosis is generally unknown, several sources of evidence support the hypothesis that a number of environmental and occupational agents play an etiologic role in the pathogenesis of this disease. The agents discussed in this review include beryllium, nylon flock, textile printing aerosols, polyvinyl chloride and didecyldimethylammonium chloride. The authors also describe a variety of animal models, including genetically modified mice, in order to investigate the molecular mechanism of pulmonary fibrosis, focusing on chemokine receptors, regulatory T cells and transforming growth factor-β and bone morphogenetic protein signaling. Overall, we propose the concept of toxicological pulmonary fibrosis as a lung disease induced in response to environmental cues.

  16. The regulatory role of interferon-γ producing gamma delta T cells via the suppression of T helper 17 cell activity in bleomycin-induced pulmonary fibrosis.

    Science.gov (United States)

    Segawa, S; Goto, D; Iizuka, A; Kaneko, S; Yokosawa, M; Kondo, Y; Matsumoto, I; Sumida, T

    2016-09-01

    Interstitial pneumonia (IP) is a chronic progressive interstitial lung disease associated with poor prognosis and high mortality. However, the pathogenesis of IP remains to be elucidated. The aim of this study was to clarify the role of pulmonary γδT cells in IP. In wild-type (WT) mice exposed to bleomycin, pulmonary γδT cells were expanded and produced large amounts of interferon (IFN)-γ and interleukin (IL)-17A. Histological and biochemical analyses showed that bleomycin-induced IP was more severe in T cell receptor (TCR-δ-deficient (TCRδ(-/-) ) mice than WT mice. In TCRδ(-/-) mice, pulmonary IL-17A(+) CD4(+) Τ cells expanded at days 7 and 14 after bleomycin exposure. In TCRδ(-/-) mice infused with γδT cells from WT mice, the number of pulmonary IL-17A(+) CD4(+) T cells was lower than in TCRδ(-/-) mice. The examination of IL-17A(-/-) TCRδ(-/-) mice indicated that γδT cells suppressed pulmonary fibrosis through the suppression of IL-17A(+) CD4(+) T cells. The differentiation of T helper (Th)17 cells was determined in vitro, and CD4(+) cells isolated from TCRδ(-/-) mice showed normal differentiation of Th17 cells compared with WT mice. Th17 cell differentiation was suppressed in the presence of IFN-γ producing γδT cells in vitro. Pulmonary fibrosis was attenuated by IFN-γ-producing γδT cells through the suppression of pulmonary IL-17A(+) CD4(+) T cells. These results suggested that pulmonary γδT cells seem to play a regulatory role in the development of bleomycin-induced IP mouse model via the suppression of IL-17A production. © 2016 British Society for Immunology.

  17. Diffuse interstitial pulmonary infiltrate associated with retroperitoneal mass: report of two cases

    International Nuclear Information System (INIS)

    Teixeira, A.A.; Ramos, M.V.; Natal, M.R.C.

    1990-01-01

    The authors describe two cases of diffuse pulmonary interstitial infiltrate associated with retroperitoneal mass. Both patients were females and presented spontaneous pneumothorax. One of them had a typical hystological presentation of lymphangiomyomatosis and in the other on the retroperitoneal mass was classified as an angiomyolipoma. Angiomyomatosis are often associated with tuberous sclerosis and lymphangiomyomatosis. A review of the literature and the differential diagnosis are presented. (author)

  18. Pneumonitis and lethal pulmonary fibrosis (Hamman-Rich syndrome) due to Parathione (E605) poisoning

    International Nuclear Information System (INIS)

    Lotz, W.; Fasske, E.; Forschungsinstitut Borstel

    1986-01-01

    A patient with chronic Parathione (E 605) poisoning was observed over a period of 55 days. During that time he developed progressive changes, which were identical to those of progressive idiopathic pulmonary fibrosis. The rapid development of an alveolitis, followed by a lethal pulmonary fibrosis, differed in no way, macroscopically nor microscopically, from the lung changes in paraquat poisoning (paraquat lung). The radiologic course has been correlated with the clinical and post mortem findings. (orig.) [de

  19. Genome sequencing of idiopathic pulmonary fibrosis in conjunction with a medical school human anatomy course.

    Directory of Open Access Journals (Sweden)

    Akash Kumar

    Full Text Available Even in cases where there is no obvious family history of disease, genome sequencing may contribute to clinical diagnosis and management. Clinical application of the genome has not yet become routine, however, in part because physicians are still learning how best to utilize such information. As an educational research exercise performed in conjunction with our medical school human anatomy course, we explored the potential utility of determining the whole genome sequence of a patient who had died following a clinical diagnosis of idiopathic pulmonary fibrosis (IPF. Medical students performed dissection and whole genome sequencing of the cadaver. Gross and microscopic findings were more consistent with the fibrosing variant of nonspecific interstitial pneumonia (NSIP, as opposed to IPF per se. Variants in genes causing Mendelian disorders predisposing to IPF were not detected. However, whole genome sequencing identified several common variants associated with IPF, including a single nucleotide polymorphism (SNP, rs35705950, located in the promoter region of the gene encoding mucin glycoprotein MUC5B. The MUC5B promoter polymorphism was recently found to markedly elevate risk for IPF, though a particular association with NSIP has not been previously reported, nor has its contribution to disease risk previously been evaluated in the genome-wide context of all genetic variants. We did not identify additional predicted functional variants in a region of linkage disequilibrium (LD adjacent to MUC5B, nor did we discover other likely risk-contributing variants elsewhere in the genome. Whole genome sequencing thus corroborates the association of rs35705950 with MUC5B dysregulation and interstitial lung disease. This novel exercise additionally served a unique mission in bridging clinical and basic science education.

  20. Effect of Emphysema Extent on Serial Lung Function in Patients with Idiopathic Pulmonary Fibrosis.

    Science.gov (United States)

    Cottin, Vincent; Hansell, David M; Sverzellati, Nicola; Weycker, Derek; Antoniou, Katerina M; Atwood, Mark; Oster, Gerry; Kirchgaessler, Klaus-Uwe; Collard, Harold R; Wells, Athol U

    2017-11-01

    Patients with idiopathic pulmonary fibrosis and emphysema may have artificially preserved lung volumes. In this post hoc analysis, we investigated the relationship between baseline emphysema and fibrosis extents, as well as pulmonary function changes, over 48 weeks. Data were pooled from two phase III, randomized, double-blind, placebo-controlled trials of IFN-γ-1b in idiopathic pulmonary fibrosis (GIPF-001 [NCT00047645] and GIPF-007 [NCT00075998]). Patients with Week 48 data, baseline high-resolution computed tomographic images, and FEV 1 /FVC ratios less than 0.8 or greater than 0.9 (0.9 in GIPF-007), as well as randomly selected patients with ratios of 0.8-0.9 and 0.7-0.8, were included. Changes from baseline in pulmonary function at Week 48 were analyzed by emphysema extent. The relationship between emphysema and fibrosis extents and change in pulmonary function was assessed using multivariate linear regression. Emphysema was identified in 38% of patients. A negative correlation was observed between fibrosis and emphysema extents (r = -0.232; P pulmonary fibrosis and emphysema extent greater than or equal to 15%.

  1. A neutrophil elastase inhibitor prevents bleomycin-induced pulmonary fibrosis in mice.

    Science.gov (United States)

    Takemasa, Akihiro; Ishii, Yoshiki; Fukuda, Takeshi

    2012-12-01

    Neutrophil elastase plays pivotal roles in the pathogenesis of pulmonary fibrosis. The neutrophil elastase inhibitor, sivelestat, could alleviate pulmonary fibrosis; however, the antifibrotic mechanisms have not yet been clarified. We examined the antifibrotic mechanisms, mainly focusing on a key fibrotic cytokine, transforming growth factor (TGF)-β1, in this study. To elucidate the antifibrotic mechanisms of sivelestat, we examined a murine model of bleomycin-induced early-stage pulmonary fibrosis. After intratracheal instillation of bleomycin, sivelestat was administered intraperitoneally once a day for 7 or 14 days. Bronchoalveolar lavage fluid and lung samples were examined on day 7 or day 14 after bleomycin instillation. In the bleomycin-induced early-stage pulmonary fibrosis model, the neutrophil elastase level was increased in the lungs. Sivelestat significantly inhibited the increase in lung collagen content, fibrotic changes, the numbers of total cells (including macrophages, neutrophils and lymphocytes), the levels of the active form of TGF-β1 and phospho-Smad2 in bleomycin-induced early-stage pulmonary fibrosis. The total TGF-β1 levels and relative changes of TGF-β1 mRNA expression, however, were not decreased significantly by sivelestat. These results suggest that sivelestat alleviated bleomycin-induced pulmonary fibrosis via inhibition of both TGF-β activation and inflammatory cell recruitment in the lung.

  2. Nitric Oxide Mediates Bleomycin-Induced Angiogenesis and Pulmonary Fibrosis via Regulation of VEGF

    Science.gov (United States)

    Iyer, Anand Krishnan V.; Ramesh, Vani; Castro, Carlos A.; Kaushik, Vivek; Kulkarni, Yogesh M.; Wright, Clayton A.; Venkatadri, Rajkumar; Rojanasakul, Yon; Azad, Neelam

    2015-01-01

    Pulmonary fibrosis is a progressive lung disease hallmarked by increased fibroblast proliferation, amplified levels of extracellular matrix deposition and increased angiogenesis. Although dysregulation of angiogenic mediators has been implicated in pulmonary fibrosis, the specific rate-limiting angiogenic markers involved and their role in the progression of pulmonary fibrosis remains unclear. We demonstrate that bleomycin treatment induces angiogenesis, and inhibition of the central angiogenic mediator VEGF using anti-VEGF antibody CBO-P11 significantly attenuates bleomycin-induced pulmonary fibrosis in vivo. Bleomycin-induced nitric oxide (NO) was observed to be the key upstream regulator of VEGF via the PI3k/Akt pathway. VEGF regulated other important angiogenic proteins including PAI-1 and IL-8 in response to bleomycin exposure. Inhibition of NO and VEGF activity significantly mitigated bleomycin-induced angiogenic and fibrogenic responses. NO and VEGF are key mediators of bleomycin-induced pulmonary fibrosis, and could serve as important targets against this debilitating disease. Overall, our data suggests an important role for angiogenic mediators in the pathogenesis of bleomycin-induced pulmonary fibrosis. PMID:25919965

  3. Microencapsulation of Lefty-secreting engineered cells for pulmonary fibrosis therapy in mice.

    Science.gov (United States)

    Ma, Hongge; Qiao, Shupei; Wang, Zeli; Geng, Shuai; Zhao, Yufang; Hou, Xiaolu; Tian, Weiming; Chen, Xiongbiao; Yao, Lifen

    2017-05-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive disease that causes unremitting deposition of extracellular matrix proteins, thus resulting in distortion of the pulmonary architecture and impaired gas exchange. Associated with high morbidity and mortality, IPF is generally refractory to current pharmacological therapies. Lefty A, a potent inhibitor of transforming growth factor-β signaling, has been shown to have promising antifibrotic ability in vitro for the treatment of renal fibrosis and other potential organ fibroses. Here, we determined whether Lefty A can attenuate bleomycin (BLM)-induced pulmonary fibrosis in vivo based on a novel therapeutic strategy where human embryonic kidney 293 (HEK293) cells are genetically engineered with the Lefty A-associated GFP gene. The engineered HEK293 cells were encapsulated in alginate microcapsules and then subcutaneously implanted in ICR mice that had 1 wk earlier been intratracheally administered BLM to induce pulmonary fibrosis. The severity of fibrosis in lung tissue was assessed using pathological morphology and collagen expression to examine the effect of Lefty A released from the microencapsulated cells. The engineered HEK293 cells with Lefty A significantly reduced the expression of connective tissue growth factor and collagen type I mRNA, lessened the morphological fibrotic effects induced by BLM, and increased the expression of matrix metalloproteinase-9. This illustrates that engineered HEK293 cells with Lefty A can attenuate pulmonary fibrosis in vivo, thus providing a novel method to treat human pulmonary fibrotic disease and other organ fibroses. Copyright © 2017 the American Physiological Society.

  4. Urinary retinol binding protein is a marker of the extent of interstitial kidney fibrosis.

    Directory of Open Access Journals (Sweden)

    Nicolas Pallet

    Full Text Available Currently, a non-invasive method to estimate the degree of interstitial fibrosis (IF in chronic kidney disease is not available in routine. The aim of our study was to evaluate the diagnostic performance of the measurement of urinary low molecular weight (LMW protein concentrations as a method to determine the extent of IF. The urines specimen from 162 consecutive patients who underwent renal biopsy were used in the analysis. Numerical quantification software based on the colorimetric analysis of fibrous areas was used to assess the percentage IF. Total proteinuria, albuminuria, and the urinary levels of retinol binding protein (RBP, alpha1-microglobulin (α1MG, beta 2-microglobulin (β2MG, transferrin, and IgG immunoglobulins were measured. There was a significant correlation between the degree of IF and the RBP/creatinine (creat ratio (R2: 0.11, p25% of the parenchyma was 95% when using a threshold of 20 mg/g creat. In conclusion, RBP appears to be a quantitative and non-invasive marker for the independent prediction of the extent of kidney IF. Because methods for the measurement of urinary RBP are available in most clinical chemistry departments, RBP measurement is appealing for implementation in the routine care of patients with chronic kidney disease.

  5. Pulmonary hypertension in chronic obstructive and interstitial lung diseases

    DEFF Research Database (Denmark)

    Andersen, Charlotte U; Mellemkjær, Søren; Nielsen-Kudsk, Jens Erik

    2013-01-01

    , and is considered one of the most frequent types of PH. However, the prevalence of PH among patients with COPD and ILD is not clear. The diagnosis of PH in chronic lung disease is often established by echocardiographic screening, but definitive diagnosis requires right heart catheterization, which...... treatment with existent drugs effective in pulmonary arterial hypertension (PAH) is beneficial in lung disease related PH. Studies investigating existing PAH drugs in animal models of lung disease related PH have indicated a positive effect, and so have case reports and open label studies. However...

  6. Gentiopicroside ameliorates bleomycin-induced pulmonary fibrosis in mice via inhibiting inflammatory and fibrotic process.

    Science.gov (United States)

    Chen, Cheng; Wang, Yong-Yan; Wang, Ying-Xia; Cheng, Meng-Qun; Yin, Jian-Bing; Zhang, Xuan; Hong, Zhi-Peng

    2018-01-22

    Pulmonary fibrosis (PF) is a chronic and ultimately fatal interstitial lung disease of various causes. The advent of nintedanib and pirfenidone provides treatment options for PF patients for the first time. However, the adverse effects of the two drugs such as gastrointestinal disorders and hepatic dysfunction often lead to treatment discontinuation. Gentiopicroside (GPS) is a natural secoiridoid glycoside from gentian species of medicinal plants, and has a variety of pharmacological activities, including hepatoprotective and cholagogic, anti-inflammatory, antinociceptive, and smooth muscle relaxing activities. The present study aimed to investigate the therapeutical effects of GPS on bleomycin (BLM)-induced PF in mice. Severe lung inflammation and fibrosis were observed in BLM-treated mice. GPS significantly ameliorated inflammatory and fibrotic responses in lungs of PF mice which were confirmed by histopathological examinations including light microscopy and transmission electron microscopy. Additionally, GPS significantly decreased the levels of inflammatory cytokines including TNF-α and IL-1β in bronchoalveolar lavage fluid and reduced the content of hydroxyproline in lungs of PF mice. Furthermore, GPS significantly downregulated the expression of TGF-β1 and CTGF in lungs of PF mice. In vitro, GPS inhibited epithelial-mesenchymal transition of A549 cells stimulated by TGF-β1, in a dose-dependent manner. Our findings suggest that GPS has the potential as an ideal drug candidate for PF, as it has both anti-inflammatory and anti-fibrotic effects. Alveolar epithelial cells and TGF-β1 may be the main target cells and molecule of GPS on BLM-induced PF, respectively. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. The K+ Channel KCa3.1 as a Novel Target for Idiopathic Pulmonary Fibrosis

    Science.gov (United States)

    Roach, Katy Morgan; Duffy, Stephen Mark; Coward, William; Feghali-Bostwick, Carol; Wulff, Heike; Bradding, Peter

    2013-01-01

    Background Idiopathic pulmonary fibrosis (IPF) is a common, progressive and invariably lethal interstitial lung disease with no effective therapy. We hypothesised that KCa3.1 K+ channel-dependent cell processes contribute to IPF pathophysiology. Methods KCa3.1 expression in primary human lung myofibroblasts was examined using RT-PCR, western blot, immunofluorescence and patch-clamp electrophysiology. The role of KCa3.1 channels in myofibroblast proliferation, wound healing, collagen secretion and contraction was examined using two specific and distinct KCa3.1 blockers (TRAM-34 and ICA-17043 [Senicapoc]). Results Both healthy non fibrotic control and IPF-derived human lung myofibroblasts expressed KCa3.1 channel mRNA and protein. KCa3.1 ion currents were elicited more frequently and were larger in IPF-derived myofibroblasts compared to controls. KCa3.1 currents were increased in myofibroblasts by TGFβ1 and basic FGF. KCa3.1 was expressed strongly in IPF tissue. KCa3.1 pharmacological blockade attenuated human myofibroblast proliferation, wound healing, collagen secretion and contractility in vitro, and this was associated with inhibition of TGFβ1-dependent increases in intracellular free Ca2+. Conclusions KCa3.1 activity promotes pro-fibrotic human lung myofibroblast function. Blocking KCa3.1 may offer a novel approach to treating IPF with the potential for rapid translation to the clinic. PMID:24392001

  8. Patient confidence and quality of life in idiopathic pulmonary fibrosis and sarcoidosis.

    Science.gov (United States)

    Kotecha, Jalpa; Atkins, Christopher; Wilson, Andrew

    2016-12-23

    Idiopathic pulmonary fibrosis (IPF) and sarcoidosis impact significantly on health-related quality of life (HRQOL). There are few studies on the impact of patient confidence on HRQOL in these conditions. 1. To investigate whether patient confidence is associated with HRQOL, anxiety, depression, dyspnoea or fatigue. 2. To assess if patient confidence is associated with inpatient admissions, access to community healthcare and, for IPF patients, mortality and disease severity. Study participants self-completed seven questionnaires: Hospital Anxiety and Depression Scale, EuroQol 5D (EQ5D), King's Brief Interstitial Lung Disease questionnaire, St George's Respiratory Questionnaire, MRC dyspnoea scale, Fatigue Assessment Scale and a non-validated questionnaire assessing patient confidence, symptom duration and access to community healthcare. Lung function and follow-up data were collected from hospital electronic databases. Spearman's rank correlation coefficients were calculated to assess for correlation between patient confidence, questionnaire variables and inpatient admissions. Chi-square tests were performed to assess for association between patient confidence, mortality and disease severity. 75 IPF patients and 69 sarcoidosis patients were recruited to the study. Patient confidence in IPF was significantly negatively correlated with depression and fatigue, and significantly positively correlated with EQ5D scores, but not healthcare outcomes. No associations were found between confidence and any of the variables assessed in sarcoidosis. Lower levels of confidence in IPF patients are associated with higher levels of depression and fatigue and worse HRQOL. Efforts should be made to improve patient confidence to assess the impact on HRQOL.

  9. Comparison of CPI and GAP models in patients with idiopathic pulmonary fibrosis: a nationwide cohort study.

    Science.gov (United States)

    Lee, Sang Hoon; Park, Jong Sun; Kim, Song Yee; Kim, Dong Soon; Kim, Young Whan; Chung, Man Pyo; Uh, Soo Taek; Park, Choon Sik; Park, Sung Woo; Jeong, Sung Hwan; Park, Yong Bum; Lee, Hong Lyeol; Shin, Jong Wook; Lee, Eun Joo; Lee, Jin Hwa; Jegal, Yangin; Lee, Hyun Kyung; Kim, Yong Hyun; Song, Jin Woo; Park, Moo Suk

    2018-03-19

    The clinical course of idiopathic pulmonary fibrosis (IPF) is difficult to predict, partly owing to its heterogeneity. Composite physiologic index (CPI) and gender-age-physiology (GAP) models are easy-to-use predictors of IPF progression. This study aimed to compare the predictive values of these two models. From 2003 to 2007, the Korean Interstitial Lung Disease (ILD) Study Group surveyed ILD patients using the 2002 ATS/ERS criteria. A total of 832 patients with IPF were enrolled in this study. CPI was calculated as follows: 91.0 - (0.65 × %DL CO ) - [0.53 × %FVC + [0.34 × %FEV 1 . GAP stage was calculated based on gender (0-1 points), age (0-2 points), and two physiologic lung function parameters (0-5 points). The two models had similar significant predictive values for patients with IPF (p GAP for prediction of 1-, 2-, and 3-year mortality in this study. The AUC was higher for surgically diagnosed IPF patients than for clinically diagnosed patients. However, neither CPI nor GAP yielded good predictions of outcomes; the AUC was approximately 0.61~0.65. Although both CPI and GAP stage are significantly useful predictors for IPF, they have limited capability to accurately predict outcomes.

  10. Patient-centred management in idiopathic pulmonary fibrosis: similar themes in three communication models.

    Science.gov (United States)

    Wuyts, Wim A; Peccatori, Fedro A; Russell, Anne-Marie

    2014-06-01

    The progressive and highly variable course of idiopathic pulmonary fibrosis (IPF) can present patients and their families with various challenges at different points of the disease. Structured communication between the healthcare professional and the patient is vital to ensure the best possible support and treatment for the patient. While research in this area has been limited, an increasing number of studies are emerging that support the role of communication in patients with debilitating and fatal lung diseases. Communication models used in other conditions that share many challenges with IPF, such as cancer, provide important insights for developing specifically designed patient support and communications models in IPF. Three communication models will be described: 1) the patient-centred care model (for oncology); 2) the three pillars of care model (for IPF); and 3) the Brompton model of care (for interstitial lung disease). Themes common to all three models include comprehensive patient education, encouraged patient participation and an accessible healthcare system, all supported by a collaborative provider-patient relationship. The development of effective communication skills is an on-going process and it is recommended to examine communication models used in other chronic diseases. ©ERS 2014.

  11. Guidelines for the diagnosis and treatment of idiopathic pulmonary fibrosis. Sociedad Española de Neumología y Cirugía Torácica (SEPAR) Research Group on Diffuse Pulmonary Diseases.

    Science.gov (United States)

    Xaubet, Antoni; Ancochea, Julio; Bollo, Elena; Fernández-Fabrellas, Estrella; Franquet, Tomás; Molina-Molina, Maria; Montero, Maria Angeles; Serrano-Mollar, Anna

    2013-08-01

    Idiopathic pulmonary fibrosis is defined as a chronic fibrosing interstitial pneumonia limited to the lung, of unknown cause, with poor prognosis and few treatment options. In recent years there has been an increase in their prevalence, probably due to the optimization of diagnostic methods and increased life expectancy. The ATS/ERS Consensus (2000) established the diagnostic criteria and recommendations for the assessment of the disease course and treatment. Later studies have helped to redefine diagnostic criteria and treatment options. In 2011, an international consensus was published, establishing diagnostic criteria and new treatment strategies. These guidelines have been updated with the newest aspects of diagnosis and treatment of idiopathic pulmonary fibrosis. A level of evidence has been identified for the most relevant questions, particularly with regard to treatment options. Copyright © 2012 SEPAR. Published by Elsevier Espana. All rights reserved.

  12. IDENTIFICATION OF SPONTANEOUS FELINE IDIOPATHIC PULMONARY FIBROSIS: MORPHOLOGY AND ULTRASTRUCTURAL EVIDENCE FOR A TYPE II PNEUMOCYTE DEFECT

    Science.gov (United States)

    AbstractIdiopathic pulmonary fibrosis currently lacks an animal model that develops the persistent, progressive lung fibrosis characteristic of the disease. Sixteen domestic cats developed dyspnea that was not responsive to therapy and which rapidly progressed until death/eu...

  13. Combined Pulmonary Fibrosis and Emphysema in Scleroderma-Related Lung Disease Has a Major Confounding Effect on Lung Physiology and Screening for Pulmonary Hypertension.

    Science.gov (United States)

    Antoniou, K M; Margaritopoulos, G A; Goh, N S; Karagiannis, K; Desai, S R; Nicholson, A G; Siafakas, N M; Coghlan, J G; Denton, C P; Hansell, D M; Wells, A U

    2016-04-01

    To assess the prevalence of combined pulmonary fibrosis and emphysema (CPFE) in systemic sclerosis (SSc) patients with interstitial lung disease (ILD) and the effect of CPFE on the pulmonary function tests used to evaluate the severity of SSc-related ILD and the likelihood of pulmonary hypertension (PH). High-resolution computed tomography (HRCT) scans were obtained in 333 patients with SSc-related ILD and were evaluated for the presence of emphysema and the extent of ILD. The effects of emphysema on the associations between pulmonary function variables and the extent of SSc-related ILD as visualized on HRCT and echocardiographic evidence of PH were quantified. Emphysema was present in 41 (12.3%) of the 333 patients with SSc-related ILD, in 26 (19.7%) of 132 smokers, and in 15 (7.5%) of 201 lifelong nonsmokers. When the extent of fibrosis was taken into account, emphysema was associated with significant additional differences from the expected values for diffusing capacity for carbon monoxide (DLco) (average reduction of 24.1%; P < 0.0005), and the forced vital capacity (FVC)/DLco ratio (average increase of 34.8%; P < 0.0005) but not FVC. These effects were identical in smokers and nonsmokers. Multivariate analysis showed that the presence of emphysema had a greater effect than echocardiographically determined PH on the FVC/DLco ratio, regardless of whether it was analyzed as a continuous variable or using a threshold value of 1.6 or 2.0. Among patients with SSc-related ILD, emphysema is sporadically present in nonsmokers and is associated with a low pack-year history in smokers. The confounding effect of CPFE on measures of gas exchange has major implications for the construction of screening algorithms for PH in patients with SSc-related ILD. © 2016, American College of Rheumatology.

  14. Pulmonary Fibrosis in BALB/c Mice Caused by Long-Term Instillation of Bleomycin

    OpenAIRE

    NAKAJIMA, Masamitsu

    1992-01-01

    It is well-known that bleomycin-induced pulmonary fibrosis is difficult to produce in BALB/c mice. To see whether bleomycin could induce pulmonary fibrosis in BALB/c mice, we repeatedly administered this drug through the airway for 10 consecutive days. Our experiment clearly showed that fibrosis can be induced, although it was rather mild, and also suggested that the bronchiolar and alveolar epithelia are the primary sites of injury. We believe this experimental model may be useful in studyin...

  15. The Mitochondrial Cardiolipin Remodeling Enzyme Lysocardiolipin Acyltransferase Is a Novel Target in Pulmonary Fibrosis

    Science.gov (United States)

    Huang, Long Shuang; Mathew, Biji; Zhao, Yutong; Noth, Imre; Reddy, Sekhar P.; Harijith, Anantha; Usatyuk, Peter V.; Berdyshev, Evgeny V.; Kaminski, Naftali; Zhou, Tong; Zhang, Wei; Zhang, Yanmin; Rehman, Jalees; Kotha, Sainath R.; Gurney, Travis O.; Parinandi, Narasimham L.; Lussier, Yves A.; Garcia, Joe G. N.

    2014-01-01

    Rationale: Lysocardiolipin acyltransferase (LYCAT), a cardiolipin-remodeling enzyme regulating the 18:2 linoleic acid pattern of mammalian mitochondrial cardiolipin, is necessary for maintaining normal mitochondrial function and vascular development. We hypothesized that modulation of LYCAT expression in lung epithelium regulates development of pulmonary fibrosis. Objectives: To define a role for LYCAT in human and murine models of pulmonary fibrosis. Methods: We analyzed the correlation of LYCAT expression in peripheral blood mononuclear cells (PBMCs) with the outcomes of pulmonary functions and overall survival, and used the murine models to establish the role of LYCAT in fibrogenesis. We studied the LYCAT action on cardiolipin remodeling, mitochondrial reactive oxygen species generation, and apoptosis of alveolar epithelial cells under bleomycin challenge. Measurements and Main Results: LYCAT expression was significantly altered in PBMCs and lung tissues from patients with idiopathic pulmonary fibrosis (IPF), which was confirmed in two preclinical murine models of IPF, bleomycin- and radiation-induced pulmonary fibrosis. LYCAT mRNA expression in PBMCs directly and significantly correlated with carbon monoxide diffusion capacity, pulmonary function outcomes, and overall survival. In both bleomycin- and radiation-induced pulmonary fibrosis murine models, hLYCAT overexpression reduced several indices of lung fibrosis, whereas down-regulation of native LYCAT expression by siRNA accentuated fibrogenesis. In vitro studies demonstrated that LYCAT modulated bleomycin-induced cardiolipin remodeling, mitochondrial membrane potential, reactive oxygen species generation, and apoptosis of alveolar epithelial cells, potential mechanisms of LYCAT-mediated lung protection. Conclusions: This study is the first to identify modulation of LYCAT expression in fibrotic lungs and offers a novel therapeutic approach for ameliorating lung inflammation and pulmonary fibrosis. PMID

  16. Disseminated dendriform pulmonary ossification associated with usual interstitial pneumonia: incidence and thin-section CT-pathologic correlation

    International Nuclear Information System (INIS)

    Kim, Tae Sung; Chung, Myung Jin; Han, Joungho; Chung, Man Pyo; Choi, Yong Soo

    2005-01-01

    The aim of this work was to assess the incidence of disseminated pulmonary dendriform ossification in usual interstitial pneumonia and nonspecific interstitial pneumonia, and to correlate thin-section computed tomography (CT) and histopathologic findings. We retrospectively reviewed thin-section CT and pathologic specimens of biopsy-proven usual interstitial pneumonia (75 patients, 57 men and 18 women, mean age 60 years, range 29-83 years) and nonspecific interstitial pneumonia (44 patients, 9 men and 35 women, mean age 55 years, range 20-73 years). On review of CT and histopathologic specimens, diffuse dendriform ossification was identified in five (four men and one woman, age range 41-68 years, mean 58 years) of 75 patients (6.7%) with usual interstitial pneumonia. It was not seen in any of 44 patients with nonspecific interstitial pneumonia. With thin-section CT (osteoporosis window; window width 818, level 273), disseminated dendriform pulmonary ossification was detected as multiple tiny calcifications in bibasilar subpleural lungs (100% sensitive and 100% specific when compared with histopathologic findings as the gold standard). The thin-section CT finding of multiple tiny calcifications in bibasilar subpleural lungs might be of some help in the differential diagnosis between usual interstitial pneumonia and nonspecific interstitial pneumonia, considering they were not seen in any patients with nonspecific interstitial pneumonia (0%, 0/44) in our series. (orig.)

  17. Enhanced endogenous bone morphogenetic protein signaling protects against bleomycin induced pulmonary fibrosis.

    Science.gov (United States)

    De Langhe, Ellen; Cailotto, Frederic; De Vooght, Vanessa; Aznar-Lopez, Carolina; Vanoirbeek, Jeroen Alfons; Luyten, Frank Prosper; Lories, Rik Jozef Urbain

    2015-03-15

    Effective treatments for fibrotic diseases such as idiopathic pulmonary fibrosis are largely lacking. Transforming growth factor beta (TGFβ) plays a central role in the pathophysiology of fibrosis. We hypothesized that bone morphogenetic proteins (BMP), another family within the TGFβ superfamily of growth factors, modulate fibrogenesis driven by TGFβ. We therefore studied the role of endogenous BMP signaling in bleomycin induced lung fibrosis. Lung fibrosis was induced in wild-type or noggin haploinsufficient (Nog +/LacZ ) mice by intratracheal instillation of bleomycin, or phosphate buffered saline as a control. Invasive pulmonary function tests were performed using the flexiVent® SCIREQ system. The mice were sacrificed and lung tissue was collected for analysis using histopathology, collagen quantification, immunohistochemistry and gene expression analysis. Nog +/LacZ mice are a known model of increased BMP signaling and were partially protected from bleomycin-induced lung fibrosis with reduced Ashcroft score, reduced collagen content and preservation of pulmonary compliance. In bleomycin-induced lung fibrosis, TGFβ and BMP signaling followed an inverse course, with dynamic activation of TGFβ signaling and repression of BMP signaling activity. Upon bleomycin exposure, active BMP signaling is decreased. Derepression of BMP signaling in Nog +/LacZ mice protects against bleomycin-induced pulmonary fibrosis. Modulating the balance between BMP and TGFβ, in particular increasing endogenous BMP signals, may therefore be a therapeutic target in fibrotic lung disease.

  18. Smoking-related interstitial lung diseases; Interstitielle Lungenerkrankungen bei Rauchern

    Energy Technology Data Exchange (ETDEWEB)

    Marten, K. [Technische Univ. Muenchen (Germany). Klinikum rechts der Isar, Inst. fuer Roentgendiagnostik

    2007-03-15

    The most important smoking-related interstitial lung diseases (ILD) are respiratory bronchiolitis, respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, and Langerhans' cell histiocytosis. Although traditionally considered to be discrete entities, smoking-related ILDs often coexist, thus accounting for the sometimes complex patterns encountered on high-resolution computed tomography (HRCT). Further studies are needed to elucidate the causative role of smoking in the development of pulmonary fibrosis.

  19. The Role of the Mammalian Target of Rapamycin (mTOR in Pulmonary Fibrosis

    Directory of Open Access Journals (Sweden)

    Jessica Lawrence

    2018-03-01

    Full Text Available The phosphoinositide 3-kinase (PI3K/protein kinase B (AKT/mammalian target of rapamycin (mTOR-dependent pathway is one of the most integral pathways linked to cell metabolism, proliferation, differentiation, and survival. This pathway is dysregulated in a variety of diseases, including neoplasia, immune-mediated diseases, and fibroproliferative diseases such as pulmonary fibrosis. The mTOR kinase is frequently referred to as the master regulator of this pathway. Alterations in mTOR signaling are closely associated with dysregulation of autophagy, inflammation, and cell growth and survival, leading to the development of lung fibrosis. Inhibitors of mTOR have been widely studied in cancer therapy, as they may sensitize cancer cells to radiation therapy. Studies also suggest that mTOR inhibitors are promising modulators of fibroproliferative diseases such as idiopathic pulmonary fibrosis (IPF and radiation-induced pulmonary fibrosis (RIPF. Therefore, mTOR represents an attractive and unique therapeutic target in pulmonary fibrosis. In this review, we discuss the pathological role of mTOR kinase in pulmonary fibrosis and examine how mTOR inhibitors may mitigate fibrotic progression.

  20. Profibrotic potential of Prominin-1+ epithelial progenitor cells in pulmonary fibrosis

    Directory of Open Access Journals (Sweden)

    Lüscher Thomas F

    2011-09-01

    Full Text Available Abstract Background In idiopathic pulmonary fibrosis loss of alveolar epithelium induces inflammation of the pulmonary tissue followed by accumulation of pathogenic myofibroblasts leading eventually to respiratory failures. In animal models inflammatory and resident cells have been demonstrated to contribute to pulmonary fibrosis. Regenerative potential of pulmonary and extra-pulmonary stem and progenitor cells raised the hope for successful treatment option against pulmonary fibrosis. Herein, we addressed the contribution of lung microenvironment and prominin-1+ bone marrow-derived epithelial progenitor cells in the mouse model of bleomycin-induced experimental pulmonary fibrosis. Methods Prominin-1+ bone marrow-derived epithelial progenitors were expanded from adult mouse lungs and differentiated in vitro by cytokines and growth factors. Pulmonary fibrosis was induced in C57Bl/6 mice by intratracheal instillation of bleomycin. Prominin-1+ progenitors were administered intratracheally at different time points after bleomycin challenge. Green fluorescence protein-expressing cells were used for cell tracking. Cell phenotypes were characterized by immunohistochemistry, flow cytometry and quantitative reverse transcription-polymerase chain reaction. Results Prominin-1+ cells expanded from healthy lung represent common progenitors of alveolar type II epithelial cells, myofibroblasts, and macrophages. Administration of prominin-1+ cells 2 hours after bleomycin instillation protects from pulmonary fibrosis, and some of progenitors differentiate into alveolar type II epithelial cells. In contrast, prominin-1+ cells administered at day 7 or 14 lose their protective effects and differentiate into myofibroblasts and macrophages. Bleomycin challenge enhances accumulation of bone marrow-derived prominin-1+ cells within inflamed lung. In contrast to prominin-1+ cells from healthy lung, prominin-1+ precursors isolated from inflamed organ lack regenerative

  1. The epithelium in idiopathic pulmonary fibrosis: breaking the barrier

    Directory of Open Access Journals (Sweden)

    Ana eCamelo

    2014-01-01

    Full Text Available Idiopathic pulmonary fibrosis is a progressive disease of unknown etiology characterised by a dysregulated wound healing response that leads to fatal accumulation of fibroblasts and extracellular matrix in the lung, which compromises tissue architecture and lung function capacity. Injury to type II alveolar epithelial cells is thought to be the key event for the initiation of the disease, and so far both genetic factors, such as mutations in telomerase and MUC5b genes as well as environmental components, like cigarette smoking, exposure to asbestos and viral infections have been implicated as potential initiating triggers. The injured epithelium then enters a state of senescence-associated secretory phenotype whereby it produces both pro-inflammatory and pro-fibrotic factors that contribute to the wound healing process in the lung. Immune cells, like macrophages and neutrophils as well as activated myofibroblasts then perpetuate this cascade of epithelial cell apoptosis and proliferation by release of pro-fibrotic TGF-β and continuous deposition of extracellular matrix stiffens the basement membrane, altogether having a deleterious impact on epithelial cell function. In this review we describe the role of the epithelium as both a physical and immunological barrier between environment and self in the homeostatic versus diseased lung and explore the potential mechanisms of epithelial cell injury and the impact of loss of epithelial cell permeability and function on cytokine production, inflammation and myofibroblast activation in the fibrotic lung.

  2. Severe idiopathic pulmonary fibrosis: what can be done?

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    Antonella Caminati

    2017-09-01

    Full Text Available Idiopathic pulmonary fibrosis (IPF remains a challenging disease to manage. Two drugs are now available that can slow disease progression in patients with mild-to-moderate IPF. This means that early diagnosis is mandatory, because there are no proven effective therapies for severe IPF. This lack of proven therapies may be at least partially due to the fact that severe IPF patients are usually not enrolled in randomised, prospective, multicentre, international trials. Clinical observation experiences and preliminary results of long-term, open-label extensions of clinical trials suggest that both pirfenidone and nintedanib may also slow or decrease progression in patients with severe IPF. However, data are sparse and obtained from a relatively small number of patients. Lung transplantation should be taken into account early and discussed with patients, when indicated. Rehabilitative strategies are important and effective supportive therapies. The needs of patients with severe IPF are similar to those of patients with an advanced neoplastic disease. Palliative care and psychological support play an important role in the relief of symptoms of anxiety and depression. Accordingly, these therapeutic approaches should start early in IPF patients.

  3. Elastase modifies bleomycin-induced pulmonary fibrosis in mice.

    Science.gov (United States)

    Trajano, Larissa Alexsandra Silva Neto; Trajano, Eduardo Tavares Lima; Lanzetti, Manuella; Mendonça, Morena Scopel Amorim; Guilherme, Rafael Freitas; Figueiredo, Rodrigo Tinoco; Benjamim, Cláudia Farias; Valenca, Samuel Santos; Costa, Andréa Monte Alto; Porto, Luís Cristóvão

    2016-04-01

    Pulmonary fibrosis (PF) is characterized by excessive accumulation of collagen in the lungs. Emphysema is characterized by loss of the extracellular matrix (ECM) and alveolar enlargement. We studied the co-participation of elastase-induced mild emphysema in bleomycin-induced PF in mice by analyzing oxidative stress, inflammation and lung histology. C57BL/6 mice were divided into four groups: control; bleomycin (0.1U/mouse); elastase (using porcine pancreatic elastase (PPE)+bleomycin (3U/mouse 14 days before 0.1U/mouse of bleomycin; PPE+B); elastase (3U/mouse). Mice were humanely sacrificed 7, 14 and 21 days after treatment with bleomycin or vehicle. PF was observed 14 days and 21 days after bleomycin treatment but was observed after 14 days only in the PPE+B group. In the PPE+B group at 21 days, we observed many alveoli and alveolar septa with few PF areas. We also observed marked and progressive increases of collagens 7, 14 and 21 days after bleomycin treatment whereas, in the PPE+B group, collagen deposition was observed only at 14 days. There was a reduction in activities of the antioxidant enzymes superoxide dismutase (pbleomycin treatment compared with the control group. These endpoints were also reduced (pbleomycin) overall histology was improved to that of the nearest control group. Copyright © 2016. Published by Elsevier GmbH.

  4. Diagnostic accuracy of a clinical diagnosis of idiopathic pulmonary fibrosis

    DEFF Research Database (Denmark)

    Walsh, Simon L. F.; Maher, Toby M.; Kolb, Martin

    2017-01-01

    We conducted an international study of idiopathic pulmonary fibrosis (IPF) diagnosis among a large group of physicians and compared their diagnostic performance to a panel of IPF experts.A total of 1141 respiratory physicians and 34 IPF experts participated. Participants evaluated 60 cases......-index.A total of 404 physicians completed the study. Agreement for IPF diagnosis was higher among expert physicians (κw=0.65, IQR 0.53-0.72, pphysicians (κw=0.56, IQR 0.45-0.65, pphysicians with access to multidisciplinary team (MDT) meetings (κw=0.54, IQR 0.45-0.64, p....0001). The prognostic accuracy of academic physicians with >20 years of experience (C-index=0.72, IQR 0.0-0.73, p=0.229) and non-university hospital physicians with more than 20 years of experience, attending weekly MDT meetings (C-index=0.72, IQR 0.70-0.72, p=0.052), did not differ significantly (p=0.229 and p=0...

  5. UK asbestos imports and mortality due to idiopathic pulmonary fibrosis.

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    Barber, C M; Wiggans, R E; Young, C; Fishwick, D

    2016-03-01

    Previous studies have demonstrated that the rising mortality due to mesothelioma and asbestosis can be predicted from historic asbestos usage. Mortality due to idiopathic pulmonary fibrosis (IPF) is also rising, without any apparent explanation. To compare mortality due to these conditions and examine the relationship between mortality and national asbestos imports. Mortality data for IPF and asbestosis in England and Wales were available from the Office for National Statistics. Data for mesothelioma deaths in England and Wales and historic UK asbestos import data were available from the Health & Safety Executive. The numbers of annual deaths due to each condition were plotted separately by gender, against UK asbestos imports 48 years earlier. Linear regression models were constructed. For mesothelioma and IPF, there was a significant linear relationship between the number of male and female deaths each year and historic UK asbestos imports. For asbestosis mortality, a similar relationship was found for male but not female deaths. The annual numbers of deaths due to asbestosis in both sexes were lower than for IPF and mesothelioma. The strength of the association between IPF mortality and historic asbestos imports was similar to that seen in an established asbestos-related disease, i.e. mesothelioma. This finding could in part be explained by diagnostic difficulties in separating asbestosis from IPF and highlights the need for a more accurate method of assessing lifetime occupational asbestos exposure. © Crown copyright 2015.

  6. Rupatadine protects against pulmonary fibrosis by attenuating PAF-mediated senescence in rodents.

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    Lv, Xiao-xi; Wang, Xiao-xing; Li, Ke; Wang, Zi-yan; Li, Zhe; Lv, Qi; Fu, Xiao-ming; Hu, Zhuo-wei

    2013-01-01

    A similar immune response is implicated in the pathogenesis of pulmonary fibrosis and allergic disorders. We investigated the potential therapeutic efficacy and mechanism of rupatadine, a dual antagonist of histamine and platelet-activation factor (PAF), in bleomycin- (BLM-) and silica-induced pulmonary fibrosis. The indicated dosages of rupatadine were administered in rodents with bleomycin or silica-induced pulmonary fibrosis. The tissue injury, fibrosis, inflammatory cells and cytokines, and lung function were examined to evaluate the therapeutic efficacy of rupatadine. The anti-fibrosis effect of rupatadine was compared with an H1 or PAF receptor antagonist, and efforts were made to reveal rupatadine's anti-fibrotic mechanism. Rupatadine promoted the resolution of pulmonary inflammation and fibrosis in a dose-dependent manner, as indicated by the reductions in inflammation score, collagen deposition and epithelial-mesenchymal transformation, and infiltration or expression of inflammatory cells or cytokines in the fibrotic lung tissue. Thus, rupatadine treatment improved the declined lung function and significantly decreased animal death. Moreover, rupatadine was able not only to attenuate silica-induced silicosis but also to produce a superior therapeutic efficacy compared to pirfenidone, histamine H1 antagonist loratadine, or PAF antagonist CV-3988. The anti-fibrotic action of rupatadine might relate to its attenuation of BLM- or PAF-induced premature senescence because rupatadine treatment protected against the in vivo and in vitro activation of the p53/p21-dependent senescence pathway. Our studies indicate that rupatadine promotes the resolution of pulmonary inflammation and fibrosis by attenuating the PAF-mediated senescence response. Rupatadine holds promise as a novel drug to treat the devastating disease of pulmonary fibrosis.

  7. Rupatadine protects against pulmonary fibrosis by attenuating PAF-mediated senescence in rodents.

    Directory of Open Access Journals (Sweden)

    Xiao-xi Lv

    Full Text Available A similar immune response is implicated in the pathogenesis of pulmonary fibrosis and allergic disorders. We investigated the potential therapeutic efficacy and mechanism of rupatadine, a dual antagonist of histamine and platelet-activation factor (PAF, in bleomycin- (BLM- and silica-induced pulmonary fibrosis. The indicated dosages of rupatadine were administered in rodents with bleomycin or silica-induced pulmonary fibrosis. The tissue injury, fibrosis, inflammatory cells and cytokines, and lung function were examined to evaluate the therapeutic efficacy of rupatadine. The anti-fibrosis effect of rupatadine was compared with an H1 or PAF receptor antagonist, and efforts were made to reveal rupatadine's anti-fibrotic mechanism. Rupatadine promoted the resolution of pulmonary inflammation and fibrosis in a dose-dependent manner, as indicated by the reductions in inflammation score, collagen deposition and epithelial-mesenchymal transformation, and infiltration or expression of inflammatory cells or cytokines in the fibrotic lung tissue. Thus, rupatadine treatment improved the declined lung function and significantly decreased animal death. Moreover, rupatadine was able not only to attenuate silica-induced silicosis but also to produce a superior therapeutic efficacy compared to pirfenidone, histamine H1 antagonist loratadine, or PAF antagonist CV-3988. The anti-fibrotic action of rupatadine might relate to its attenuation of BLM- or PAF-induced premature senescence because rupatadine treatment protected against the in vivo and in vitro activation of the p53/p21-dependent senescence pathway. Our studies indicate that rupatadine promotes the resolution of pulmonary inflammation and fibrosis by attenuating the PAF-mediated senescence response. Rupatadine holds promise as a novel drug to treat the devastating disease of pulmonary fibrosis.

  8. Rapamycin protects against paraquat-induced pulmonary fibrosis: Activation of Nrf2 signaling pathway.

    Science.gov (United States)

    Xu, Yiheng; Tai, Wenlin; Qu, Xiaoyuan; Wu, Wenjuan; Li, ZhenKun; Deng, Shuhao; Vongphouttha, Chanthasone; Dong, Zhaoxing

    2017-08-19

    Paraquat (PQ) is a widely used herbicide indeveloping countries worldwide, and pulmonary fibrosis is one of the most typical features of PQ poisoning. The molecular mechanism of PQ toxicity especially how to treat PQ-induced pulmonary fibrosis is still largely unknown. In animal model of pulmonary fibrosis, we used HE staining, western blotting assay and Real-time PCR assay to analyze the effects of rapamycin on the PQ-induced epithelial mesenchymal transition (EMT). We found that PQ induced the pulmonary fibrosis using HE staining and Masson's staining, and up-regulated the activity of HYP and the mRNA expressions of Collagen I and III (COL-1and COL-3) in pulmonary tissues. We also found that rapamycin down-regulated the mesenchymal cell marker Vimentin and up-regulated the epithelial cell marker E-cadherin both in mRNA and protein levels compared with PQ group. And the EMT associated transcription factor Snail was decreased by rapamycin treatment compared with PQ group. And PQ decreased the Nrf2 expression both in mRNA and protein levels, and rapamycin inhibited these effects of PQ. SFN, a activator of Nrf2, could inhibit the EMT and the expression of Snail. And knockdowon of Nrf2 could abolish the inhibitory effects of rapamycin of PQ-induced EMT. In conclusion, rapamycin protects against paraquat-induced pulmonary fibrosis by activation of Nrf2 signaling pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Pulmonary CCR2+CD4+T cells are immune regulatory and attenuate lung fibrosis development.

    Science.gov (United States)

    Milger, Katrin; Yu, Yingyan; Brudy, Eva; Irmler, Martin; Skapenko, Alla; Mayinger, Michael; Lehmann, Mareike; Beckers, Johannes; Reichenberger, Frank; Behr, Jürgen; Eickelberg, Oliver; Königshoff, Melanie; Krauss-Etschmann, Susanne

    2017-11-01

    Animal models have suggested that CCR2-dependent signalling contributes to the pathogenesis of pulmonary fibrosis, but global blockade of CCL2 failed to improve the clinical course of patients with lung fibrosis. However, as levels of CCR2 + CD4 + T cells in paediatric lung fibrosis had previously been found to be increased, correlating with clinical symptoms, we hypothesised that distinct CCR2 + cell populations might either increase or decrease disease pathogenesis depending on their subtype. To investigate the role of CCR2 + CD4 + T cells in experimental lung fibrosis and in patients with idiopathic pulmonary fibrosis and other fibrosis. Pulmonary CCR2 + CD4 + T cells were analysed using flow cytometry and mRNA profiling, followed by in silico pathway analysis, in vitro assays and adoptive transfer experiments. Frequencies of CCR2 + CD4 + T cells were increased in experimental fibrosis-specifically the CD62L - CD44 + effector memory T cell phenotype, displaying a distinct chemokine receptor profile. mRNA profiling of isolated CCR2 + CD4 + T cells from fibrotic lungs suggested immune regulatory functions, a finding that was confirmed in vitro using suppressor assays. Importantly, adoptive transfer of CCR2 + CD4 + T cells attenuated fibrosis development. The results were partly corroborated in patients with lung fibrosis, by showing higher percentages of Foxp3 + CD25 + cells within bronchoalveolar lavage fluid CCR2 + CD4 + T cells as compared with CCR2 - CD4 + T cells. Pulmonary CCR2 + CD4 + T cells are immunosuppressive, and could attenuate lung inflammation and fibrosis. Therapeutic strategies completely abrogating CCR2-dependent signalling will therefore also eliminate cell populations with protective roles in fibrotic lung disease. This emphasises the need for a detailed understanding of the functions of immune cell subsets in fibrotic lung disease. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights

  10. Protective roles of polysaccharides from Ganoderma lucidum on bleomycin-induced pulmonary fibrosis in rats.

    Science.gov (United States)

    Chen, Jianhui; Shi, Yingying; He, Lian; Hao, Hairong; Wang, Baolan; Zheng, Yulong; Hu, Chengping

    2016-11-01

    The purpose of this paper was to investigate the protective effects of polysaccharides from (PGL) Ganoderma lucidum on bleomycin-induced pulmonary fibrosis in rats. Our study demonstrated that treatment with PGL of 100-300mg/kg for 28 days led to significant reduction in the pulmonary index, inflammatory cell infiltration and collagen deposition in rats with bleomycin-induced pulmonary fibrosis, which was associated with increased levels of glutathione, glutathione peroxidase, catalase and superoxide dismutase and decreased contents of malondialdehyde and hydroxyproline in the lung. These results indicated that PGL played a positive protective role in the pulmonary fibrosis and its possible mechanism was to improve lung antioxidant ability. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Consensus document for the diagnosis and treatment of idiopathic pulmonary fibrosis: Joint Consensus of Sociedade Portuguesa de Pneumologia, Sociedade Portuguesa de Radiologia e Medicina Nuclear e Sociedade Portuguesa de Anatomia Patológica.

    Science.gov (United States)

    Robalo Cordeiro, C; Campos, P; Carvalho, L; Campainha, S; Clemente, S; Figueiredo, L; Jesus, J M; Marques, A; Souto-Moura, C; Pinto Basto, R; Ribeiro, A; Serrado, M; Morais, A

    2016-01-01

    Idiopathic pulmonary fibrosis is a rare interstitial lung disease included in the Idiopathic Interstitial Pneumonias group. Although several potential risk factors have been described, it is a progressive fibrosing disease of unknown cause affecting mainly adults over 50 years and associated with a poor prognosis, reflected in a median survival of 2-3 years after diagnosis. The concept of a multidisciplinary working group for the diagnosis of idiopathic pulmonary fibrosis is based on the need to have experienced pulmonologists, radiologists and pathologists in the evaluation and correct treatment of the disease, and requires the use of all available data about individual patients, standardized (largely through High Resolution Computed Tomography and pathology when needed) as well as non-standardized data (laboratory, serology and biomarkers). This approach helps to increase diagnostic accuracy and is an internationally accepted recommendation. In regard to therapy, the situation has changed radically since the publication of the ATS/ERS/JRS/ALAT 2011 guidelines on the diagnosis and management of idiopathic pulmonary fibrosis where it was stressed that no proven therapy exists for this disease. Currently besides non-pharmacological treatment, therapy of complications and comorbidities and palliative care, nintedanib and pirfenidone, two compounds with pleiotropic mechanisms of action, are to date, the two drugs with confirmed efficacy in slowing functional decline and disease progression in idiopathic pulmonary fibrosis patients. Copyright © 2016 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.

  12. Pulmonary artery enlargement and cystic fibrosis pulmonary exacerbations: a cohort study

    Science.gov (United States)

    Wells, J. Michael; Farris, Roopan F.; Gosdin, Taylor A.; Dransfield, Mark T.; Wood, Michelle E.; Bell, Scott C.; Rowe, Steven M.

    2017-01-01

    Background Acute pulmonary exacerbations are associated with progressive lung function decline and increased mortality in cystic fibrosis (CF). The role of pulmonary vascular disease in pulmonary exacerbations is unknown. We investigated the association between pulmonary artery enlargement (PA:A>1), a marker of pulmonary vascular disease, and exacerbations. Methods We analyzed clinical, computed tomography (CT), and prospective exacerbation data in a derivation cohort of 74 adult CF patients, measuring the PA:A at the level of the PA bifurcation. We then replicated our findings in a validation cohort of 190 adult CF patients. Patients were separated into groups based on the presence or absence of a PA:A>1 and were followed for 1-year in the derivation cohort and 2-years in the validation cohort. The primary endpoint was developing ≥1 acute pulmonary exacerbation during follow-up. Linear and logistic regression models were used to determine associations between clinical factors, the PA:A ratio, and pulmonary exacerbations. We used Cox regression to determine time to first exacerbation in the validation cohort. Findings We found that PA:A>1 was present in n=37/74 (50%) of the derivation and n=89/190 (47%) of the validation cohort. In the derivation cohort, n=50/74 (68%) had ≥1 exacerbation at 1 year and n=133/190 (70%) in the validation cohort had ≥1 exacerbation after 2 years. PA:A>1 was associated with younger age in both cohorts and with elevated sweat chloride (100.5±10.9 versus 90.4±19.9mmol/L, difference between groups 10.1mmol/L [95%CI 2.5–17.7], P=0.017) in the derivation group. PA:A>1 was associated with exacerbations in the derivation (OR 3.49, 95%CI 1.18–10.3, P=0.023) and validation (OR 2.41, 95%CI 1.06–5.52, P=0.037) cohorts when adjusted for confounders. Time to first exacerbation was shorter in PA:A>1 versus PA:Apulmonary exacerbation risk in two well-characterized cohorts. PA:A may be a predictive marker in CF. PMID:27298019

  13. B cell activating factor is central to bleomycin- and IL-17-mediated experimental pulmonary fibrosis.

    Science.gov (United States)

    François, Antoine; Gombault, Aurélie; Villeret, Bérengère; Alsaleh, Ghada; Fanny, Manoussa; Gasse, Paméla; Adam, Sylvain Marchand; Crestani, Bruno; Sibilia, Jean; Schneider, Pascal; Bahram, Seiamak; Quesniaux, Valérie; Ryffel, Bernhard; Wachsmann, Dominique; Gottenberg, Jacques-Eric; Couillin, Isabelle

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive devastating, yet untreatable fibrotic disease of unknown origin. We investigated the contribution of the B-cell activating factor (BAFF), a TNF family member recently implicated in the regulation of pathogenic IL-17-producing cells in autoimmune diseases. The contribution of BAFF was assessed in a murine model of lung fibrosis induced by airway administered bleomycin. We show that murine BAFF levels were strongly increased in the bronchoalveolar space and lungs after bleomycin exposure. We identified Gr1(+) neutrophils as an important source of BAFF upon BLM-induced lung inflammation and fibrosis. Genetic ablation of BAFF or BAFF neutralization by a soluble receptor significantly attenuated pulmonary fibrosis and IL-1β levels. We further demonstrate that bleomycin-induced BAFF expression and lung fibrosis were IL-1β and IL-17A dependent. BAFF was required for rIL-17A-induced lung fibrosis and augmented IL-17A production by CD3(+) T cells from murine fibrotic lungs ex vivo. Finally we report elevated levels of BAFF in bronchoalveolar lavages from IPF patients. Our data therefore support a role for BAFF in the establishment of pulmonary fibrosis and a crosstalk between IL-1β, BAFF and IL-17A. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Mortality on the Waiting List for Lung Transplantation in Patients with Idiopathic Pulmonary Fibrosis: A Single-Centre Experience.

    Science.gov (United States)

    Bennett, David; Fossi, Antonella; Bargagli, Elena; Refini, Rosa Metella; Pieroni, Maria; Luzzi, Luca; Ghiribelli, Claudia; Paladini, Piero; Voltolini, Luca; Rottoli, Paola

    2015-10-01

    Lung transplantation (LTX) is nowadays accepted as a treatment option for selected patients with end-stage pulmonary disease. Idiopathic pulmonary fibrosis (IPF) is characterized by the radiological and histologic appearance of usual interstitial pneumonia. It is associated with a poor prognosis, and LTX is considered an effective treatment to significantly modify the natural history of this disease. The aim of the present study was to analyse mortality during the waiting list in IPF patients at a single institution. A retrospective analysis on IPF patients (n = 90) referred to our Lung Transplant Program in the period 2001-2014 was performed focusing on patients' characteristics and associated risk factors. Diagnosis of IPF was associated with high mortality on the waiting list with respect to other diagnosis (p Pulmonary function tests failed to predict mortality and no other medical conditions were associated with survival. Patients newly diagnosed with IPF, especially in small to medium lung transplant volume centres and in Countries where a long waiting list is expected, should be immediately referred to transplantation, delay results in increased mortality. Early identification of IPF patients with a rapid progressive phenotype is strongly needed.

  15. Irreversible Respiratory Failure in a Full-Term Infant with Features of Pulmonary Interstitial Glycogenosis as Well as Bronchopulmonary Dysplasia

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    Maresa E. C. Jiskoot-Ermers

    2015-10-01

    Full Text Available Pulmonary interstitial glycogenosis (PIG is a rare interstitial lung disease in the newborns. We report on the clinical presentation and pathological findings of a full-term male infant with pulmonary hypertension requiring extracorporeal membrane oxygenation (ECMO. An open lung biopsy demonstrated interstitial changes resembling pulmonary interstitial glycogenosis as well as bronchopulmonary dysplasia (BPD, without convincing evidence of maturational arrest, infection, alveolar proteinosis, or alveolar capillary dysplasia. The boy was treated with glucocorticoids and, after a few days, was weaned from ECMO. A few hours later, the patient died due to acute severe pulmonary hypertension with acute right ventricular failure. The etiology and underlying pathogenic mechanisms of PIG are unknown. The clinical outcomes are quite varied. Deaths have been reported when PIG exists with abnormal lung development and pulmonary vascular growth and congenital heart disease. No mortality has been reported in PIG together with BPD in full-term infants. In this article, we reported on a full-term infant with interstitial changes resembling PIG and BPD who expired despite no convincing evidence of an anatomical maturational arrest or congenital heart disease.

  16. Bone marrow stem cells expressing keratinocyte growth factor via an inducible lentivirus protects against bleomycin-induced pulmonary fibrosis.

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    Susana Aguilar

    2009-11-01

    Full Text Available Many common diseases of the gas exchange surface of the lung have no specific treatment but cause serious morbidity and mortality. Idiopathic Pulmonary Fibrosis (IPF is characterized by alveolar epithelial cell injury, interstitial inflammation, fibroblast proliferation and collagen accumulation within the lung parenchyma. Keratinocyte Growth Factor (KGF, also known as FGF-7 is a critical mediator of pulmonary epithelial repair through stimulation of epithelial cell proliferation. During repair, the lung not only uses resident cells after injury but also recruits circulating bone marrow-derived cells (BMDC. Several groups have used Mesenchymal Stromal Cells (MSCs as therapeutic vectors, but little is known about the potential of Hematopoietic Stem cells (HSCs. Using an inducible lentiviral vector (Tet-On expressing KGF, we were able to efficiently transduce both MSCs and HSCs, and demonstrated that KGF expression is induced in a regulated manner both in vitro and in vivo. We used the in vivo bleomycin-induced lung fibrosis model to assess the potential therapeutic effect of MSCs and HSCs. While both populations reduced the collagen accumulation associated with bleomycin-induced lung fibrosis, only transplantation of transduced HSCs greatly attenuated the histological damage. Using double immunohistochemistry, we show that the reduced lung damage likely occurs through endogenous type II pneumocyte proliferation induced by KGF. Taken together, our data indicates that bone marrow transplantation of lentivirus-transduced HSCs can attenuate lung damage, and shows for the first time the potential of using an inducible Tet-On system for cell based gene therapy in the lung.

  17. The Role of Mitochondrial DNA in Mediating Alveolar Epithelial Cell Apoptosis and Pulmonary Fibrosis

    Science.gov (United States)

    Kim, Seok-Jo; Cheresh, Paul; Jablonski, Renea P.; Williams, David B.; Kamp, David W.

    2015-01-01

    Convincing evidence has emerged demonstrating that impairment of mitochondrial function is critically important in regulating alveolar epithelial cell (AEC) programmed cell death (apoptosis) that may contribute to aging-related lung diseases, such as idiopathic pulmonary fibrosis (IPF) and asbestosis (pulmonary fibrosis following asbestos exposure). The mammalian mitochondrial DNA (mtDNA) encodes for 13 proteins, including several essential for oxidative phosphorylation. We review the evidence implicating that oxidative stress-induced mtDNA damage promotes AEC apoptosis and pulmonary fibrosis. We focus on the emerging role for AEC mtDNA damage repair by 8-oxoguanine DNA glycosylase (OGG1) and mitochondrial aconitase (ACO-2) in maintaining mtDNA integrity which is important in preventing AEC apoptosis and asbestos-induced pulmonary fibrosis in a murine model. We then review recent studies linking the sirtuin (SIRT) family members, especially SIRT3, to mitochondrial integrity and mtDNA damage repair and aging. We present a conceptual model of how SIRTs modulate reactive oxygen species (ROS)-driven mitochondrial metabolism that may be important for their tumor suppressor function. The emerging insights into the pathobiology underlying AEC mtDNA damage and apoptosis is suggesting novel therapeutic targets that may prove useful for the management of age-related diseases, including pulmonary fibrosis and lung cancer. PMID:26370974

  18. Blockade of advanced glycation end product formation attenuates bleomycin-induced pulmonary fibrosis in rats

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    Liu Dai-Shun

    2009-06-01

    Full Text Available Abstract Background Advanced glycation end products (AGEs have been proposed to be involved in pulmonary fibrosis, but its role in this process has not been fully understood. To investigate the role of AGE formation in pulmonary fibrosis, we used a bleomycin (BLM-stimulated rat model treated with aminoguanidine (AG, a crosslink inhibitor of AGE formation. Methods Rats were intratracheally instilled with BLM (5 mg/kg and orally administered with AG (40, 80, 120 mg/kg once daily for two weeks. AGEs level in lung tissue was determined by ELISA and pulmonary fibrosis was evaluated by Ashcroft score and hydroxyproline assay. The expression of heat shock protein 47 (HSP47, a collagen specific molecular chaperone, was measured with RT-PCR and Western blot. Moreover, TGFβ1 and its downstream Smad proteins were analyzed by Western blot. Results AGEs level in rat lungs, as well as lung hydroxyproline content and Ashcroft score, was significantly enhanced by BLM stimulation, which was abrogated by AG treatment. BLM significantly increased the expression of HSP47 mRNA and protein in lung tissues, and AG treatment markedly decreased BLM-induced HSP47 expression in a dose-dependent manner (p Conclusion These findings suggest AGE formation may participate in the process of BLM-induced pulmonary fibrosis, and blockade of AGE formation by AG treatment attenuates BLM-induced pulmonary fibrosis in rats, which is implicated in inhibition of HSP47 expression and TGFβ/Smads signaling.

  19. [Nintedanib for the treatment of idiopathic pulmonary fibrosis in Italy

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    Andrea Belisari

    2017-04-01

    Full Text Available To date, there are few therapeutic answers for Idiopathic pulmonary fibrosis (IPF and only two pharmacological treatments have a marketing authorization for this disease. Recently nintedanib (Ofev® has been authorized as a new therapeutic option and its economic profile has been evaluated by international Health Technology Assessment (HTA bodies. IPF has important implications for everyday life of patients and their carers, negatively influencing their quality of life and bringing heavy economic burden to the NHS and to the entire society. It is, therefore important to consider these aspects for the Italian environment and to perform a pharmacoeconomic evaluation to define the efficiency of nintedanib in IPF by means of a Cost-Utility Analysis (CUA. As IPF is a chronic and progressive disease, a lifetime Markov model has been therefore developed with health states describing the patient’s condition as a combination of lung function and exacerbation history. The cohort entered in the model at different Forced Vital Capacity (FVC% predicted health states, without exacerbation. The Clinical data used to perform this CUA were derived from clinical trials and the relative efficacy of nintedanib versus the comparator (pirfenidone was then obtained from a Network Meta-Analysis (NMA combining data reported in each primary study (INPULSIS 1-2 and TOMORROW trials for nintedanib, and CAPACITY and ASCEND trials for pirfenidone, respectively. At base-case, treatment with nintedanib resulted in a slightly lower estimated total cost vs pirfenidone, better safety profile and lower risk of acute exacerbations with an advantage in Quality Adjusted Life years (QALYs gained. These results were confirmed by the sensitivity analysis. Although nintedanib appears to be a valuable option for the NHS to treat IPF patients, future data evidence, as long-term or real-life data, will help to confirm these results. [In Italian

  20. Pirfenidone treatment in idiopathic pulmonary fibrosis: A Saudi experience

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    Esam H Alhamad

    2015-01-01

    Full Text Available Background: Recent trials involving pirfenidone suggest a beneficial effect in the treatment of idiopathic pulmonary fibrosis (IPF. Objective: To report on the efficacy and safety of pirfenidone in the treatment of patients with IPF, at a tertiary care hospital in Saudi Arabia. Methods: The study included 58 patients with IPF who were evaluated from March 2012 to March 2013. During the study period, 33 patients received pirfenidone, and the remaining patients (n = 25 served as a control group. Baseline clinical characteristics, physiological parameters and the results of a 36-Item Short Form Health Survey (SF-36 were compared between the groups. Furthermore, we compared changes in forced vital capacity (FVC, diffusion capacity of the lung for carbon monoxide (DLco, six-minute walk distance (6MWD and SF-36 for both groups during follow-up. The last follow-up period ended in January 2014. Results: There were no significant differences in baseline clinical characteristics between the groups. Furthermore, we found no differences in FVC, DLco and SF-36 during follow-up (median, 12 months. However, patients receiving pirfenidone treatment were less likely to experience reductions in 6MWD compared with the control group (13% vs. 52%, respectively; P = 0.001. Although adverse events were more frequently reported by the pirfenidone group compared with the control group (85 vs. 56%, respectively; P = 0.015, these patients did not require discontinuation of treatment. Conclusion: Pirfenidone treatment preserves functional capacity, as reflected by the 6MWD. Adverse events associated with pirfenidone treatment were generally well tolerated by the patients.

  1. Inflammation and airway microbiota during cystic fibrosis pulmonary exacerbations.

    Directory of Open Access Journals (Sweden)

    Edith T Zemanick

    Full Text Available Pulmonary exacerbations (PEx, frequently associated with airway infection and inflammation, are the leading cause of morbidity in cystic fibrosis (CF. Molecular microbiologic approaches detect complex microbiota from CF airway samples taken during PEx. The relationship between airway microbiota, inflammation, and lung function during CF PEx is not well understood.To determine the relationships between airway microbiota, inflammation, and lung function in CF subjects treated for PEx.Expectorated sputum and blood were collected and lung function testing performed in CF subjects during early (0-3d. and late treatment (>7d. for PEx. Sputum was analyzed by culture, pyrosequencing of 16S rRNA amplicons, and quantitative PCR for total and specific bacteria. Sputum IL-8 and neutrophil elastase (NE; and circulating C-reactive protein (CRP were measured.Thirty-seven sputum samples were collected from 21 CF subjects. At early treatment, lower diversity was associated with high relative abundance (RA of Pseudomonas (r = -0.67, p<0.001, decreased FEV(1% predicted (r = 0.49, p = 0.03 and increased CRP (r = -0.58, p = 0.01. In contrast to Pseudomonas, obligate and facultative anaerobic genera were associated with less inflammation and higher FEV₁. With treatment, Pseudomonas RA and P. aeruginosa by qPCR decreased while anaerobic genera showed marked variability in response. Change in RA of Prevotella was associated with more variability in FEV₁ response to treatment than Pseudomonas or Staphylococcus.Anaerobes identified from sputum by sequencing are associated with less inflammation and higher lung function compared to Pseudomonas at early exacerbation. CF PEx treatment results in variable changes of anaerobic genera suggesting the need for larger studies particularly of patients without traditional CF pathogens.

  2. Disease severity staging system for idiopathic pulmonary fibrosis in Japan.

    Science.gov (United States)

    Kondoh, Yasuhiro; Taniguchi, Hiroyuki; Kataoka, Kensuke; Furukawa, Taiki; Ando, Masahiko; Murotani, Kenta; Mishima, Michiaki; Inoue, Yoshikazu; Ogura, Takashi; Bando, Masashi; Hagiwara, Koichi; Suda, Takafumi; Chiba, Hirofumi; Takahashi, Hiroki; Sugiyama, Yukihiko; Homma, Sakae

    2017-11-01

    In Japan, the classification of disease severity of idiopathic pulmonary fibrosis (IPF) (J-system) has been used in making decisions on medical care subsidies. The present J-system consists of arterial partial pressure of oxygen (PaO 2 ) and exercise desaturation in stages of I-IV. It provides a good prognostic classification in stages III and IV, but not in stages I and II. Therefore, we propose a revised system to improve discriminative ability in stages I and II. We compared the revised J-system with the present J-system using Cox proportional hazards model to predict mortality rate. We also evaluated the recently proposed GAP (Gender, Age and Physiology) system in comparison to both J-systems. Two-hundred and fifteen IPF patients were studied retrospectively. A univariate model showed that the present and revised J-systems and a modified GAP system were all significant prognostic factors. The C-statistic for discriminating prognosis was higher in the revised J-system than the modified GAP system and the present J-system (0.677, 0.652 and 0.659, respectively). The C-statistics of these models produced from the 10 000 bootstrap samples were similar to those of the original models, suggesting good internal validation (0.665 (95% CI: 0.621-0.705), 0.645 (0.600-0.686) and 0.659 (0.616-0.700), respectively). Multivariate analysis revealed that the revised J-system (P = 0.0038) and the modified GAP system (P = 0.0029) were independent prognostic factors. The revised J-system can provide a better mortality prediction than the present one. Both the revised J-system and the modified GAP system are independent and valuable tools for prognostication and clinical management for IPF. © 2017 Asian Pacific Society of Respirology.

  3. Upregulation of RGS2: a new mechanism for pirfenidone amelioration of pulmonary fibrosis.

    Science.gov (United States)

    Xie, Yan; Jiang, Haihong; Zhang, Qian; Mehrotra, Suneet; Abel, Peter W; Toews, Myron L; Wolff, Dennis W; Rennard, Stephen; Panettieri, Reynold A; Casale, Thomas B; Tu, Yaping

    2016-08-22

    Pirfenidone was recently approved for treatment of idiopathic pulmonary fibrosis. However, the therapeutic dose of pirfenidone is very high, causing side effects that limit its doses and therapeutic effectiveness. Understanding the molecular mechanisms of action of pirfenidone could improve its safety and efficacy. Because activated fibroblasts are critical effector cells associated with the progression of fibrosis, this study investigated the genes that change expression rapidly in response to pirfenidone treatment of pulmonary fibroblasts and explored their contributions to the anti-fibrotic effects of pirfenidone. We used the GeneChip microarray to screen for genes that were rapidly up-regulated upon exposure of human lung fibroblast cells to pirfenidone, with confirmation for specific genes by real-time PCR and western blots. Biochemical and functional analyses were used to establish their anti-fibrotic effects in cellular and animal models of pulmonary fibrosis. We identified Regulator of G-protein Signaling 2 (RGS2) as an early pirfenidone-induced gene. Treatment with pirfenidone significantly increased RGS2 mRNA and protein expression in both a human fetal lung fibroblast cell line and primary pulmonary fibroblasts isolated from patients without or with idiopathic pulmonary fibrosis. Pirfenidone treatment or direct overexpression of recombinant RGS2 in human lung fibroblasts inhibited the profibrotic effects of thrombin, whereas loss of RGS2 exacerbated bleomycin-induced pulmonary fibrosis and mortality in mice. Pirfenidone treatment reduced bleomycin-induced pulmonary fibrosis in wild-type but not RGS2 knockout mice. Endogenous RGS2 exhibits anti-fibrotic functions. Upregulated RGS2 contributes significantly to the anti-fibrotic effects of pirfenidone.

  4. Plzf as a Candidate Gene Predisposing the Spontaneously Hypertensive Rat to Hypertension, Left Ventricular Hypertrophy, and Interstitial Fibrosis

    Czech Academy of Sciences Publication Activity Database

    Liška, F.; Mancini, M.; Krupková, M.; Chylíková, B.; Křenová, D.; Šeda, O.; Šilhavý, Jan; Mlejnek, Petr; Landa, Vladimír; Zídek, Václav; d´Amati, G.; Pravenec, Michal; Křen, Vladimír

    2014-01-01

    Roč. 27, č. 1 (2014), s. 99-106 ISSN 0895-7061 R&D Projects: GA ČR(CZ) GAP301/10/0756; GA ČR(CZ) GAP301/12/0696; GA MŠk(CZ) LL1204; GA MŠk(CZ) 7E10067 Grant - others:Univerzita Karlova(CZ) PRVOUK-P25/LF1/2 Institutional support: RVO:67985823 Keywords : hypertension * left ventricular hypertrophy * myocardial interstitial fibrosis * spontaneously hypertensive rat * Plzf (promyelocytic leukemia zinc finger) gene Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.852, year: 2014

  5. Inflammatory Response Mechanisms Exacerbating Hypoxemia in Coexistent Pulmonary Fibrosis and Sleep Apnea

    Directory of Open Access Journals (Sweden)

    Ayodeji Adegunsoye

    2015-01-01

    Full Text Available Mediators of inflammation, oxidative stress, and chemoattractants drive the hypoxemic mechanisms that accompany pulmonary fibrosis. Patients with idiopathic pulmonary fibrosis commonly have obstructive sleep apnea, which potentiates the hypoxic stimuli for oxidative stress, culminating in systemic inflammation and generalized vascular endothelial damage. Comorbidities like pulmonary hypertension, obesity, gastroesophageal reflux disease, and hypoxic pulmonary vasoconstriction contribute to chronic hypoxemia leading to the release of proinflammatory cytokines that may propagate clinical deterioration and alter the pulmonary fibrotic pathway. Tissue inhibitor of metalloproteinase (TIMP-1, interleukin- (IL- 1α, cytokine-induced neutrophil chemoattractant (CINC-1, CINC-2α/β, lipopolysaccharide induced CXC chemokine (LIX, monokine induced by gamma interferon (MIG-1, macrophage inflammatory protein- (MIP- 1α, MIP-3α, and nuclear factor- (NF- κB appear to mediate disease progression. Adipocytes may induce hypoxia inducible factor (HIF 1α production; GERD is associated with increased levels of lactate dehydrogenase (LDH, alkaline phosphatase (ALP, and tumor necrosis factor alpha (TNF-α; pulmonary artery myocytes often exhibit increased cytosolic free Ca2+. Protein kinase C (PKC mediated upregulation of TNF-α and IL-1β also occurs in the pulmonary arteries. Increased understanding of the inflammatory mechanisms driving hypoxemia in pulmonary fibrosis and obstructive sleep apnea may potentiate the identification of appropriate therapeutic targets for developing effective therapies.

  6. Protease-activated receptor-2 induces myofibroblast differentiation and tissue factor up-regulation during bleomycin-induced lung injury: Potential role in pulmonary fibrosis

    NARCIS (Netherlands)

    K. Borensztajn (Keren); P. Bresser (Paul); C.M. van der Loos (Chris); I. Bot (Ilze); B. van den Blink (Bernt); M.A. den Bakker (Michael); J. Daalhuisen (Joost); A.P. Groot (Angelique); M.P. Peppelenbosch (Maikel); J. von der Thusen (Jan); C.A. Spek (Arnold)

    2010-01-01

    textabstractIdiopathic pulmonary fibrosis constitutes the most devastating form of fibrotic lung disorders and remains refractory to current therapies. The coagulation cascade is frequently activated during pulmonary fibrosis, but this observation has so far resisted a mechanistic explanation.

  7. Novel form of miR-29b suppresses bleomycin-induced pulmonary fibrosis.

    Directory of Open Access Journals (Sweden)

    Yuko Yamada

    Full Text Available MicroRNA 29b (miR-29b replacement therapy is effective for suppressing fibrosis in a mouse model. However, to develop clinical applications for miRNA mimics, the side effects of nucleic acid drugs have to be addressed. In this study, we focused on miRNA mimics in order to develop therapies for idiopathic pulmonary fibrosis. We developed a single-stranded RNA, termed "miR-29b Psh-match," that has a unique structure to avoid problems associated with the therapeutic uses of miRNAs. A comparison of miR-29b Psh-match and double-stranded one, termed "miR-29b mimic" indicated that the single-stranded form was significantly effective towards fibrosis according to both in vivo and in vitro experiments. This novel form of miR-29b may become the foundation for developing an effective therapeutic drug for pulmonary fibrosis.

  8. The Processes and Mechanisms of Cardiac and Pulmonary Fibrosis

    Directory of Open Access Journals (Sweden)

    Lucy A. Murtha

    2017-10-01

    Full Text Available Fibrosis is the formation of fibrous connective tissue in response to injury. It is characterized by the accumulation of extracellular matrix components, particularly collagen, at the site of injury. Fibrosis is an adaptive response that is a vital component of wound healing and tissue repair. However, its continued activation is highly detrimental and a common final pathway of numerous disease states including cardiovascular and respiratory disease. Worldwide, fibrotic diseases cause over 800,000 deaths per year, accounting for ~45% of total deaths. With an aging population, the incidence of fibrotic disease and subsequently the number of fibrosis-related deaths will rise further. Although, fibrosis is a well-recognized cause of morbidity and mortality in a range of disease states, there are currently no viable therapies to reverse the effects of chronic fibrosis. Numerous predisposing factors contribute to the development of fibrosis. Biological aging in particular, interferes with repair of damaged tissue, accelerating the transition to pathological remodeling, rather than a process of resolution and regeneration. When fibrosis progresses in an uncontrolled manner, it results in the irreversible stiffening of the affected tissue, which can lead to organ malfunction and death. Further investigation into the mechanisms of fibrosis is necessary to elucidate novel, much needed, therapeutic targets. Fibrosis of the heart and lung make up a significant proportion of fibrosis-related deaths. It has long been established that the heart and lung are functionally and geographically linked when it comes to health and disease, and thus exploring the processes and mechanisms that contribute to fibrosis of each organ, the focus of this review, may help to highlight potential avenues of therapeutic investigation.

  9. Pulmonary hypertension in childhood interstitial lung disease: A systematic review of the literature.

    Science.gov (United States)

    Bromley, Susan; Vizcaya, David

    2017-05-01

    Childhood interstitial lung disease (chILD) comprises a wide heterogeneous group of rare parenchymal lung disorders associated with substantial morbidity and mortality. Pulmonary hypertension is a common comorbidity in adults with interstitial lung disease (ILD) and associated with poor survival. We aimed to systematically review the literature regarding the occurrence of pulmonary hypertension (PH) in chILD, its effect on prognosis and healthcare use, and its treatment in clinical practice. Searches of PubMed and EMBASE databases (up to February 2016), and American Thoracic Society conference abstracts (2009-2015) were conducted using relevant keywords. References from selected articles and review papers were scanned to identify further relevant articles. A total of 20 articles were included; estimates of PH in chILD ranged from 1% to 64% with estimates among specific chILD entities ranging from 0% to 43%. Comparisons between studies were limited by differences in the study populations, including the size, age range, and heterogeneous composition of the ILD case series in terms of the nature and severity of the clinical entities, and also the methods used to diagnose PH. Three studies found that among patients with chILD, those with PH had a significantly higher risk (up to sevenfold) of death compared with those without PH. Information on the treatment of pulmonary hypertension in chILD or the effect of PH on healthcare use was not available. Data on the use and effectiveness of treatments for pulmonary hypertension in chILD are required to address this area of unmet need. Pediatr Pulmonol. 2017;52:689-698. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  10. Pyrrolidinedithiocarbamate attenuates bleomycin-induced pulmonary fibrosis in rats: Modulation of oxidative stress, fibrosis, and inflammatory parameters.

    Science.gov (United States)

    Zaafan, Mai A; Zaki, Hala F; El-Brairy, Amany I; Kenawy, Sanaa A

    The current study aimed to investigate the modulatory effects of pyrrolidinedithiocarbamate (PDTC; 100 mg/kg) on bleomycin-induced pulmonary fibrosis (5 mg/kg; intratracheal) in rats. Rats were randomly assigned to three groups: normal control, bleomycin control, and PDTC-treated groups. Lung injury was evaluated through histological examination, immunohistochemical detection of inducible nitric oxide synthase (iNOS) in lung tissue and evaluating the total and differential leucocytes count in bronchoalveolar lavage fluid. Lung tissue was used for biochemical assessment of lung content of hydroxyproline, transforming growth factor beta-1 (TGF-β1), tumor necrosis factor-alpha (TNF-α) as well as analysis of lipid peroxides, reduced glutathione (GSH), and total nitrite contents. PDTC attenuated bleomycin-induced pulmonary fibrosis as evidenced by histological observations, decreased iNOS expression and prevention of bleomycin-induced altered total and differential leukocytes count. Additionally, PDTC caused a significant decrease in lung contents of hydroxyproline, TGF-β1, TNF-α, lipid peroxides, and total nitrite coupled with increase in lung GSH content as compared to bleomycin control group. PDTC attenuated bleomycin-induced pulmonary fibrosis in rats via its anti-inflammatory, antioxidant, and antifibrotic activities.

  11. Protocatechuic aldehyde ameliorates experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Liang, E-mail: countryspring@sina.com; Ji, Yunxia, E-mail: 413499057@qq.com; Kang, Zechun, E-mail: davidjiangwl@163.com; Lv, Changjun, E-mail: Lucky_lcj@sina.com; Jiang, Wanglin, E-mail: jwl518@163.com

    2015-02-15

    An abnormal high mobility group box 1 (HMGB1) activation and a decrease in receptor for advanced glycation end-product (RAGE) play a key role in the pathogenesis of pulmonary fibrosis. Protocatechuic aldehyde (PA) is a naturally occurring compound, which is extracted from the degradation of phenolic acids. However, whether PA has anti-fibrotic functions is unknown. In this study, the effects of PA on the transforming growth factor-β1 (TGF-β1)-mediated epithelial–mesenchymal transition (EMT) in A549 cells, on the apoptosis of human type I alveolar epithelial cells (AT I), on the proliferation of human lung fibroblasts (HLF-1) in vitro, and on bleomycin (BLM)-induced pulmonary fibrosis in vivo were investigated. PA treatment resulted in a reduction of EMT in A549 cells with a decrease in vimentin and HMGB, an increase of E-cadherin and RAGE, a reduction of HLF-1 proliferation with a decrease of fibroblast growth factor 2 (FGF-2) and platelet-derived growth factor (PDGF). Apoptosis of AT I was attenuated with an increase of RAGE. PA ameliorated BLM-induced pulmonary fibrosis in rats with a reduction of histopathological scores and collagen deposition, and a lower FGF-2, PDGF, α-smooth muscle actin (α-SMA) and HMGB1 expression, whereas higher RAGE was found in BLM-instilled lungs. Through the decrease of HGMB1 and the regulation of RAGE, PA reversed the EMT, inhibited HLF-1 proliferation as well as reduced apoptosis in AT I, and prevented pulmonary fibrosis in vivo. Collectively, our results demonstrate that PA prevents experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway. - Highlights: • PA prevents EMT, reduces the apoptosis of AT1 in vitro. • PA decreases proliferation of HLF-1, reduces PDGF and FGF expression in vitro. • PA prevents experimental pulmonary fibrosis by modulating the HMGB1/RAGE pathway.

  12. [Expression of PEPT2 mRNA in lung tissue of rats with pulmonary fibrosis].

    Science.gov (United States)

    Li, Li; Wang, Dianhua; Zhang, Xuan; Song, Xin; Ma, Xiaobiao; Hu, Zaoxiu

    2013-10-20

    Pulmonary fibrosis is a common pathological phenomenon in lung cancer patients after chemotherapy or radiotherapy. It is also a key hindrance to the transport of drugs to lung tissue. Peptide transporters have become a target of the rational design of peptides and peptide drugs. The aim of this study is to investigates the expression of peptide transporter 2 (PEPT2) mRNA in the lungs of rats with bleomycin (BLM)-induced pulmonary fibrosis. Fifty healthy adult Sprague-Dawley rats were randomly divided into five groups. One group was untreated (control), the second group was injected with normal saline solution (NS), and the three remaining groups were treated with a single dose of bleomycin to induce pulmonary fibrosis (BLM). Rats from the NS group were killed by exsanguination on day 14. Rats from the BLM group were killed by exsanguination on days 7, 14, and 28. The lung samples were observed under light microscopy and the hydroxyproline concentration was determined. The expression levels of PEPT2 mRNA were measured by RT-PCR. The morphological study showed that collagenous fiber proliferated in the lungs of rats injected with BLM, indicating pulmonary fibrosis. This proliferation was apparent at 14 d post-injection and especially at 28 d post-injection. Hydroxyproline levels increased seven days post-injection compared with the control group and NS group, but there was no significant statistical difference (P>0.05). Hydroxyproline levels significantly increased (Ppulmonary PEPT2 mRNA expression levels among the different groups (P>0.05). PEPT2 is a potential peptide drug target in the treatment of pulmonary fibrosis, although there were no significant changes of PEPT2 mRNA expression in the lungs of rats with bleomycin-induced pulmonary fibrosis.

  13. Adiponectin attenuates lung fibroblasts activation and pulmonary fibrosis induced by paraquat.

    Science.gov (United States)

    Yao, Rong; Cao, Yu; He, Ya-rong; Lau, Wayne Bond; Zeng, Zhi; Liang, Zong-an

    2015-01-01

    Pulmonary fibrosis is one of the most common complications of paraquat (PQ) poisoning, which demands for more effective therapies. Accumulating evidence suggests adiponectin (APN) may be a promising therapy against fibrotic diseases. In the current study, we determine whether the exogenous globular APN isoform protects against pulmonary fibrosis in PQ-treated mice and human lung fibroblasts, and dissect the responsible underlying mechanisms. BALB/C mice were divided into control group, PQ group, PQ + low-dose APN group, and PQ + high-dose APN group. Mice were sacrificed 3, 7, 14, and 21 days after PQ treatment. We compared pulmonary histopathological changes among different groups on the basis of fibrosis scores, TGF-β1, CTGF and α-SMA pulmonary content via Western blot and real-time quantitative fluorescence-PCR (RT-PCR). Blood levels of MMP-9 and TIMP-1 were determined by ELISA. Human lung fibroblasts WI-38 were divided into control group, PQ group, APN group, and APN receptor (AdipoR) 1 small-interfering RNA (siRNA) group. Fibroblasts were collected 24, 48, and 72 hours after PQ exposure for assay. Cell viability and apoptosis were determined via Kit-8 (CCK-8) and fluorescein Annexin V-FITC/PI double labeling. The protein and mRNA expression level of collagen type III, AdipoR1, and AdipoR2 were measured by Western blot and RT-PCR. APN treatment significantly decreased the lung fibrosis scores, protein and mRNA expression of pulmonary TGF-β1, CTGF and α-SMA content, and blood MMP-9 and TIMP-1 in a dose-dependent manner (ppulmonary fibrosis in a dose-dependent manner, via suppression of lung fibroblast activation. Functional AdipoR1 are expressed by human WI-38 lung fibroblasts, suggesting potential future clinical applicability of APN against pulmonary fibrosis.

  14. Expression of PEPT2 mRNA in Lung Tissue of Rats with Pulmonary Fibrosis

    Directory of Open Access Journals (Sweden)

    Li LI

    2013-10-01

    Full Text Available Background and objective Pulmonary fibrosis is a common pathological phenomenon in lung cancer patients after chemotherapy or radiotherapy. It is also a key hindrance to the transport of drugs to lung tissue. Peptide transporters have become a target of the rational design of peptides and peptide drugs. The aim of this study is to investigates the expression of peptide transporter 2 (PEPT2 mRNA in the lungs of rats with bleomycin (BLM-induced pulmonary fibrosis. Methods Fifty healthy adult Sprague-Dawley rats were randomly divided into five groups. One group was untreated (control, the second group was injected with normal saline solution (NS, and the three remaining groups were treated with a single dose of bleomycin to induce pulmonary fibrosis (BLM. Rats from the NS group were killed by exsanguination on day 14. Rats from the BLM group were killed by exsanguination on days 7, 14, and 28. The lung samples were observed under light microscopy and the hydroxyproline concentration was determined. The expression levels of PEPT2 mRNA were measured by RT-PCR. Results The morphological study showed that collagenous fiber proliferated in the lungs of rats injected with BLM, indicating pulmonary fibrosis. This proliferation was apparent at 14 d post-injection and especially at 28 d post-injection. Hydroxyproline levels increased seven days post-injection compared with the control group and NS group, but there was no significant statistical difference (P>0.05. Hydroxyproline levels significantly increased (P0.05. Conclusion PEPT2 is a potential peptide drug target in the treatment of pulmonary fibrosis, although there were no significant changes of PEPT2 mRNA expression in the lungs of rats with bleomycin-induced pulmonary fibrosis.

  15. Pulmonary fibrosis in youth treated with radioiodine for juvenile thyroid cancer and lung metastases after Chernobyl

    International Nuclear Information System (INIS)

    Hebestreit, Helge; Burkhardt, Antje; Biko, Johannes; Reiners, Christoph; Drozd, Valentina; Demidchik, Yuri; Trusen, Andreas; Beer, Meinrad

    2011-01-01

    The objective of this project was to systematically determine the prevalence and consequences of pulmonary fibrosis in youth with thyroid carcinoma and lung metastases from Belarus who were treated with radioiodine ( 131 I). A total of 69 patients treated for juvenile thyroid carcinoma and lung metastasis with 131 I were assessed. A group of 29 patients without lung metastases and prior 131 I treatment served as controls. The assessments included a CT scan of the lungs, extensive pulmonary function testing and an incremental cycle test to volitional fatigue with measurements of oxygen uptake (V. O 2 ), oxygen saturation and alveolar-arterial difference in oxygen partial pressure (ΔaaO 2 ). Five patients with lung metastases showed advanced pulmonary fibrosis on CT scans and also had poorer lung functions compared with the 62 patients with none or minor signs of fibrosis and the 29 controls. Furthermore, these five patients showed lower peak V.O 2 , lower oxygen saturation at peak exercise and higher exercise ΔaaO 2 . They were younger at the time of cancer diagnosis and had received chemotherapy more frequently than youth with pulmonary metastases who did not develop fibrosis. One of the five patients subsequently died from pulmonary fibrosis. Following the Chernobyl catastrophe, about 7% of children treated with radioiodine for thyroid carcinoma and lung metastases displayed pulmonary fibrosis which was associated with functional impairments. Based on the characteristics of affected individuals, the number of radioiodine courses may have to be limited, especially in young children, and chemotherapy should be avoided. (orig.)

  16. The Processes and Mechanisms of Cardiac and Pulmonary Fibrosis

    NARCIS (Netherlands)

    Murtha, Lucy A.; Schuliga, Michael J.; Mabotuwana, Nishani S.; Hardy, Sean A.; Waters, David W.; Burgess, Janette K.; Knight, Darryl A.; Boyle, Andrew J.

    2017-01-01

    Fibrosis is the formation of fibrous connective tissue in response to injury. It is characterized by the accumulation of extracellular matrix components, particularly collagen, at the site of injury. Fibrosis is an adaptive response that is a vital component of wound healing and tissue repair.

  17. Optimization of a Collagen-Targeted PET Probe for Molecular Imaging of Pulmonary Fibrosis.

    Science.gov (United States)

    Désogère, Pauline; Tapias, Luis F; Rietz, Tyson A; Rotile, Nicholas; Blasi, Francesco; Day, Helen; Elliott, Justin; Fuchs, Bryan C; Lanuti, Michael; Caravan, Peter

    2017-12-01

    There is a large unmet need for a simple, accurate, noninvasive, quantitative, and high-resolution imaging modality to detect lung fibrosis at early stage and to monitor disease progression. Overexpression of collagen is a hallmark of organ fibrosis. Here, we describe the optimization of a collagen-targeted PET probe for staging pulmonary fibrosis. Methods: Six peptides were synthesized, conjugated to a copper chelator, and radiolabeled with 64 Cu. The collagen affinity of each probe was measured in a plate-based assay. The pharmacokinetics and metabolic stability of the probes were studied in healthy rats. The capacity of these probes to detect and stage pulmonary fibrosis in vivo was assessed in a mouse model of bleomycin-induced fibrosis using PET imaging. Results: All probes exhibited affinities in the low micromolar range (1.6 μM collagen was confirmed by comparison with a nonbinding isomer. Conclusion: 64 Cu-CBP7 is a promising candidate for in vivo imaging of pulmonary fibrosis. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

  18. The in vivo fibrotic role of FIZZ1 in pulmonary fibrosis.

    Directory of Open Access Journals (Sweden)

    Tianju Liu

    Full Text Available FIZZ (found in inflammatory zone 1, a member of a cysteine-rich secreted protein family, is highly induced in lung allergic inflammation and bleomycin induced lung fibrosis, and primarily expressed by airway and type II alveolar epithelial cells. This novel mediator is known to stimulate α-smooth muscle actin and collagen expression in lung fibroblasts. The objective of this study was to investigate the in vivo effects of FIZZ1 on the development of lung fibrosis by evaluating bleomycin-induced pulmonary fibrosis in FIZZ1 deficient mice. FIZZ1 knockout mice exhibited no detectable abnormality. When these mice were treated with bleomycin they exhibited significantly impaired pulmonary fibrosis relative to wild type mice, along with impaired proinflammatory cytokine/chemokine expression. Deficient lung fibroblast activation was also noted in the FIZZ1 knockout mice. Moreover, recruitment of bone marrow-derived cells to injured lung was deficient in FIZZ1 knockout mice. Interestingly in vitro FIZZ1 was shown to have chemoattractant activity for bone marrow cells, including bone marrow-derived dendritic cells. Finally, overexpression of FIZZ1 exacerbated fibrosis. These findings suggested that FIZZ1 exhibited profibrogenic properties essential for bleomycin induced pulmonary fibrosis, as reflected by its ability to induce myofibroblast differentiation and recruit bone marrow-derived cells.

  19. Increased hemoglobin-oxygen affinity ameliorates bleomycin-induced hypoxemia and pulmonary fibrosis.

    Science.gov (United States)

    Geng, Xin; Dufu, Kobina; Hutchaleelaha, Athiwat; Xu, Qing; Li, Zhe; Li, Chien-Ming; Patel, Mira P; Vlahakis, Nicholas; Lehrer-Graiwer, Josh; Oksenberg, Donna

    2016-09-01

    Although exertional dyspnea and worsening hypoxia are hallmark clinical features of idiopathic pulmonary fibrosis (IPF), no drug currently available could treat them. GBT1118 is a novel orally bioavailable small molecule that binds to hemoglobin and produces a concentration-dependent left shift of the oxygen-hemoglobin dissociation curve with subsequent increase in hemoglobin-oxygen affinity and arterial oxygen loading. To assess whether pharmacological modification of hemoglobin-oxygen affinity could ameliorate hypoxemia associated with lung fibrosis, we evaluated GBT1118 in a bleomycin-induced mouse model of hypoxemia and fibrosis. After pulmonary fibrosis and hypoxemia were induced, GBT1118 was administered for eight consecutive days. Hypoxemia was determined by monitoring arterial oxygen saturation, while the severity of pulmonary fibrosis was assessed by histopathological evaluation and determination of collagen and leukocyte levels in bronchoalveolar lavage fluid. We found that hemoglobin modification by GBT1118 had strong antihypoxemic therapeutic effects with improved arterial oxygen saturation to near normal level. Moreover, GBT1118 treatment significantly attenuated bleomycin-induced lung fibrosis, collagen accumulation, body weight loss, and leukocyte infiltration. This study is the first to suggest the beneficial effects of hemoglobin modification in fibrotic lungs and offers a promising and novel therapeutic strategy for the treatment of hypoxemia associated with chronic fibrotic lung disorders in human, including IPF. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  20. The K+ channel KCa3.1 as a novel target for idiopathic pulmonary fibrosis.

    Directory of Open Access Journals (Sweden)

    Katy M Roach

    Full Text Available Idiopathic pulmonary fibrosis (IPF is a common, progressive and invariably lethal interstitial lung disease with no effective therapy. We hypothesised that K(Ca3.1 K(+ channel-dependent cell processes contribute to IPF pathophysiology.K(Ca3.1 expression in primary human lung myofibroblasts was examined using RT-PCR, western blot, immunofluorescence and patch-clamp electrophysiology. The role of K(Ca3.1 channels in myofibroblast proliferation, wound healing, collagen secretion and contraction was examined using two specific and distinct K(Ca3.1 blockers (TRAM-34 and ICA-17043 [Senicapoc].Both healthy non fibrotic control and IPF-derived human lung myofibroblasts expressed K(Ca3.1 channel mRNA and protein. K(Ca3.1 ion currents were elicited more frequently and were larger in IPF-derived myofibroblasts compared to controls. K(Ca3.1 currents were increased in myofibroblasts by TGFβ1 and basic FGF. K(Ca3.1 was expressed strongly in IPF tissue. K(Ca3.1 pharmacological blockade attenuated human myofibroblast proliferation, wound healing, collagen secretion and contractility in vitro, and this was associated with inhibition of TGFβ1-dependent increases in intracellular free Ca(2+.K(Ca3.1 activity promotes pro-fibrotic human lung myofibroblast function. Blocking K(Ca3.1 may offer a novel approach to treating IPF with the potential for rapid translation to the clinic.

  1. Sleep as a New Target for Improving Outcomes in Idiopathic Pulmonary Fibrosis.

    Science.gov (United States)

    Mermigkis, Charalampos; Bouloukaki, Izolde; Schiza, Sophia E

    2017-12-01

    Idiopathic pulmonary fibrosis (IPF) is the most common type of interstitial pneumonia but remains a disease with a poor outcome. Two drugs, pirfenidone and nintedanib, have shown promising results at stalling disease progression; however, the interplay of sleep disruption or sleep disorders overall and in relation to medication effectiveness remains understudied. In the past, there was limited interest in the role of sleep in patients with IPF. Treating physicians tended to address only the daily disabling symptoms while disregarding the possible significant role of sleep alterations or coexisting sleep disorders. During the past few years, there has been more research related to sleep disturbances in patients with IPF and their possible role in sleep and overall life quality, disease progression, and outcome. In summary, sleep in patients with IPF is significantly impaired, with alterations in sleep architecture, changes in sleep breathing pattern, and decreases in oxygen saturation mainly during vulnerable rapid eye movement sleep. There also is evidence that OSA has an increased prevalence in these patients, playing an important role in the already worse sleep quality related to the disease itself. The focus of this review is not only to present current data related to sleep in patients with IPF but also to point out that therapy for sleep problems and OSA is likely to improve sleep and life quality as well as disease outcome. The main priority remains to increase awareness among treating physicians about early diagnosis of OSA in patients with IPF and to emphasize the need for intense future research, especially on the role of intermittent hypoxia superimposed on chronic hypoxia during sleep in patients with IPF. Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

  2. Incidence and prevalence of idiopathic pulmonary fibrosis: review of the literature

    Directory of Open Access Journals (Sweden)

    Luba Nalysnyk

    2012-12-01

    Full Text Available Idiopathic pulmonary fibrosis (IPF is a chronic, progressive, fibrosing interstitial pneumonia of unknown aetiology. It is a rare disease, and its incidence and prevalence are not clear. Therefore, we sought to review the published evidence on the global epidemiology of IPF. A comprehensive review of English language literature was performed by searching Medline and EMBASE for studies on IPF epidemiology published between January 1990 and August 2011. Studies providing quantitative data on IPF incidence and/or prevalence were identified and key data collected. 15 studies reporting on the incidence and/or prevalence of IPF were identified and summarised. IPF prevalence estimates in the USA varied between 14 and 27.9 cases per 100,000 population using narrow case definitions, and 42.7 and 63 per 100,000 population using broad case definitions. In Europe, IPF prevalence ranged from 1.25 to 23.4 cases per 100,000 population. The annual incidence of IPF in the USA was estimated at 6.8–8.8 per 100,000 population using narrow case definitions and 16.3–17.4 per 100,000 population using broad case definitions. In Europe, the annual incidence ranged between 0.22 and 7.4 per 100,000 population. IPF prevalence and incidence increase with age, are higher among males and appear to be on the increase in recent years. IPF is an orphan disease that affects a potentially increasing number of people in Europe and the USA. The observed variability in IPF incidence and prevalence may be explained by the differences in diagnostic criteria used, case definition, study population and study design.

  3. Cleaved cytokeratin-18 is a mechanistically informative biomarker in idiopathic pulmonary fibrosis

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    Cha Seung-Ick

    2012-11-01

    Full Text Available Abstract Background Stress of the endoplasmic reticulum (ER leading to activation of the unfolded protein response (UPR and alveolar epithelial cell (AEC apoptosis may play a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF. Our objectives were to determine whether circulating caspase-cleaved cytokeratin-18 (cCK-18 is a marker of AEC apoptosis in IPF, define the relationship of cCK-18 with activation of the UPR, and assess its utility as a diagnostic biomarker. Methods IPF and normal lung tissues were stained with the antibody (M30 that specifically binds cCK-18. The relationship between markers of the UPR and cCK-18 was determined in AECs exposed in vitro to thapsigargin to induce ER stress. cCK-18 was measured in serum from subjects with IPF, hypersensitivity pneumonitis (HP, nonspecific interstitial pneumonia (NSIP, and control subjects. Results cCK-18 immunoreactivity was present in AECs of IPF lung, but not in control subjects. Markers of the UPR (phosphorylated IRE-1α and spliced XBP-1 were more highly expressed in IPF type II AECs than in normal type II AECs. Phosphorylated IRE-1α and cCK-18 increased following thapsigargin-induced ER stress. Serum cCK-18 level distinguished IPF from diseased and control subjects. Serum cCK-18 was not associated with disease severity or outcome. Conclusions cCK-18 may be a marker of AEC apoptosis and UPR activation in patients with IPF. Circulating levels of cCK-18 are increased in patients with IPF and cCK-18 may be a useful diagnostic biomarker.

  4. Clinical and economic burden of idiopathic pulmonary fibrosis in Quebec, Canada.

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    Tarride, Jean-Eric; Hopkins, Robert B; Burke, Natasha; Guertin, Jason R; O'Reilly, Daria; Fell, Charlene D; Dion, Genevieve; Kolb, Martin

    2018-01-01

    Idiopathic pulmonary fibrosis (IPF), although rare, is a severe and costly disease. To estimate the clinical and economic burden of IPF over multiple years before and after diagnosis using comprehensive administrative databases for the province of Quebec, Canada. Several administrative databases from Quebec, providing information on hospital care, community care, and pharmaceuticals, were linked over a 5-year period ending March 31, 2011, which was before approval of antifibrotic drugs in Canada. Prevalent and incident IPF cases were defined using International Classification Disease-10-CA codes and International Classification Disease-9-CM codes. We used a broad definition that excluded cases with subsequent diagnosis of other interstitial lung diseases and a narrow definition that required further diagnostic testing to confirm IPF diagnosis. Incident cases had an IPF code in a particular year without any IPF code in the 2 previous years. Health care resource utilization before and after the index diagnosis date was determined and costs calculated. Costs were expressed in 2016 Canadian dollars. Over 5-years, 10,579 (mean age: 76.4; 58% male) satisfied the broad definition of IPF and 8,683 (mean age: 74.5; 57% male) satisfied the narrow definition (82% of broad). Incidences of IPF overall were 25.8 and 21.7/100,000 population for broad and narrow definitions, respectively. Three-year survival was 40% and 37% in broad and narrow cohorts, respectively. For both cohorts, health care resource utilization and costs increased several years before diagnosis ($2,721 and $7,049/patient 5 years and 2 years prior to diagnosis using a broad definition, respectively) and remained elevated for multiple years post diagnosis ($12,978 and $8,267 at 2 and 3 years postdiagnosis). Health care resource utilization and costs of IPF increase many years prior to diagnosis. Incorporating multiyear annual costs before and after diagnosis results in a higher estimate of the economic burden

  5. Improving biocuration of microRNAs in diseases: a case study in idiopathic pulmonary fibrosis

    Science.gov (United States)

    Rinaldi, Fabio; Contreras, Gabriela; Solano-Lira, Hilda; Sánchez-Pérez, Mishael; Collado-Vides, Julio; Selman, Moisés; Pardo, Annie

    2017-01-01

    Abstract MicroRNAs (miRNAs) are small and non-coding RNA molecules that inhibit gene expression posttranscriptionally. They play important roles in several biological processes, and in recent years there has been an interest in studying how they are related to the pathogenesis of diseases. Although there are already some databases that contain information for miRNAs and their relation with illnesses, their curation represents a significant challenge due to the amount of information that is being generated every day. In particular, respiratory diseases are poorly documented in databases, despite the fact that they are of increasing concern regarding morbidity, mortality and economic impacts. In this work, we present the results that we obtained in the BioCreative Interactive Track (IAT), using a semiautomatic approach for improving biocuration of miRNAs related to diseases. Our procedures will be useful to complement databases that contain this type of information. We adapted the OntoGene text mining pipeline and the ODIN curation system in a full-text corpus of scientific publications concerning one specific respiratory disease: idiopathic pulmonary fibrosis, the most common and aggressive of the idiopathic interstitial cases of pneumonia. We curated 823 miRNA text snippets and found a total of 246 miRNAs related to this disease based on our semiautomatic approach with the system OntoGene/ODIN. The biocuration throughput improved by a factor of 12 compared with traditional manual biocuration. A significant advantage of our semiautomatic pipeline is that it can be applied to obtain the miRNAs of all the respiratory diseases and offers the possibility to be used for other illnesses. Database URL: http://odin.ccg.unam.mx/ODIN/bc2015-miRNA/ PMID:28605770

  6. Immunoglobulin free light chains are increased in hypersensitivity pneumonitis and idiopathic pulmonary fibrosis.

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    Tom Groot Kormelink

    Full Text Available BACKGROUND: Idiopathic pulmonary fibrosis (IPF, a devastating lung disorder of unknown aetiology, and chronic hypersensitivity pneumonitis (HP, a disease provoked by an immunopathologic reaction to inhaled antigens, are two common interstitial lung diseases with uncertain pathogenic mechanisms. Previously, we have shown in other upper and lower airway diseases that immunoglobulin free light chains (FLCs are increased and may be involved in initiating a local inflammation. In this study we explored if such a mechanism may also apply to HP and IPF. METHODS: In this study we examined the presence of FLC in serum and BAL fluid from 21 IPF and 22 HP patients and controls. IgG, IgE and tryptase concentrations were measured in BAL fluid only. The presence of FLCs, plasma cells, B cells and mast cells in lung tissue of 3 HP and 3 IPF patients and 1 control was analyzed using immunohistochemistry. RESULTS: FLC concentrations in serum and BAL fluid were increased in IPF and HP patients as compared to control subjects. IgG concentrations were only increased in HP patients, whereas IgE concentrations were comparable to controls in both patient groups. FLC-positive cells, B cells, plasma cells, and large numbers of activated mast cells were all detected in the lungs of HP and IPF patients, not in control lung. CONCLUSION: These results show that FLC concentrations are increased in serum and BAL fluid of IPF and HP patients and that FLCs are present within affected lung tissue. This suggests that FLCs may be involved in mediating pathology in both diseases.

  7. Contribution of Fetal, but Not Adult, Pulmonary Mesothelium to Mesenchymal Lineages in Lung Homeostasis and Fibrosis.

    Science.gov (United States)

    von Gise, Alexander; Stevens, Sean M; Honor, Leah B; Oh, Jin Hee; Gao, Chi; Zhou, Bin; Pu, William T

    2016-02-01

    The lung is enveloped by a layer of specialized epithelium, the pulmonary mesothelium. In other organs, mesothelial cells undergo epithelial-mesenchymal transition and contribute to organ stromal cells. The contribution of pulmonary mesothelial cells (PMCs) to the developing lung has been evaluated with differing conclusions. PMCs have also been indirectly implicated in lung fibrosis in the progressive, fatal lung disease idiopathic pulmonary fibrosis. We used fetal or postnatal genetic pulse labeling of PMCs to assess their fate in murine development, normal lung homeostasis, and models of pulmonary fibrosis. We found that most fetal PMC-derived mesenchymal cells (PMCDCs) expressed markers of pericytes and fibroblasts, only a small minority expressed smooth muscle markers, and none expressed endothelial cell markers. Postnatal PMCs did not contribute to lung mesenchyme during normal lung homeostasis or in models of lung fibrosis. However, fetal PMCDCs were abundant and actively proliferating within fibrotic regions in lung fibrosis models, suggesting that they actively participate in the fibrotic process. These data clarify the role of fetal and postnatal PMCDCs in lung development and disease.

  8. Repetitive intradermal bleomycin injections evoke T-helper cell 2 cytokine-driven pulmonary fibrosis.

    Science.gov (United States)

    Singh, Brijendra; Kasam, Rajesh K; Sontake, Vishwaraj; Wynn, Thomas A; Madala, Satish K

    2017-11-01

    IL-4 and IL-13 are major T-helper cell (Th) 2 cytokines implicated in the pathogenesis of several lung diseases, including pulmonary fibrosis. In this study, using a novel repetitive intradermal bleomycin model in which mice develop extensive lung fibrosis and a progressive decline in lung function compared with saline-treated control mice, we investigated profibrotic functions of Th2 cytokines. To determine the role of IL-13 signaling in the pathogenesis of bleomycin-induced pulmonary fibrosis, wild-type, IL-13, and IL-4Rα-deficient mice were treated with bleomycin, and lungs were assessed for changes in lung function and pulmonary fibrosis. Histological staining and lung function measurements demonstrated that collagen deposition and lung function decline were attenuated in mice deficient in either IL-13 or IL-4Rα-driven signaling compared with wild-type mice treated with bleomycin. Furthermore, our results demonstrated that IL-13 and IL-4Rα-driven signaling are involved in excessive migration of macrophages and fibroblasts. Notably, our findings demonstrated that IL-13-driven migration involves increased phospho-focal adhesion kinase signaling and F-actin polymerization. Importantly, in vivo findings demonstrated that IL-13 augments matrix metalloproteinase (MMP)-2 and MMP9 activity that has also been shown to increase migration and invasiveness of fibroblasts in the lungs during bleomycin-induced pulmonary fibrosis. Together, our findings demonstrate a pathogenic role for Th2-cytokine signaling that includes excessive migration and protease activity involved in severe fibrotic lung disease.

  9. mTOR Overactivation and Compromised Autophagy in the Pathogenesis of Pulmonary Fibrosis.

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    Yao-Song Gui

    Full Text Available The mammalian target of rapamycin (mTOR signaling pathway in pulmonary fibrosis was investigated in cell and animal models. mTOR overactivation in alveolar epithelial cells (AECs was achieved in the conditional and inducible Tsc1 knock-down mice SPC-rtTA/TetO-Cre/Tsc1(fx/+ (STT. Doxycycline caused Tsc1 knock-down and consequently mTOR activation in AECs for the STT mice. Mice treated with bleomycin exhibited increased mortality and pulmonary fibrosis compared with control mice. In wild-type C57BL/6J mice, pretreatment with rapamycin attenuated the bleomycin-mediated mortality and fibrosis. Rapamycin-mediated mouse survival benefit was inhibited by chloroquine, an autophagy inhibitor. Autophagosomes were decreased in the lungs after bleomycin exposure. Rapamycin induced the production of autophagosomes and diminished p62. We concluded that mTOR overactivation in AECs and compromised autophagy in the lungs are involved in the pathogenesis of pulmonary fibrosis. The suppression of mTOR and enhancement of autophagy may be used for treatment of pulmonary fibrosis.

  10. Blocking follistatin-like 1 attenuates bleomycin-induced pulmonary fibrosis in mice

    Science.gov (United States)

    Dong, Yingying; Geng, Yan; Li, Lian; Li, Xiaohe; Yan, Xiaohua; Fang, Yinshan; Li, Xinxin; Dong, Siyuan; Liu, Xue; Li, Xue; Yang, Xiuhong; Zheng, Xiaohong; Xie, Ting; Liang, Jiurong; Dai, Huaping; Liu, Xinqi; Yin, Zhinan; Noble, Paul W.

    2015-01-01

    Progressive tissue fibrosis is a cause of major morbidity and mortality. Pulmonary fibrosis is an epithelial-mesenchymal disorder in which TGF-β1 plays a central role in pathogenesis. Here we show that follistatin-like 1 (FSTL1) differentially regulates TGF-β and bone morphogenetic protein signaling, leading to epithelial injury and fibroblast activation. Haplodeletion of Fstl1 in mice or blockage of FSTL1 with a neutralizing antibody in mice reduced bleomycin-induced fibrosis in vivo. Fstl1 is induced in response to lung injury and promotes the accumulation of myofibroblasts and subsequent fibrosis. These data suggest that Fstl1 may serve as a novel therapeutic target for treatment of progressive lung fibrosis. PMID:25584011

  11. Preventive and curative effects of dicaffeoylquinic acid on early pulmonary fibrosis in mice

    International Nuclear Information System (INIS)

    Liu Tao; Song Liangwen; Dong Junxing; Huang Shanying; Li Yang

    2005-01-01

    Objective: To explore the effect of dicaffeoylquinic acid (IBE5) on prevention and treatment of pulmonary fibrosis induced by bleomycin (BLM) in mice and its mechanism. Methods: Hydroxyproline content determination, imaging analysis, collagen I and III assay, α-smooth muscle actin (α-SMA) and matrix metalloproteinase 7 (MMP-7 ) immunohistochemistry were performed. Results: 1)Hydroxyproline content decreased in fibrotic lung tissue after administration of IBE5(P<0.05). 2)The number of pulmonary alveoli reduced, alveolus interstitium was thickened and collagen deposition and fibrosis were formed in lung tissue of BLM group. The break of pulmonary alveoli and extension of pulmonary fibrosis were decreased by use of IBE5 (P<0.05). 3)A lot of collagen I and III were synthesized in lung interstitium in BLM group and their quantity was reduced in IBE5 group (P<0.05). 4) In BLM group, α-SMA expression increased and located in myofibroblasts in fibrotic area, and MMP7 immunohistochemical signal was located in myofibroblasts also. They were decreased in IBE5 group(P<0.05). Conclusion: IBE5 plays a preventive and curative role in pulmonary fibrosis by inhibition of transformation of fibroblasts towards myofibroblasts and MMP7 expression. (authors)

  12. Use of a genealogical database demonstrates heritability of pulmonary fibrosis.

    Science.gov (United States)

    Scholand, Mary Beth; Coon, Hilary; Wolff, Roger; Cannon-Albright, Lisa

    2013-10-01

    Pulmonary fibrosis (PF) is a progressive fatal disease of unknown etiology. Identification of risk genes and pathways will enhance our understanding of this disease. Analysis of Utah genealogical resources has shown previously strong evidence for a genetic contribution to other disease, such as cancer. This approach has led to gene discovery in diseases, such as breast cancer and colon cancer and is used here for PF to quantify the heritability. We hypothesize that there is a heritable contribution to death from PF and use existing genealogic and death certificate data to examine patterns of relatedness amongst individuals who have died of PF. We analyzed familial clustering of individuals who died from PF using the Utah Population Database, a unique population-based genealogical resource that has been linked to death certificates dating from 1904. We identified 1,000 individuals with at least three generations of genealogy data and a cause of death documented as PF (cases). We estimated the relative risk (RR) of death from PF among the first-, second-, and third-degree relatives of cases. We also tested the hypothesis of excess relatedness among the cases by comparing the average pairwise relatedness of all cases to the average pair-wise relatedness of 1,000 sets of matched controls. We observed significantly increased risk for death from PF among the first- (RR = 4.69), second- (RR = 1.92), and third-degree relatives (RR = 1.14) of cases. The average relatedness of the 1,000 cases was significantly higher than the expected average relatedness of matched control sets (p < 0.001). When close (first- and second-degree) relationships were ignored, significantly increased relatedness remained (p = 0.002). Our results demonstrate significant clustering among both close and distant relatives, providing strong support for genetic contributions to death from PF. High-risk pedigrees derived from this unique resource may help identify new risk genes and gene

  13. Quantification of Pulmonary Fibrosis in a Bleomycin Mouse Model Using Automated Histological Image Analysis.

    Science.gov (United States)

    Gilhodes, Jean-Claude; Julé, Yvon; Kreuz, Sebastian; Stierstorfer, Birgit; Stiller, Detlef; Wollin, Lutz

    2017-01-01

    Current literature on pulmonary fibrosis induced in animal models highlights the need of an accurate, reliable and reproducible histological quantitative analysis. One of the major limits of histological scoring concerns the fact that it is observer-dependent and consequently subject to variability, which may preclude comparative studies between different laboratories. To achieve a reliable and observer-independent quantification of lung fibrosis we developed an automated software histological image analysis performed from digital image of entire lung sections. This automated analysis was compared to standard evaluation methods with regard to its validation as an end-point measure of fibrosis. Lung fibrosis was induced in mice by intratracheal administration of bleomycin (BLM) at 0.25, 0.5, 0.75 and 1 mg/kg. A detailed characterization of BLM-induced fibrosis was performed 14 days after BLM administration using lung function testing, micro-computed tomography and Ashcroft scoring analysis. Quantification of fibrosis by automated analysis was assessed based on pulmonary tissue density measured from thousands of micro-tiles processed from digital images of entire lung sections. Prior to analysis, large bronchi and vessels were manually excluded from the original images. Measurement of fibrosis has been expressed by two indexes: the mean pulmonary tissue density and the high pulmonary tissue density frequency. We showed that tissue density indexes gave access to a very accurate and reliable quantification of morphological changes induced by BLM even for the lowest concentration used (0.25 mg/kg). A reconstructed 2D-image of the entire lung section at high resolution (3.6 μm/pixel) has been performed from tissue density values allowing the visualization of their distribution throughout fibrotic and non-fibrotic regions. A significant correlation (pfibrosis in mice, which will be very valuable for future preclinical drug explorations.

  14. Protective role of andrographolide in bleomycin-induced pulmonary fibrosis in mice.

    Science.gov (United States)

    Zhu, Tao; Zhang, Wei; Xiao, Min; Chen, Hongying; Jin, Hong

    2013-12-03

    Idiopathic pulmonary fibrosis (IPF) is a chronic devastating disease with poor prognosis. Multiple pathological processes, including inflammation, epithelial mesenchymal transition (EMT), apoptosis, and oxidative stress, are involved in the pathogenesis of IPF. Recent findings suggested that nuclear factor-κB (NF-κB) is constitutively activated in IPF and acts as a central regulator in the pathogenesis of IPF. The aim of our study was to reveal the value of andrographolide on bleomycin-induced inflammation and fibrosis in mice. The indicated dosages of andrographolide were administered in mice with bleomycin-induced pulmonary fibrosis. On day 21, cell counts of total cells, macrophages, neutrophils and lymphocytes, alone with TNF-α in bronchoalveolar lavage fluid (BALF) were measured. HE staining and Masson's trichrome (MT) staining were used to observe the histological alterations of lungs. The Ashcroft score and hydroxyproline content of lungs were also measured. TGF-β1 and α-SMA mRNA and protein were analyzed. Activation of NF-κB was determined by western blotting and electrophoretic mobility shift assay (EMSA). On day 21 after bleomycin stimulation, andrographolide dose-dependently inhibited the inflammatory cells and TNF-α in BALF. Meanwhile, our data demonstrated that the Ashcroft score and hydroxyproline content of the bleomycin-stimulated lung were reduced by andrographolide administration. Furthermore, andrographloide suppressed TGF-β1 and α-SMA mRNA and protein expression in bleomycin-induced pulmonary fibrosis. Meanwhile, andrographolide significantly dose-dependently inhibited the ratio of phospho-NF-κB p65/total NF-κB p65 and NF-κB p65 DNA binding activities. Our findings indicate that andrographolide compromised bleomycin-induced pulmonary inflammation and fibrosis possibly through inactivation of NF-κB. Andrographolide holds promise as a novel drug to treat the devastating disease of pulmonary fibrosis.

  15. Protective Role of Andrographolide in Bleomycin-Induced Pulmonary Fibrosis in Mice

    Directory of Open Access Journals (Sweden)

    Tao Zhu

    2013-12-01

    Full Text Available Idiopathic pulmonary fibrosis (IPF is a chronic devastating disease with poor prognosis. Multiple pathological processes, including inflammation, epithelial mesenchymal transition (EMT, apoptosis, and oxidative stress, are involved in the pathogenesis of IPF. Recent findings suggested that nuclear factor-κB (NF-κB is constitutively activated in IPF and acts as a central regulator in the pathogenesis of IPF. The aim of our study was to reveal the value of andrographolide on bleomycin-induced inflammation and fibrosis in mice. The indicated dosages of andrographolide were administered in mice with bleomycin-induced pulmonary fibrosis. On day 21, cell counts of total cells, macrophages, neutrophils and lymphocytes, alone with TNF-α in bronchoalveolar lavage fluid (BALF were measured. HE staining and Masson’s trichrome (MT staining were used to observe the histological alterations of lungs. The Ashcroft score and hydroxyproline content of lungs were also measured. TGF-β1 and α-SMA mRNA and protein were analyzed. Activation of NF-κB was determined by western blotting and electrophoretic mobility shift assay (EMSA. On day 21 after bleomycin stimulation, andrographolide dose-dependently inhibited the inflammatory cells and TNF-α in BALF. Meanwhile, our data demonstrated that the Ashcroft score and hydroxyproline content of the bleomycin-stimulated lung were reduced by andrographolide administration. Furthermore, andrographloide suppressed TGF-β1 and α-SMA mRNA and protein expression in bleomycin-induced pulmonary fibrosis. Meanwhile, andrographolide significantly dose-dependently inhibited the ratio of phospho-NF-κB p65/total NF-κB p65 and NF-κB p65 DNA binding activities. Our findings indicate that andrographolide compromised bleomycin-induced pulmonary inflammation and fibrosis possibly through inactivation of NF-κB. Andrographolide holds promise as a novel drug to treat the devastating disease of pulmonary fibrosis.

  16. Impact of a CXCL12/CXCR4 Antagonist in Bleomycin (BLM Induced Pulmonary Fibrosis and Carbon Tetrachloride (CCl4 Induced Hepatic Fibrosis in Mice.

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    Leola N Chow

    Full Text Available Modulation of chemokine CXCL12 and its receptor CXCR4 has been implicated in attenuation of bleomycin (BLM-induced pulmonary fibrosis and carbon tetrachloride (CCl4-induced hepatic injury. In pulmonary fibrosis, published reports suggest that collagen production in the injured lung is derived from fibrocytes recruited from the circulation in response to release of pulmonary CXCL12. Conversely, in hepatic fibrosis, resident hepatic stellate cells (HSC, the key cell type in progression of fibrosis, upregulate CXCR4 expression in response to activation. Further, CXCL12 induces HSC proliferation and subsequent production of collagen I. In the current study, we evaluated AMD070, an orally bioavailable inhibitor of CXCL12/CXCR4 in alleviating BLM-induced pulmonary and CCl4-induced hepatic fibrosis in mice. Similar to other CXCR4 antagonists, treatment with AMD070 significantly increased leukocyte mobilization. However, in these two models of fibrosis, AMD070 had a negligible impact on extracellular matrix deposition. Interestingly, our results indicated that CXCL12/CXCR4 signaling has a role in improving mortality associated with BLM induced pulmonary injury, likely through dampening an early inflammatory response and/or vascular leakage. Together, these findings indicate that the CXCL12-CXCR4 signaling axis is not an effective target for reducing fibrosis.

  17. Distinct Roles of Wnt/β-Catenin Signaling in the Pathogenesis of Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

    Science.gov (United States)

    Shi, Juan; Li, Feng; Luo, Meihui; Wei, Jun

    2017-01-01

    Wnt signaling pathways are tightly controlled under a physiological condition, under which they play key roles in many biological functions, including cell fate specification and tissue regeneration. Increasing lines of evidence recently demonstrated that a dysregulated activation of Wnt signaling, particularly the Wnt/β-catenin signaling, was involved in the pathogenesis of chronic pulmonary diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). In this respect, Wnt signaling interacts with other cellular signaling pathways to regulate the initiation and pathogenic procedures of airway inflammation and remodeling, pulmonary myofibroblast proliferation, epithelial-to-mesenchymal transition (EMT), and development of emphysema. Intriguingly, Wnt/β-catenin signaling is activated in IPF; an inhibition of this signaling leads to an alleviation of pulmonary inflammation and fibrosis in experimental models. Conversely, Wnt/β-catenin signaling is inactivated in COPD tissues, and its reactivation results in an amelioration of airspace enlargement with a restored alveolar epithelial structure and function in emphysema models. These studies thus imply distinct mechanisms of Wnt/β-catenin signaling in the pathogenesis of these two chronic pulmonary diseases, indicating potential targets for COPD and IPF treatments. This review article aims to summarize the involvement and pathogenic roles of Wnt signaling pathways in the COPD and IPF, with a focus on the implication of Wnt/β-catenin signaling as underlying mechanisms and therapeutic targets in these two incurable diseases. PMID:28588349

  18. Association between nutritional status measurements and pulmonary function in children and adolescents with cystic fibrosis.

    Science.gov (United States)

    Chaves, Célia Regina Moutinho de Miranda; Britto, José Augusto Alves de; Oliveira, Cristiano Queiroz de; Gomes, Miriam Martins; Cunha, Ana Lúcia Pereira da

    2009-05-01

    To evaluate the association between nutritional status measurements and pulmonary function in children and adolescents with cystic fibrosis. We evaluated the nutritional status of 48 children and adolescents (aged 6-18 years) with cystic fibrosis based on body mass index (BMI) and body composition measurements-mid-arm muscle circumference (MAMC) and triceps skinfold thickness (TST)-at a referral center in the city of Rio de Janeiro, Brazil. Pulmonary function was assessed by means of spirometry, using FEV1 to classify the severity of airway obstruction. We used Student's t-tests for comparisons between proportions and linear regression analysis for associations between continuous variables. The level of significance was set at p evaluation of nutritional status based on BMI identified a smaller number of malnourished patients than did that based on MAMC (14 vs. 25 patients, respectively). Most of the patients presented mild pulmonary disease. Mean FEV1 was 82.5% of predicted. Pulmonary function was found to correlate significantly with BMI, MAMC and TST (p = 0.001, p = 0.001 and p = 0.03, respectively). All subjects with moderate or severe pulmonary involvement were considered malnourished based on BMI and body composition parameters. Of the 25 patients considered malnourished based on body composition (MAMC), 19 were considered well-nourished based on their BMI. In the present study, all nutritional status measurements correlated directly with the pulmonary function of children and adolescents with cystic fibrosis. However, body composition measurements allowed earlier detection of nutritional deficiencies.

  19. Overexpression of IL-38 protein in anticancer drug-induced lung injury and acute exacerbation of idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Tominaga, Masaki; Okamoto, Masaki; Kawayama, Tomotaka; Matsuoka, Masanobu; Kaieda, Shinjiro; Sakazaki, Yuki; Kinoshita, Takashi; Mori, Daisuke; Inoue, Akira; Hoshino, Tomoaki

    2017-09-01

    Interleukin (IL)-38, a member of the IL-1 family, shows high homology to IL-1 receptor antagonist (IL-1Ra) and IL-36 receptor antagonist (IL-36Ra). Its function in interstitial lung disease (ILD) is still unknown. To determine the expression pattern of IL-38 mRNA, a panel of cDNAs derived from various tissues was analyzed by quantitative real-time PCR. Immunohistochemical reactivity with anti-human IL-38 monoclonal antibody (clone H127C) was evaluated semi-quantitatively in lung tissue samples from 12 patients with idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP), 5 with acute exacerbation of IPF, and 10 with anticancer drug-induced ILD (bleomycin in 5 and epidermal growth factor receptor-tyrosine kinase inhibitor in 5). Control lung tissues were obtained from areas of normal lung in 22 lung cancer patients who underwent extirpation surgery. IL-38 transcripts were strongly expressed in the lung, spleen, synoviocytes, and peripheral blood mononuclear cells, and at a lower level in pancreas and muscle. IL-38 protein was not strongly expressed in normal pulmonary alveolar tissues in all 22 control lungs. In contrast, IL-38 was overexpressed in the lungs of 4 of 5 (80%) patients with acute IPF exacerbation and 100% (10/10) of the patients with drug-induced ILD. IL-38 overexpression was limited to hyperplastic type II pneumocytes, which are considered to reflect regenerative change following diffuse alveolar damage in ILD. IL-38 may play an important role in acute and/or chronic inflammation in anticancer drug-induced lung injury and acute exacerbation of IPF. Copyright © 2017 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

  20. Renal Fibrosis mRNA Classifier: Validation in Experimental Lithium-Induced Interstitial Fibrosis in the Rat Kidney.

    Science.gov (United States)

    Marti, Hans-Peter; Jeffs, Aaron; Scherer, Andreas; Leader, John; Leader, Catherine; Bedford, Jennifer; Walker, Robert

    2016-01-01

    Accurate diagnosis of fibrosis is of paramount clinical importance. A human fibrosis classifier based on metzincins and related genes (MARGS) was described previously. In this investigation, expression changes of MARGS genes were explored and evaluated to examine whether the MARGS-based algorithm has any diagnostic value in a rat model of lithium nephropathy. Male Wistar rats (n = 12) were divided into 2 groups (n = 6). One group was given a diet containing lithium (40 mmol/kg food for 7 days, followed by 60mmol/kg food for the rest of the experimental period), while a control group (n = 6) was fed a normal diet. After six months, animals were sacrificed and the renal cortex and medulla of both kidneys removed for analysis. Gene expression changes were analysed using 24 GeneChip® Affymetrix Rat Exon 1.0 ST arrays. Statistically relevant genes (p-value1.5, t-test) were further examined. Matrix metalloproteinase-2 (MMP2), CD44, and nephroblastoma overexpressed gene (NOV) were overexpressed in the medulla and cortex of lithium-fed rats compared to the control group. TGFβ2 was overrepresented in the cortex of lithium-fed animals 1.5-fold, and 1.3-fold in the medulla of the same animals. In Gene Set Enrichment Analysis (GSEA), both the medulla and cortex of lithium-fed animals showed an enrichment of the MARGS, TGFβ network, and extracellular matrix (ECM) gene sets, while the cortex expression signature was enriched in additional fibrosis-related-genes and the medulla was also enriched in immune response pathways. Importantly, the MARGS-based fibrosis classifier was able to classify all samples correctly. Immunohistochemistry and qPCR confirmed the up-regulation of NOV, CD44, and TGFβ2. The MARGS classifier represents a cross-organ and cross-species classifier of fibrotic conditions and may help to design a test to diagnose and to monitor fibrosis. The results also provide evidence for a common pathway in the pathogenesis of fibrosis.

  1. YKL-40 and mast cells are associated with detrusor fibrosis in patients diagnosed with bladder pain syndrome/interstitial cystitis according to the 2008 criteria of the European Society for the Study of Interstitial Cystitis

    DEFF Research Database (Denmark)

    Richter, Benedikte; Roslind, A.; Hesse, U.

    2010-01-01

    Aims: Bladder pain syndrome/interstitial cystitis (BPS/IC), diagnosed according to the new 2008 criteria of the European Society for the Study of Interstitial Cystitis (ESSIC), may lead to detrusor fibrosis. In some inflammatory diseases, fibrosis is related to YKL-40. The aims were to examine YKL......-40 antigenic expression in bladder tissue and levels in serum and urine in BPS/IC and to evaluate whether YKL-40 could be a non-invasive, prognostic biomarker for bladder fibrogenesis and treatment intensity. Methods and results: Immunohistochemistry, immunoelectron microscopy and enzyme...... of detrusor fibrosis with YKL-40-positive cells (P = 0.001), mast cells (P = 0.014) and urine YKL-40 (P = 0.009). Bladder capacity correlated inversely with YKL-40-positive cells (P Treatment intensity was not associated with YKL-40. Conclusion: Serum and urine levels...

  2. A novel segmental challenge model for bleomycin-induced pulmonary fibrosis in sheep.

    Science.gov (United States)

    Organ, Louise; Bacci, Barbara; Koumoundouros, Emmanuel; Barcham, Garry; Kimpton, Wayne; Nowell, Cameron J; Samuel, Chrishan; Snibson, Ken

    2015-04-01

    Idiopathic Pulmonary fibrosis (IPF) is a fatal respiratory disease, characterized by a progressive fibrosis and worsening lung function. While the outcomes of recent clinical trials have resulted in therapies to slow the progression of the disease, there is still a need to develop alternative therapies, which are able to prevent fibrosis. This study uses a segmental lung infusion of bleomycin (BLM) to investigate pulmonary fibrosis in a physiologically relevant large animal species. Two separate lung segments in eight sheep received two fortnightly challenges of either 3U or 30U BLM per segment, and a third segment received saline (control). Lung function was assessed using a wedged-bronchoscope procedure. Bronchoalveolar lavage fluid and lung tissue were assessed for inflammation, fibrosis and collagen content two weeks after the final dose of BLM. Instillation of both BLM doses resulted in prominent fibrosis in the treated lobes. More diffuse fibrosis and loss of alveolar airspace was observed in high-dose BLM-treated segments, while multifocal fibrosis was seen in low-dose BLM-treated segments. Extensive and disorganised collagen deposition occurred in the BLM-treated lobes, compared to controls. Significant loss of lung compliance was also observed in the BLM-treated lobes, which did not occur in controls. Fibrosis comparable to IPF was induced into isolated lung segments, without compromising the respiratory functioning of the animal. This model may have potential for investigating novel therapies for IPF by allowing direct comparison of multiple treatments with internal controls, and sampling and drug delivery that are clinically relevant.

  3. Netrin-1 regulates fibrocyte accumulation in the decellularized fibrotic scleroderma lung microenvironment and in bleomycin induced pulmonary fibrosis

    Science.gov (United States)

    Sun, Huanxing; Zhu, Yangyang; Pan, Hongyi; Chen, Xiaosong; Balestrini, Jenna L.; Lam, TuKiet T.; Kanyo, Jean E.; Eichmann, Anne; Gulati, Mridu; Fares, Wassim H.; Bai, Hanwen; Feghali-Bostwick, Carol A.; Gan, Ye; Peng, Xueyan; Moore, Meagan W.; White, Eric S.; Sava, Parid; Gonzalez, Anjelica L.; Cheng, Yuwei; Niklason, Laura E.; Herzog, Erica L.

    2017-01-01

    Objectives Fibrocytes are collagen-producing leukocytes that accumulate in Scleroderma-associated interstitial lung disease (SSc-ILD) via unknown mechanisms. The extracellular matrix (ECM) influences cellular phenotypes. However, a relationship between the lung ECM and fibrocytes in Scleroderma has not been explored. This study uses a novel translational platform based on decellularized human lungs to determine whether the scleroderma lung ECM controls fibrocyte development from peripheral blood mononuclear cells. Methods Decellularized scaffolds prepared from healthy and fibrotic Scleroderma lung explants underwent biomechanical evaluation using tensile testing and biochemical analysis using proteomics. Cells from healthy and SSc-ILD subjects were cultured on these scaffolds, and CD45+Pro-ColIα1+ cells meeting criteria for fibrocytes were quantified. The contribution of Netrin-1 to fibrosis was assessed using neutralizing antibodies in this system and via the inhalational administration of bleomycin to Netrin-1+/− mice. Results Compared to control lung scaffold, SSc-ILD lung scaffolds showed aberrant anatomy, enhanced stiffness, and abnormal extracellular matrix composition. Culture of control cells in Scleroderma scaffolds increased Pro-ColIα1+ production, which was stimulated by enhanced stiffness and abnormal ECM composition. SSc-ILD cells demonstrated increased Pro-ColIα1 responsiveness to Scleroderma lung scaffolds, but not enhanced stiffness. Enhanced Netrin-1 expression was seen on CD14lo SSc-ILD cells and antibody mediated Netrin-1 neutralization attenuated CD45+Pro-ColIα1+ detection in all settings. Netrin-1+/− mice were protected from bleomycin induced lung fibrosis and fibrocyte accumulation. Conclusion Factors present in Scleroderma lung matrices regulate fibrocyte accumulation via a Netrin-1-dependent pathway. Netrin-1 regulates bleomycin induced murine pulmonary fibrosis. Netrin-1 might be a novel therapeutic target in SSc-ILD. PMID:26749424

  4. Exercise-induced interstitial pulmonary edema at sea-level in young and old healthy humans.

    Science.gov (United States)

    Taylor, Bryan J; Carlson, Alex R; Miller, Andrew D; Johnson, Bruce D

    2014-01-15

    We asked whether aged adults are more susceptible to exercise-induced pulmonary edema relative to younger individuals. Lung diffusing capacity for carbon monoxide (DLCO), alveolar-capillary membrane conductance (Dm) and pulmonary-capillary blood volume (Vc) were measured before and after exhaustive discontinuous incremental exercise in 10 young (YNG; 27±3 years) and 10 old (OLD; 69±5 years) males. In YNG subjects, Dm increased (11±7%, P=0.031), Vc decreased (-10±9%, P=0.01) and DLCO was unchanged (30.5±4.1 vs. 29.7±2.9mL/min/mmHg, P=0.44) pre- to post-exercise. In OLD subjects, DLCO and Dm increased (11±14%, P=0.042; 16±14%, P=0.025) but Vc was unchanged (58±23 vs. 56±23mL, P=0.570) pre- to post-exercise. Group-mean Dm/Vc was greater after vs. before exercise in the YNG and OLD subjects. However, Dm/Vc was lower post-exercise in 2 of the 10 YNG (-7±4%) and 2 of the 10 OLD subjects (-10±5%). These data suggest that exercise decreases interstitial lung fluid in most YNG and OLD subjects, with a small number exhibiting evidence for exercise-induced pulmonary edema. Copyright © 2013 Elsevier B.V. All rights reserved.

  5. Exercise-induced interstitial pulmonary edema at sea-level in young and old healthy humans

    Science.gov (United States)

    Taylor, Bryan J.; Carlson, Alex R.; Miller, Andrew D.; Johnson, Bruce D.

    2014-01-01

    We asked whether aged adults are more susceptible to exercise-induced pulmonary edema relative to younger individuals. Lung diffusing capacity for carbon monoxide (DLCO), alveolar-capillary membrane conductance (Dm) and pulmonary-capillary blood volume (Vc) were measured before and after exhaustive discontinuous incremental exercise in 10 young (YNG; 27±3 yr) and 10 old (OLD; 69±5 yr) males. In YNG subjects, Dm increased (11±7%, P=0.031), Vc decreased (−10±9%, P=0.01) and DLCO was unchanged (30.5±4.1 vs. 29.7±2.9 ml/min/mmHg, P=0.44) pre- to post-exercise. In OLD subjects, DLCO and Dm increased (11±14%, P=0.042; 16±14%, P=0.025) but Vc was unchanged (58±23 vs. 56±23 ml, P=0.570) pre- to post-exercise. Group-mean Dm/Vc was greater after vs. before exercise in the YNG and OLD subjects. However, Dm/Vc was lower post-exercise in 2 of the 10 YNG (−7±4%) and 2 of the 10 OLD subjects (−10±5%). These data suggest that exercise decreases interstitial lung fluid in most YNG and OLD subjects, with a small number exhibiting evidence for exercise-induced pulmonary edema. PMID:24200644

  6. Relationship between dyspnoea, pulmonary function and exercise capacity in patients with cystic fibrosis

    NARCIS (Netherlands)

    deJong, W; vanderSchans, CP; Mannes, GPM; vanAalderen, WMC; Grevink, RG; Koeter, GH

    The median age of survival in patients with cystic fibrosis (CF) has improved considerably. Despite this improvement, deterioration of pulmonary function and decrease in exercise capacity are still the main problems for many patients. Although dyspnoea is a common complaint in CF patients,

  7. Relationship between dyspnoea, pulmonary function and exercise capacity in patients with cystic fibrosis

    NARCIS (Netherlands)

    de Jong, W.; van der Schans, C. P.; Mannes, G. P.; van Aalderen, W. M.; Grevink, R. G.; Koëter, G. H.

    1997-01-01

    The median age of survival in patients with cystic fibrosis (CF) has improved considerably. Despite this improvement, deterioration of pulmonary function and decrease in exercise capacity are still the main problems for many patients. Although dyspnoea is a common complaint in CF patients,

  8. Oxygen-assisted exercise training in adult cystic fibrosis patients with pulmonary limitation to exercise

    NARCIS (Netherlands)

    Heijerman, H. G.; Bakker, W.; Sterk, P. J.; Dijkman, J. H.

    1991-01-01

    Exercise training has been considered suitable only in cystic fibrosis (CF) patients with mild to moderate pulmonary dysfunction without progressive hypoxaemia during exercise. We trained 16 CF patients, all with advanced lung disease (mean standardized forced expiratory volume in 1 s (FEV1), 30%

  9. IL-4 polymorphisms, HRCT score and lung tissue markers in idiopathic pulmonary fibrosis

    Czech Academy of Sciences Publication Activity Database

    Vašáková, M.; Šterclová, M.; Matěj, R.; Olejár, Tomáš; Kolesár, L.; Skibová, J.; Stříž, I.

    2013-01-01

    Roč. 74, č. 10 (2013), s. 1346-1351 ISSN 0198-8859 Institutional support: RVO:67985823 Keywords : IL-4 * gene polymorphism * idiopathic pulmonary fibrosis * PAR-2 * CD124 * TGF beta * YY-1 * TSLP Subject RIV: FC - Pulmology Impact factor: 2.282, year: 2013

  10. Idiopathic Pulmonary Fibrosis: A Genetic Disease That Involves Mucociliary Dysfunction of the Peripheral Airways

    Science.gov (United States)

    Evans, Christopher M.; Fingerlin, Tasha E.; Schwarz, Marvin I.; Lynch, David; Kurche, Jonathan; Warg, Laura; Yang, Ivana V.; Schwartz, David A.

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is an incurable complex genetic disorder that is associated with sequence changes in 7 genes (MUC5B, TERT, TERC, RTEL1, PARN, SFTPC, and SFTPA2) and with variants in at least 11 novel loci. We have previously found that 1) a common gain-of-function promoter variant in MUC5B rs35705950 is the strongest risk factor (genetic and otherwise), accounting for 30-35% of the risk of developing IPF, a disease that was previously considered idiopathic; 2) the MUC5B promoter variant can potentially be used to identify individuals with preclinical pulmonary fibrosis and is predictive of radiologic progression of preclinical pulmonary fibrosis; and 3) MUC5B may be involved in the pathogenesis of pulmonary fibrosis with MUC5B message and protein expressed in bronchiolo-alveolar epithelia of IPF and the characteristic IPF honeycomb cysts. Based on these considerations, we hypothesize that excessive production of MUC5B either enhances injury due to reduced mucociliary clearance or impedes repair consequent to disruption of normal regenerative mechanisms in the distal lung. In aggregate, these novel considerations should have broad impact, resulting in specific etiologic targets, early detection of disease, and novel biologic pathways for use in the design of future intervention, prevention, and mechanistic studies of IPF. PMID:27630174

  11. Macrophage Akt1 Kinase-Mediated Mitophagy Modulates Apoptosis Resistance and Pulmonary Fibrosis.

    Science.gov (United States)

    Larson-Casey, Jennifer L; Deshane, Jessy S; Ryan, Alan J; Thannickal, Victor J; Carter, A Brent

    2016-03-15

    Idiopathic pulmonary fibrosis (IPF) is a devastating lung disorder with increasing incidence. Mitochondrial oxidative stress in alveolar macrophages is directly linked to pulmonary fibrosis. Mitophagy, the selective engulfment of dysfunctional mitochondria by autophagasomes, is important for cellular homeostasis and can be induced by mitochondrial oxidative stress. Here, we show Akt1 induced macrophage mitochondrial reactive oxygen species (ROS) and mitophagy. Mice harboring a conditional deletion of Akt1 in macrophages (Akt1(-/-)Lyz2-cre) and Park2(-/-) mice had impaired mitophagy and reduced active transforming growth factor-β1 (TGF-β1). Although Akt1 increased TGF-β1 expression, mitophagy inhibition in Akt1-overexpressing macrophages abrogated TGF-β1 expression and fibroblast differentiation. Importantly, conditional Akt1(-/-)Lyz2-cre mice and Park2(-/-) mice had increased macrophage apoptosis and were protected from pulmonary fibrosis. Moreover, IPF alveolar macrophages had evidence of increased mitophagy and displayed apoptosis resistance. These observations suggest that Akt1-mediated mitophagy contributes to alveolar macrophage apoptosis resistance and is required for pulmonary fibrosis development. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Potential novel targets: Protease-activated receptors in idiopathic pulmonary fibrosis

    NARCIS (Netherlands)

    Lin, C.

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is the most devastating diffuse fibrosing lung disease of unknown etiology. IPF patients suffer from severe breathlessness caused by decreasing lung compliance eventually leading to respiratory failure and death. The prognosis of IPF is devastating: there is only

  13. Prostaglandin D2 Attenuates Bleomycin-Induced Lung Inflammation and Pulmonary Fibrosis.

    Science.gov (United States)

    Kida, Taiki; Ayabe, Shinya; Omori, Keisuke; Nakamura, Tatsuro; Maehara, Toko; Aritake, Kosuke; Urade, Yoshihiro; Murata, Takahisa

    2016-01-01

    Pulmonary fibrosis is a progressive and fatal lung disease with limited therapeutic options. Although it is well known that lipid mediator prostaglandins are involved in the development of pulmonary fibrosis, the role of prostaglandin D2 (PGD2) remains unknown. Here, we investigated whether genetic disruption of hematopoietic PGD synthase (H-PGDS) affects the bleomycin-induced lung inflammation and pulmonary fibrosis in mouse. Compared with H-PGDS naïve (WT) mice, H-PGDS-deficient mice (H-PGDS-/-) represented increased collagen deposition in lungs 14 days after the bleomycin injection. The enhanced fibrotic response was accompanied by an increased mRNA expression of inflammatory mediators, including tumor necrosis factor-α, monocyte chemoattractant protein-1, and cyclooxygenase-2 on day 3. H-PGDS deficiency also increased vascular permeability on day 3 and infiltration of neutrophils and macrophages in lungs on day 3 and 7. Immunostaining showed that the neutrophils and macrophages expressed H-PGDS, and its mRNA expression was increased on day 3and 7 in WT lungs. These observations suggest that H-PGDS-derived PGD2 plays a protective role in bleomycin-induced lung inflammation and pulmonary fibrosis.

  14. Anti-profibrotic effects of artesunate on bleomycin-induced pulmonary fibrosis in Sprague Dawley rats.

    Science.gov (United States)

    Wang, Changming; Xuan, Xiuping; Yao, Wenmin; Huang, Guojin; Jin, Junfei

    2015-07-01

    The present study aimed to determine whether artesunate has beneficial effects on bleomycin-induced pulmonary fibrosis in rats and to examine the possible mechanisms underlying these effects. All experiments were performed with male Sprague Dawley rats weighing 180-250 g. Animals were randomly divided into four experimental groups that were administered either saline alone, artesunate alone, bleomycin alone or bleomycin + artesunate. Lung histopathology was investigated by hematoxylin and eosin staining and Masson staining. Lung profibrotic molecules were analyzed by reverse transcription polymerase chain reaction, immunoblotting and immunohistochemistry. In rats treated with artesunate, pulmonary fibrosis induced by bleomycin was significantly reduced. Administration of artesunate significantly improved bleomycin-induced morphological alterations. Profibrotic molecules, including transforming growth factor-β1, Smad3, heat shock protein 47, α-smooth muscle actin and collagen type I were also reduced by artesunate. These findings suggest that artesunate improves bleomycin-induced pulmonary fibrosis pathology in rats possibly by inhibiting profibrotic molecules associated with pulmonary fibrosis.

  15. Prostaglandin D2 Attenuates Bleomycin-Induced Lung Inflammation and Pulmonary Fibrosis.

    Directory of Open Access Journals (Sweden)

    Taiki Kida

    Full Text Available Pulmonary fibrosis is a progressive and fatal lung disease with limited therapeutic options. Although it is well known that lipid mediator prostaglandins are involved in the development of pulmonary fibrosis, the role of prostaglandin D2 (PGD2 remains unknown. Here, we investigated whether genetic disruption of hematopoietic PGD synthase (H-PGDS affects the bleomycin-induced lung inflammation and pulmonary fibrosis in mouse. Compared with H-PGDS naïve (WT mice, H-PGDS-deficient mice (H-PGDS-/- represented increased collagen deposition in lungs 14 days after the bleomycin injection. The enhanced fibrotic response was accompanied by an increased mRNA expression of inflammatory mediators, including tumor necrosis factor-α, monocyte chemoattractant protein-1, and cyclooxygenase-2 on day 3. H-PGDS deficiency also increased vascular permeability on day 3 and infiltration of neutrophils and macrophages in lungs on day 3 and 7. Immunostaining showed that the neutrophils and macrophages expressed H-PGDS, and its mRNA expression was increased on day 3and 7 in WT lungs. These observations suggest that H-PGDS-derived PGD2 plays a protective role in bleomycin-induced lung inflammation and pulmonary fibrosis.

  16. A rare case of cor pulmonale secondary to idiopathic pulmonary fibrosis in Nigeria.

    Science.gov (United States)

    Anakwue, Raphael Chinedu; Chijioke, Chioli Paschal; Iloanusi, Nneka Ifeyinwa

    2011-06-29

    Idiopathic pulmonary fibrosis (IPF) is a rarely reported disease in Nigeria. Cor pulmonale, one of the complications of this type of diffuse parenchymal lung disease is even rarer. The authors present a Nigerian patient with IPF with a classical high-resolution CT features, managed in our centre together with associated problems.

  17. Prevention of Pulmonary Fibrosis via Trichostatin A (TSA) in Bleomycin Induced Rats.

    Science.gov (United States)

    Ye, Qing; Li, Yanqin; Jiang, Handong; Xiong, Jianfei; Xu, Jiabo; Qin, Hui; Liu, Bin

    2014-10-20

    To investigate the effects of non selective histone deacetylase inhibitors Trichostatin A (TSA)on bleomycin-induced pulmonary fibrosis. To investigate the effects of non selective histone deacetylase inhibitors Trichostatin A ( TSA ) on HDAC2, p-SMAD2, HDAC2 mRNA, SMAD2mRNA in pulmonary fibrosis rats and investigate impossible mechanism. 46 SPF level male SD rats were randomly divided into four groups: ten for normal control group, fourteen for model control group I, twelve for model control group II and ten for treatment group. Rat pulmonary fibrosis was induced by bleomycin(5mg/kg) via single intratracheal perfusion in the two model control groups and treatment group. Normal control mice were instilled with a corresponding volume of 0.9% saline intratracheally. Treatment group was treated by the dilution of TSA 2mg/kg DMSO 60ul and0.9% saline 1.2ml intraperitoneal injection from the next day ,once a day for three days. Model control group II was treated by the dilution of DMSO 60ul and0.9% saline 1.2ml intraperitoneal injection from the next day once a day for three days. Model control group I and normal control group were treated by 0.9% saline 1.2ml intraperitoneal injection from the next day once a day for three days. All the animals were sacrificed on the 21 day after modeling. The pathological changes were observed by hematoxylin and eosin(HE)stain and masson trichrome stain. The expression of HDAC2 mRNA,SMAD2 mRNA were measured by real-time PCR. The protein level of HDAC2 and p-SMAD2 in serum was measured by Western blot. The pulmonary fibrosis in treatment group were significantly alleviated compared to the two model control groups (P0.05). Western blot indicated that the protein level of HDAC2 and p-SMAD2 in serum increased in the two model control groups compared with normal control group(P0.05). Non selective histone deacetylase inhibitors of Trichostatin A (TSA) can reduce the bleomycin induced pulmonary fibrosis in rats. TSA attenuates pulmonary

  18. The Prognosis of Small Cell Lung Cancer in Patients with Pulmonary Fibrosis.

    Science.gov (United States)

    Matsumoto, Yoko; Ohara, Sayaka; Furukawa, Ryutaro; Usui, Kazuhiro

    2017-10-01

    The purpose of this study was to assess the prognosis of small cell lung cancer (SCLC) based on the underlying pulmonary disease. A total of 204 patients with SCLC were reviewed and categorized into three groups: normal, emphysema and fibrosis. The median overall survival duration (OS) in patients with normal lungs (n=57), with emphysema (n=105) and fibrosis (n=42) was 21.3, 16.4 and 10.8 months (p=0.063). In limited-stage disease (LD), the median OS in patients with fibrosis (7.4 months) was shorter than normal (52.7 months) or emphysema patients (26.4 months) (p=0.034). In extensive-stage disease (ED), the median OS in patients with fibrosis (12.7 months) was not significantly different from normal (11.4 months) or emphysema patients (13.5 months) (p=0.600). Patients with fibrosis had a poorer prognosis than normal or emphysema patients in LD-SCLC, but the coexistence of pulmonary fibrosis did not affect the prognostic outcomes in ED-SCLC. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  19. A novel telomerase activator suppresses lung damage in a murine model of idiopathic pulmonary fibrosis.

    Directory of Open Access Journals (Sweden)

    Claude Jourdan Le Saux

    Full Text Available The emergence of diseases associated with telomere dysfunction, including AIDS, aplastic anemia and pulmonary fibrosis, has bolstered interest in telomerase activators. We report identification of a new small molecule activator, GRN510, with activity ex vivo and in vivo. Using a novel mouse model, we tested the potential of GRN510 to limit fibrosis induced by bleomycin in mTERT heterozygous mice. Treatment with GRN510 at 10 mg/kg/day activated telomerase 2-4 fold both in hematopoietic progenitors ex vivo and in bone marrow and lung tissue in vivo, respectively. Telomerase activation was countered by co-treatment with Imetelstat (GRN163L, a potent telomerase inhibitor. In this model of bleomycin-induced fibrosis, treatment with GRN510 suppressed the development of fibrosis and accumulation of senescent cells in the lung via a mechanism dependent upon telomerase activation. Treatment of small airway epithelial cells (SAEC or lung fibroblasts ex vivo with GRN510 revealed telomerase activating and replicative lifespan promoting effects only in the SAEC, suggesting that the mechanism accounting for the protective effects of GRN510 against induced lung fibrosis involves specific types of lung cells. Together, these results support the use of small molecule activators of telomerase in therapies to treat idiopathic pulmonary fibrosis.

  20. Role of eukaryotic translation initiation factor 3a in bleomycin-induced pulmonary fibrosis.

    Science.gov (United States)

    Li, Xian-Wei; Wu, Yue-Han; Li, Xiao-Hui; Li, Dai; Du, Jie; Hu, Chang-Ping; Li, Yuan-Jian

    2015-02-15

    Eukaryotic translation initiation factor 3a (eIF3a) is a multifunctional protein and plays an important role in regulation of cellular function including proliferation and differentiation. In the present study, we tested the function of eIF3a in pulmonary fibrosis. Pulmonary fibrosis was induced by intratracheal instillation of bleomycin (5mg/kg) in rats. Primary pulmonary fibroblasts were cultured for proliferation investigation by BrdU incorporation method and flow cytometry. The expression/level of eIF3a, TGF-β1, ERK1/2 and α-SMA were analyzed by ELISA, real-time PCR or western blot. Results showed that the expression of eIF3a was obviously increased in lungs of pulmonary fibrosis rats accompanied by up-regulation of α-SMA and collagens. In cultured pulmonary fibroblasts, application of exogenous TGF-β1 induced cell proliferation and differentiation concomitantly with up-regulation of eIF3a expression and ERK1/2 phosphorylation. The effects of TGF-β1-induced proliferation of fibroblasts and up-regulation of α-SMA were abolished by eIF3a siRNA. TGF-β1-induced eIF3a expression was reversed in the presence of PD98059, an inhibitor of ERK1/2. These findings suggest that eIF3a plays an important role in bleomycin-induced pulmonary fibrosis by regulating pulmonary fibroblasts׳ function, and up-regulation of eIF3a induced by TGF-β1 is mediated via the ERK1/2 pathway. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Intragraft Tubular Vimentin and CD44 Expression Correlate With Long-Term Renal Allograft Function and Interstitial Fibrosis and Tubular Atrophy

    NARCIS (Netherlands)

    Kers, Jesper; Xu-Dubois, Yi-Chun; Rondeau, Eric; Claessen, Nike; Idu, Mirza M.; Roelofs, Joris J. T. H.; Bemelman, Fréderike J.; ten Berge, Ineke J. M.; Florquin, Sandrine

    2010-01-01

    Background. Development of interstitial fibrosis and tubular atrophy (IF/TA) is the main histologic feature involved in renal allograft deterioration. The aim of this study was to validate whether de novo tubular expression of CD44 (transmembrane glycoprotein) and vimentin (mesenchymal cell marker),

  2. Ultramicronized palmitoylethanolamide (PEA-um(®)) in the treatment of idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Di Paola, Rosanna; Impellizzeri, Daniela; Fusco, Roberta; Cordaro, Marika; Siracusa, Rosalba; Crupi, Rosalia; Esposito, Emanuela; Cuzzocrea, Salvatore

    2016-09-01

    Pulmonary fibrosis is a chronic condition characterized by progressive scarring of lung parenchyma. The aim of this study was to examine the effects of an ultramicronized preparation of palmitoylethanolamide (PEA-um(®)), an endogenous fatty acid amide, in mice subjected to idiopathic pulmonary fibrosis. Idiopathic pulmonary fibrosis was induced in male mice by a single intratracheal administration of saline with bleomycin sulphate (1mg/kg body weight) in a volume of 100μL. PEA-um(®) was injected intraperitoneally at 1, 3 or 10mg/kg 1h after bleomycin instillation and daily thereafter. Animals were sacrificed after 7 and 21days by pentobarbitone overdose. One cohort of mice was sacrificed after seven days of bleomycin administration, followed by bronchoalveloar lavage and determination of myeloperoxidase activity, lung edema and histopathology features. In the 21-day cohort, mortality was assessed daily, and surviving mice were sacrificed followed by the above analyses together with immunohistochemical localization of CD8, tumor necrosis factor-α, CD4, interleukin-1β, transforming growth factor-β, inducible nitric oxide synthase and basic fibroblast growth factor. Compared to bleomycin-treated mice, animals that received also PEA-um(®) (3 or 10mg/kg) had significantly decreased weight loss, mortality, inflammation, lung damage at the histological level, and lung fibrosis at 7 and 21days. PEA-um(®) (1mg/kg) did not significantly inhibit the inflammation response and lung fibrosis. This study demonstrates that PEA-um(®) (3 and 10mg/kg) reduces the extent of lung inflammation in a mouse model of idiopathic pulmonary fibrosis. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Lung-specific loss of α3 laminin worsens bleomycin-induced pulmonary fibrosis.

    Science.gov (United States)

    Morales-Nebreda, Luisa I; Rogel, Micah R; Eisenberg, Jessica L; Hamill, Kevin J; Soberanes, Saul; Nigdelioglu, Recep; Chi, Monica; Cho, Takugo; Radigan, Kathryn A; Ridge, Karen M; Misharin, Alexander V; Woychek, Alex; Hopkinson, Susan; Perlman, Harris; Mutlu, Gokhan M; Pardo, Annie; Selman, Moises; Jones, Jonathan C R; Budinger, G R Scott

    2015-04-01

    Laminins are heterotrimeric proteins that are secreted by the alveolar epithelium into the basement membrane, and their expression is altered in extracellular matrices from patients with pulmonary fibrosis. In a small number of patients with pulmonary fibrosis, we found that the normal basement membrane distribution of the α3 laminin subunit was lost in fibrotic regions of the lung. To determine if these changes play a causal role in the development of fibrosis, we generated mice lacking the α3 laminin subunit specifically in the lung epithelium by crossing mice expressing Cre recombinase driven by the surfactant protein C promoter (SPC-Cre) with mice expressing floxed alleles encoding the α3 laminin gene (Lama3(fl/fl)). These mice exhibited no developmental abnormalities in the lungs up to 6 months of age, but, compared with control mice, had worsened mortality, increased inflammation, and increased fibrosis after the intratracheal administration of bleomycin. Similarly, the severity of fibrosis induced by an adenovirus encoding an active form of transforming growth factor-β was worse in mice deficient in α3 laminin in the lung. Taken together, our results suggest that the loss of α3 laminin in the lung epithelium does not affect lung development, but plays a causal role in the development of fibrosis in response to bleomycin or adenovirally delivered transforming growth factor-β. Thus, we speculate that the loss of the normal basement membrane organization of α3 laminin that we observe in fibrotic regions from the lungs of patients with pulmonary fibrosis contributes to their disease progression.

  4. Rheumatoid Arthritis Associated with Pulmonary Fibrosis in Nigerians

    African Journals Online (AJOL)

    Rheumatoid arthritis may sometimes present with extra-articular involvement, pulmonary involvement is not common. Rheumatoid arthritis has been reported among Nigerians and extra-articular manifestations are rarely seen. One of the patients was misdiagnosed and mismanaged as a patient with pulmonary tuberculosis ...

  5. P2Y6 Receptor Activation Promotes Inflammation and Tissue Remodeling in Pulmonary Fibrosis

    Directory of Open Access Journals (Sweden)

    Tobias Müller

    2017-08-01

    Full Text Available Idiopathic pulmonary fibrosis (IPF is a disease with a poor prognosis and very few available treatment options. The involvement of the purinergic receptor subtypes P2Y2 and P2X7 in fibrotic lung disease has been demonstrated recently. In this study, we investigated the role of P2Y6 receptors in the pathogenesis of IPF in humans and in the animal model of bleomycin-induced lung injury. P2Y6R expression was upregulated in lung structural cells but not in bronchoalveolar lavage (BAL cells derived from IPF patients as well as in animals following bleomycin administration. Furthermore, BAL fluid levels of the P2Y6R agonist uridine-5′-diphosphate were elevated in animals with bleomycin-induced pulmonary fibrosis. Inflammation and fibrosis following bleomycin administration were reduced in P2Y6R-deficient compared to wild-type animals confirming the pathophysiological relevance of P2Y6R subtypes for fibrotic lung diseases. Experiments with bone marrow chimeras revealed the importance of P2Y6R expression on lung structural cells for pulmonary inflammation and fibrosis. Similar effects were obtained when animals were treated with the P2Y6R antagonist MRS2578. In vitro studies demonstrated that proliferation and secretion of the pro-inflammatory/pro-fibrotic cytokine IL-6 by lung fibroblasts are P2Y6R-mediated processes. In summary, our results clearly demonstrate the involvement of P2Y6R subtypes in the pathogenesis of pulmonary fibrosis. Thus, blocking pulmonary P2Y6 receptors might be a new target for the treatment of IPF.

  6. Megakaryoblastic leukemia-1 is required for the development of bleomycin-induced pulmonary fibrosis.

    Science.gov (United States)

    Bernau, Ksenija; Ngam, Caitlyn; Torr, Elizabeth E; Acton, Benjamin; Kach, Jacob; Dulin, Nickolai O; Sandbo, Nathan

    2015-03-27

    Fibrosing disorders of the lung, such as idiopathic pulmonary fibrosis, are characterized by progressive extracellular matrix accumulation that is driven by myofibroblasts. The transcription factor megakaryoblastic leukemia-1 (MKL1) mediates myofibroblast differentiation in response to several profibrotic stimuli, but the role it plays in mediating pulmonary fibrosis has not been fully elucidated. In this study, we utilized mice that had a germline deletion of MKL1 (MKL1 (-,-)) to determine the role that MKL1 plays in the development of bleomycin-induced pulmonary fibrosis. Bleomycin or normal saline were intratracheally delivered to 9 to 12 week old female MKL1 (+,+) and MKL1 (-,-) mice. Mice were assessed for weight loss and survival to 28 days. Inflammatory responses were assessed through bronchoalveolar lavage at days 3 and 7 post-treatment. The development of pulmonary fibrosis was characterized using hydroxyproline assay and histological staining. MKL1 (+,+) and MKL1 (-,-) mouse lung fibroblasts were isolated to compare morphologic, gene expression and functional differences. MKL1 (-,-) mice demonstrated increased survival, attenuated weight loss, and decreased collagen accumulation compared to wild-type animals 28-days after intratracheal instillation of bleomycin. Histological analysis demonstrated decreased trichrome, smooth muscle α-actin, and fibronectin staining in MKL1(-,-) mice compared to MKL1 (+,+) controls. Differential cell counts from bronchoalveolar lavage demonstrated that there was attenuated neutrophilia 3 days after bleomycin administration, but no difference at day 7. Isolated mouse lung fibroblasts from MKL1 (-,-) mice had decreased contractility and deposited less fibronectin matrix compared to wild-type controls, suggesting a defect in key remodeling functions. Altogether, these data demonstrate that MKL1 plays a significant role in mediating the fibrotic response to bleomycin injury. Loss of MKL1 attenuated early neutrophil influx, as

  7. Hypertonic Saline in Treatment of Pulmonary Disease in Cystic Fibrosis

    Directory of Open Access Journals (Sweden)

    Emer P. Reeves

    2012-01-01

    Full Text Available The pathogenesis of lung disease in cystic fibrosis is characterised by decreased airway surface liquid volume and subsequent failure of normal mucociliary clearance. Mucus within the cystic fibrosis airways is enriched in negatively charged matrices composed of DNA released from colonizing bacteria or inflammatory cells, as well as F-actin and elevated concentrations of anionic glycosaminoglycans. Therapies acting against airway mucus in cystic fibrosis include aerosolized hypertonic saline. It has been shown that hypertonic saline possesses mucolytic properties and aids mucociliary clearance by restoring the liquid layer lining the airways. However, recent clinical and bench-top studies are beginning to broaden our view on the beneficial effects of hypertonic saline, which now extend to include anti-infective as well as anti-inflammatory properties. This review aims to discuss the described therapeutic benefits of hypertonic saline and specifically to identify novel models of hypertonic saline action independent of airway hydration.

  8. Hypertonic saline in treatment of pulmonary disease in cystic fibrosis.

    LENUS (Irish Health Repository)

    Reeves, Emer P

    2012-01-01

    The pathogenesis of lung disease in cystic fibrosis is characterised by decreased airway surface liquid volume and subsequent failure of normal mucociliary clearance. Mucus within the cystic fibrosis airways is enriched in negatively charged matrices composed of DNA released from colonizing bacteria or inflammatory cells, as well as F-actin and elevated concentrations of anionic glycosaminoglycans. Therapies acting against airway mucus in cystic fibrosis include aerosolized hypertonic saline. It has been shown that hypertonic saline possesses mucolytic properties and aids mucociliary clearance by restoring the liquid layer lining the airways. However, recent clinical and bench-top studies are beginning to broaden our view on the beneficial effects of hypertonic saline, which now extend to include anti-infective as well as anti-inflammatory properties. This review aims to discuss the described therapeutic benefits of hypertonic saline and specifically to identify novel models of hypertonic saline action independent of airway hydration.

  9. Triptolide suppresses paraquat induced idiopathic pulmonary fibrosis by inhibiting TGFB1-dependent epithelial mesenchymal transition.

    Science.gov (United States)

    Chen, Hong; Chen, Qun; Jiang, Chun-Ming; Shi, Guang-Yue; Sui, Bo-Wen; Zhang, Wei; Yang, Li-Zhen; Li, Zhu-Ying; Liu, Li; Su, Yu-Ming; Zhao, Wen-Cheng; Sun, Hong-Qiang; Li, Zhen-Zi; Fu, Zhou

    2018-03-01

    Idiopathic pulmonary fibrosis (IPF) and tumor are highly similar to abnormal cell proliferation that damages the body. This malignant cell evolution in a stressful environment closely resembles that of epithelial-mesenchymal transition (EMT). As a popular EMT-inducing factor, TGFβ plays an important role in the progression of multiple diseases. However, the drugs that target TGFB1 are limited. In this study, we found that triptolide (TPL), a Chinese medicine extract, exerts an anti-lung fibrosis effect by inhibiting the EMT of lung epithelial cells. In addition, triptolide directly binds to TGFβ and subsequently increase E-cadherin expression and decrease vimentin expression. In in vivo studies, TPL improves the survival state and inhibits lung fibrosis in mice. In summary, this study revealed the potential therapeutic effect of paraquat induced TPL in lung fibrosis by regulating TGFβ-dependent EMT progression. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Tumor necrosis factor-α accelerates the resolution of established pulmonary fibrosis in mice by targeting profibrotic lung macrophages.

    Science.gov (United States)

    Redente, Elizabeth F; Keith, Rebecca C; Janssen, William; Henson, Peter M; Ortiz, Luis A; Downey, Gregory P; Bratton, Donna L; Riches, David W H

    2014-04-01

    Idiopathic pulmonary fibrosis (IPF) is a relentless, fibrotic parenchymal lung disease in which alternatively programmed macrophages produce profibrotic molecules that promote myofibroblast survival and collagen synthesis. Effective therapies to treat patients with IPF are lacking, and conventional therapy may be harmful. We tested the hypothesis that therapeutic lung delivery of the proinflammatory cytokine tumor necrosis factor (TNF)-α into wild-type fibrotic mice would reduce the profibrotic milieu and accelerate the resolution of established pulmonary fibrosis. Fibrosis was assessed in bleomycin-instilled wild-type and TNF-α(-/-) mice by measuring hydroxyproline levels, static compliance, and Masson's trichrome staining. Macrophage infiltration and programming status was assessed by flow cytometry of enzymatically digested lung and in situ immunostaining. Pulmonary delivery of TNF-α to wild-type mice with established pulmonary fibrosis was found to reduce their fibrotic burden, to improve lung function and architecture, and to reduce the number and programming status of profibrotic alternatively programmed macrophages. In contrast, fibrosis and alternative macrophage programming were prolonged in bleomycin-instilled TNF-α(-/-) mice. To address the role of the reduced numbers of alternatively programmed macrophages in the TNF-α-induced resolution of established pulmonary fibrosis, we conditionally depleted macrophages in MAFIA (MAcrophage Fas-Induced Apoptosis) mice. Conditional macrophage depletion phenocopied the resolution of established pulmonary fibrosis observed after therapeutic TNF-α delivery. Taken together, our results show for the first time that TNF-α is involved in the resolution of established pulmonary fibrosis via a mechanism involving reduced numbers and programming status of profibrotic macrophages. We speculate that pulmonary delivery of TNF-α or augmenting its signaling pathway represent a novel therapeutic strategy to resolve

  11. Tumor Necrosis Factor-α Accelerates the Resolution of Established Pulmonary Fibrosis in Mice by Targeting Profibrotic Lung Macrophages

    Science.gov (United States)

    Redente, Elizabeth F.; Keith, Rebecca C.; Janssen, William; Henson, Peter M.; Ortiz, Luis A.; Downey, Gregory P.; Bratton, Donna L.

    2014-01-01

    Idiopathic pulmonary fibrosis (IPF) is a relentless, fibrotic parenchymal lung disease in which alternatively programmed macrophages produce profibrotic molecules that promote myofibroblast survival and collagen synthesis. Effective therapies to treat patients with IPF are lacking, and conventional therapy may be harmful. We tested the hypothesis that therapeutic lung delivery of the proinflammatory cytokine tumor necrosis factor (TNF)-α into wild-type fibrotic mice would reduce the profibrotic milieu and accelerate the resolution of established pulmonary fibrosis. Fibrosis was assessed in bleomycin-instilled wild-type and TNF-α−/− mice by measuring hydroxyproline levels, static compliance, and Masson’s trichrome staining. Macrophage infiltration and programming status was assessed by flow cytometry of enzymatically digested lung and in situ immunostaining. Pulmonary delivery of TNF-α to wild-type mice with established pulmonary fibrosis was found to reduce their fibrotic burden, to improve lung function and architecture, and to reduce the number and programming status of profibrotic alternatively programmed macrophages. In contrast, fibrosis and alternative macrophage programming were prolonged in bleomycin-instilled TNF-α−/− mice. To address the role of the reduced numbers of alternatively programmed macrophages in the TNF-α–induced resolution of established pulmonary fibrosis, we conditionally depleted macrophages in MAFIA (MAcrophage Fas-Induced Apoptosis) mice. Conditional macrophage depletion phenocopied the resolution of established pulmonary fibrosis observed after therapeutic TNF-α delivery. Taken together, our results show for the first time that TNF-α is involved in the resolution of established pulmonary fibrosis via a mechanism involving reduced numbers and programming status of profibrotic macrophages. We speculate that pulmonary delivery of TNF-α or augmenting its signaling pathway represent a novel therapeutic strategy to resolve

  12. Fasudil, a Rho-Kinase Inhibitor, Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice

    Directory of Open Access Journals (Sweden)

    Zuojun Xu

    2012-07-01

    Full Text Available The mechanisms underlying the pathogenesis of idiopathic pulmonary fibrosis (IPF involve multiple pathways, such as inflammation, epithelial mesenchymal transition, coagulation, oxidative stress, and developmental processes. The small GTPase, RhoA, and its target protein, Rho-kinase (ROCK, may interact with other signaling pathways known to contribute to pulmonary fibrosis. This study aimed to determine the beneficial effects and mechanisms of fasudil, a selective ROCK inhibitor, on bleomycin-induced pulmonary fibrosis in mice. Our results showed that the Aschcroft score and hydroxyproline content of the bleomycin-treated mouse lung decreased in response to fasudil treatment. The number of infiltrated inflammatory cells in the bronchoalveolar lavage fluid (BALF was attenuated by fasudil. In addition, fasudil reduced the production of transforming growth factor-β1 (TGF-β1, connective tissue growth factor (CTGF, alpha-smooth muscle actin (α-SMA, and plasminogen activator inhibitor-1 (PAI-1 mRNA and protein expression in bleomycin-induced pulmonary fibrosis. These findings suggest that fasudil may be a potential therapeutic candidate for the treatment of pulmonary fibrosis.

  13. Pulmonary interstitial emphysema presenting in a woman on the intensive care unit: case report and review of literature

    Directory of Open Access Journals (Sweden)

    Jovaisa Tomas

    2011-06-01

    Full Text Available Abstract Introduction Pulmonary interstitial emphysema is a life-threatening form of ventilator-induced lung injury. We present one of the few reported adult cases of pulmonary interstitial emphysema in a woman with respiratory failure admitted to our intensive care unit. Case presentation An 87-year-old Caucasian woman with a diagnosis of community-acquired pneumonia was admitted to our intensive care unit requiring invasive ventilation. The combination of a poor oxygenation index and bilateral alveolar/interstitial infiltrates on a chest radiograph fulfilled the criteria for adult respiratory distress syndrome; the cause was thought to be a combination of the direct pneumonic pulmonary injury and extrapulmonary severe sepsis. By day seven, the fraction of inspired oxygen, peak airway and positive end expiratory pressures weaned sufficiently to allow an uncomplicated percutaneous tracheostomy. On day 10, problems with ventilation necessitated recruitment maneuvers with a Mapleson C circuit, after which dramatic surgical emphysema was noted. An upper airway bronchoscopy showed no obvious tracheal wall injury, and computed tomography of her chest showed extensive surgical emphysema, perivascular emphysema and peribronchial emphysema, which were consistent with a diagnosis of pulmonary interstitial emphysema. Over the following days, despite protective ventilatory strategies and intercostal tube thoracostomy, lung compliance along with oxygenation deteriorated and our patient died on day 14. Conclusion The development of pulmonary interstitial emphysema is a rare but real risk when caring for patients with worsening lung compliance on the intensive care unit. Improved awareness of the condition, early protective ventilation strategies and timely treatment of any of the lethal complications will hopefully result in improved survival from the condition in adults.

  14. Pulmonary interstitial emphysema presenting in a woman on the intensive care unit: case report and review of literature

    Science.gov (United States)

    2011-01-01

    Introduction Pulmonary interstitial emphysema is a life-threatening form of ventilator-induced lung injury. We present one of the few reported adult cases of pulmonary interstitial emphysema in a woman with respiratory failure admitted to our intensive care unit. Case presentation An 87-year-old Caucasian woman with a diagnosis of community-acquired pneumonia was admitted to our intensive care unit requiring invasive ventilation. The combination of a poor oxygenation index and bilateral alveolar/interstitial infiltrates on a chest radiograph fulfilled the criteria for adult respiratory distress syndrome; the cause was thought to be a combination of the direct pneumonic pulmonary injury and extrapulmonary severe sepsis. By day seven, the fraction of inspired oxygen, peak airway and positive end expiratory pressures weaned sufficiently to allow an uncomplicated percutaneous tracheostomy. On day 10, problems with ventilation necessitated recruitment maneuvers with a Mapleson C circuit, after which dramatic surgical emphysema was noted. An upper airway bronchoscopy showed no obvious tracheal wall injury, and computed tomography of her chest showed extensive surgical emphysema, perivascular emphysema and peribronchial emphysema, which were consistent with a diagnosis of pulmonary interstitial emphysema. Over the following days, despite protective ventilatory strategies and intercostal tube thoracostomy, lung compliance along with oxygenation deteriorated and our patient died on day 14. Conclusion The development of pulmonary interstitial emphysema is a rare but real risk when caring for patients with worsening lung compliance on the intensive care unit. Improved awareness of the condition, early protective ventilation strategies and timely treatment of any of the lethal complications will hopefully result in improved survival from the condition in adults. PMID:21702976

  15. The pathogenesis of bleomycin-induced lung injury in animals and its applicability to human idiopathic pulmonary fibrosis.

    Science.gov (United States)

    Williamson, James D; Sadofsky, Laura R; Hart, Simon P

    2015-03-01

    Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown etiology, for which there is no curative pharmacological therapy. Bleomycin, an anti-neoplastic agent that causes lung fibrosis in human patients has been used extensively in rodent models to mimic IPF. In this review, we compare the pathogenesis and histological features of human IPF and bleomycin-induced pulmonary fibrosis (BPF) induced in rodents by intratracheal delivery. We discuss the current understanding of IPF and BPF disease development, from the contribution of alveolar epithelial cells and inflammation to the role of fibroblasts and cytokines, and draw conclusions about what we have learned from the intratracheal bleomycin model of lung fibrosis.

  16. Pulmonary interstitial hemosiderin in infancy: a common consequence of normal labor.

    Science.gov (United States)

    Becroft, David M O; Thompson, John M D; Mitchell, Edwin A

    2005-01-01

    Deposits of hemosiderin are found frequently in the interstitium of the lungs of infants who die suddenly and have been a suggested marker for hypoxia during previous episodes of apnea. We studied the epidemiology of pulmonary interstitial hemosiderin (PIH) in 94 infants with a diagnosis of the sudden infant death syndrome that was established during the New Zealand Cot Death Study. Twenty-seven infants (29%) had widely distributed PIH. Associations were sought between PIH and variables on which information had been obtained from parental interviews or from medical records. Previous suggestions of associations with increasing birth weight and decreasing age at death were confirmed in multivariate analysis (P = 0.0018 and P = 0.03, respectively) and with increasing gestation in univariate analysis (P < 0.0001). PIH was not found in any of the 13 infants delivered by elective cesarean section compared with a 33% incidence in those exposed to labor (P = 0.02). There was no association with previous apnea. We consider that the likely explanation of these findings is that PIH is a residue of interstitial hemorrhage caused by chest compression during labor that occurs particularly in larger infants of greater gestational age and then clears gradually during early infancy.

  17. Percutaneous evacuation of diffuse pulmonary interstitial emphysema by lung puncture in a baby with extremely low birth weight: a case report

    Directory of Open Access Journals (Sweden)

    Watanabe Masahiro

    2012-09-01

    Full Text Available Abstract Introduction Pulmonary interstitial emphysema is a serious complication of mechanical ventilation and can become life-threatening if progression occurs. Therapeutic lung puncture is a treatment option for severe pulmonary interstitial emphysema but has a limited use in babies with extremely low birth weight. We present a case of pulmonary interstitial emphysema in a Japanese baby (1-day-old boy with extremely low birth weight. The emphysema was successfully decompressed by therapeutic lung puncture performed with a trocar catheter. Case presentation The baby was born with a weight of 420g, which, to the best of our knowledge, is the lowest reported birth weight among babies with pulmonary interstitial emphysema. A chest X-ray on postnatal day 2 revealed pulmonary interstitial emphysema, which gradually progressed to diffuse pseudocystic changes. His condition became life-threatening despite the use of high-frequency oscillatory ventilation and lateral decubitus positioning. We evacuated the pulmonary interstitial emphysema by lung puncture with a trocar catheter to avoid respiratory and cardiovascular collapse. This resulted in adequate evacuation of the emphysema and a dramatic improvement in his clinical condition. Conclusions Therapeutic lung puncture performed with a trocar catheter is beneficial in babies with extremely low birth weight and diffuse pulmonary interstitial emphysema. This treatment option may be broadly applicable, especially in an emergency situation.

  18. Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis.

    Science.gov (United States)

    Cao, Zhongwei; Lis, Raphael; Ginsberg, Michael; Chavez, Deebly; Shido, Koji; Rabbany, Sina Y; Fong, Guo-Hua; Sakmar, Thomas P; Rafii, Shahin; Ding, Bi-Sen

    2016-02-01

    Although the lung can undergo self-repair after injury, fibrosis in chronically injured or diseased lungs can occur at the expense of regeneration. Here we study how a hematopoietic-vascular niche regulates alveolar repair and lung fibrosis. Using intratracheal injection of bleomycin or hydrochloric acid in mice, we show that repetitive lung injury activates pulmonary capillary endothelial cells (PCECs) and perivascular macrophages, impeding alveolar repair and promoting fibrosis. Whereas the chemokine receptor CXCR7, expressed on PCECs, acts to prevent epithelial damage and ameliorate fibrosis after a single round of treatment with bleomycin or hydrochloric acid, repeated injury leads to suppression of CXCR7 expression and recruitment of vascular endothelial growth factor receptor 1 (VEGFR1)-expressing perivascular macrophages. This recruitment stimulates Wnt/β-catenin-dependent persistent upregulation of the Notch ligand Jagged1 (encoded by Jag1) in PCECs, which in turn stimulates exuberant Notch signaling in perivascular fibroblasts and enhances fibrosis. Administration of a CXCR7 agonist or PCEC-targeted Jag1 shRNA after lung injury promotes alveolar repair and reduces fibrosis. Thus, targeting of a maladapted hematopoietic-vascular niche, in which macrophages, PCECs and perivascular fibroblasts interact, may help to develop therapy to spur lung regeneration and alleviate fibrosis.

  19. The distribution of immunomodulatory cells in the lungs of patients with idiopathic pulmonary fibrosis

    Science.gov (United States)

    Nuovo, Gerard J.; Hagood, James S.; Magro, Cynthia M.; Chin, Nena; Kapil, Rubina; Davis, Luke; Marsh, Clay B.; Folcik, Virginia A.

    2011-01-01

    We have characterized the immune system involvement in the disease processes of idiopathic pulmonary fibrosis in novel ways. To do so, we analyzed lung tissue from 21 cases of idiopathic pulmonary fibrosis and 21 (non-fibrotic, non-cancerous) controls for immune cell and inflammation-related markers. The immunohistochemical analysis of the tissue was grouped by patterns of severity in disease pathology. There were significantly greater numbers of CD68+ and CD80+ cells, and significantly fewer CD3+, CD4+, and CD45RO+ cells in areas of relatively (histologically) normal lung in biopsies from idiopathic pulmonary fibrosis patients compared to controls. In zones of active disease, characterized by epithelial cell regeneration and fibrosis, there were significantly more cells expressing CD4, CD8, CD20, CD68, CD80, CCR6, S100, IL-17, tumor necrosis factor-α, and retinoic acid-related orphan receptors compared to histologically normal lung areas from idiopathic pulmonary fibrosis patients. Inflammation was implicated in these active regions by the cells that expressed retinoid orphan receptor-α, -β, and -γ, CCR6, and IL-17. The regenerating epithelial cells predominantly expressed these pro-inflammatory molecules, as evidenced by co-expression analyses with epithelial cytokeratins. Macrophages in pseudo-alveoli and CD3+ T cells in the fibrotic interstitium also expressed IL-17. Co-expression of IL-17 with retinoid orphan receptors, and epithelial cytoskeletal proteins, CD68, and CD3 in epithelial cells, macrophages, and T-cells, respectively, confirmed the production of IL-17 by these cell types. There was little staining for Foxp3, CD56, or CD34 in any idiopathic pulmonary fibrosis lung regions. The fibrotic regions had fewer immune cells overall. In summary, our study shows participation of innate and adaptive mononuclear cells in active-disease regions of idiopathic pulmonary fibrosis lung, where the regenerating epithelial cells appear to propagate inflammation

  20. rheumatoid arthritis associated with pulmonary fibrosis in nigerians

    African Journals Online (AJOL)

    productive cough and mild dyspnea on exertion. Examination of affected patients can reveal an increased respiratory rate, clubbing, and crepitations particularly at the lung bases (8, 10). Chest radiographs typically showed a reticulated pattern with progress to a fine nodularity and honeycomb fibrosis (11). The CXR of both ...

  1. Moxibustion has a positive effect on pulmonary fibrosis: an ...

    African Journals Online (AJOL)

    Background: An increasing number of people suffered idiopathic fibrosis (IPF) and the current treatment was far from clinical satisfaction. Moxibustion, another effective and safe unconventional therapy, had been introduced to treat this refractory disease. The study aimed to investigate the effect of moxibustion on a ...

  2. Idiopathic pulmonary fibrosis complicated by acute thromboembolic disease: chest X-ray, HRCT and multi-detector row CT angiographic findings.

    Science.gov (United States)

    Camera, Luigi; Campanile, Francesco; Imbriaco, Massimo; Ippolito, Renato; Sirignano, Cesare; Santoro, Ciro; Galderisi, Maurizio; Salvatore, Marco

    2013-02-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic diffuse interstitial disease characterized by a predominant reticular pattern of involvement of the lung parenchyma which can be well documented by High Resolution Computed Tomography (HRCT). While almost half of the patients with IPF may develop pulmonary arterial hypertension, the occurrence of superimposed acute thrombo-embolic disease is rare.We describe a case of an 87 yrs old female who was found to have IPF complicated by acute pulmonary thrombo-embolism during the clinical and radiological investigation of a rapidly worsening dyspnea. While chest x-ray findings were initially considered consistent with a congestive heart failure, a bed side echocardiography revealed findings suggestive of pulmonary arterial hypertension and right ventricular failure with enlargement of both right cavities and associated valvular regurgitations. An acute thrombo-embolic disease was initially ruled out by a perfusion lung scintigraphy and subsequently confirmed by contrast-enhanced multi-detector CT which showed an embolus at the emergency of the right inter-lobar artery with associated signs of chronic pulmonary hypertension. However, unenhanced scans performed with both conventional and high resolution techniques also depicted a reticular pattern of involvement of lung parenchyma considered suggestive of IPF despite a atypical upper lobe predominance. IPF was later confirmed by further clinical, serological and instrumental follow-up.

  3. MAP3K19 Is a Novel Regulator of TGF-β Signaling That Impacts Bleomycin-Induced Lung Injury and Pulmonary Fibrosis.

    Directory of Open Access Journals (Sweden)

    Stefen A Boehme

    Full Text Available Idiopathic pulmonary fibrosis (IPF is a progressive, debilitating disease for which two medications, pirfenidone and nintedanib, have only recently been approved for treatment. The cytokine TGF-β has been shown to be a central mediator in the disease process. We investigated the role of a novel kinase, MAP3K19, upregulated in IPF tissue, in TGF-β-induced signal transduction and in bleomycin-induced pulmonary fibrosis. MAP3K19 has a very limited tissue expression, restricted primarily to the lungs and trachea. In pulmonary tissue, expression was predominantly localized to alveolar and interstitial macrophages, bronchial epithelial cells and type II pneumocytes of the epithelium. MAP3K19 was also found to be overexpressed in bronchoalveolar lavage macrophages from IPF patients compared to normal patients. Treatment of A549 or THP-1 cells with either MAP3K19 siRNA or a highly potent and specific inhibitor reduced phospho-Smad2 & 3 nuclear translocation following TGF-β stimulation. TGF-β-induced gene transcription was also strongly inhibited by both the MAP3K19 inhibitor and nintedanib, whereas pirfenidone had a much less pronounced effect. In combination, the MAP3K19 inhibitor appeared to act synergistically with either pirfenidone or nintedanib, at the level of target gene transcription or protein production. Finally, in an animal model of IPF, inhibition of MAP3K19 strongly attenuated bleomycin-induced pulmonary fibrosis when administered either prophylactically ortherapeutically. In summary, these results strongly suggest that inhibition of MAP3K19 may have a beneficial therapeutic effect in the treatment of IPF and represents a novel strategy to target this disease.

  4. MAP3K19 Is a Novel Regulator of TGF-β Signaling That Impacts Bleomycin-Induced Lung Injury and Pulmonary Fibrosis.

    Science.gov (United States)

    Boehme, Stefen A; Franz-Bacon, Karin; DiTirro, Danielle N; Ly, Tai Wei; Bacon, Kevin B

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive, debilitating disease for which two medications, pirfenidone and nintedanib, have only recently been approved for treatment. The cytokine TGF-β has been shown to be a central mediator in the disease process. We investigated the role of a novel kinase, MAP3K19, upregulated in IPF tissue, in TGF-β-induced signal transduction and in bleomycin-induced pulmonary fibrosis. MAP3K19 has a very limited tissue expression, restricted primarily to the lungs and trachea. In pulmonary tissue, expression was predominantly localized to alveolar and interstitial macrophages, bronchial epithelial cells and type II pneumocytes of the epithelium. MAP3K19 was also found to be overexpressed in bronchoalveolar lavage macrophages from IPF patients compared to normal patients. Treatment of A549 or THP-1 cells with either MAP3K19 siRNA or a highly potent and specific inhibitor reduced phospho-Smad2 & 3 nuclear translocation following TGF-β stimulation. TGF-β-induced gene transcription was also strongly inhibited by both the MAP3K19 inhibitor and nintedanib, whereas pirfenidone had a much less pronounced effect. In combination, the MAP3K19 inhibitor appeared to act synergistically with either pirfenidone or nintedanib, at the level of target gene transcription or protein production. Finally, in an animal model of IPF, inhibition of MAP3K19 strongly attenuated bleomycin-induced pulmonary fibrosis when administered either prophylactically ortherapeutically. In summary, these results strongly suggest that inhibition of MAP3K19 may have a beneficial therapeutic effect in the treatment of IPF and represents a novel strategy to target this disease.

  5. Adiponectin attenuates lung fibroblasts activation and pulmonary fibrosis induced by paraquat.

    Directory of Open Access Journals (Sweden)

    Rong Yao

    Full Text Available Pulmonary fibrosis is one of the most common complications of paraquat (PQ poisoning, which demands for more effective therapies. Accumulating evidence suggests adiponectin (APN may be a promising therapy against fibrotic diseases. In the current study, we determine whether the exogenous globular APN isoform protects against pulmonary fibrosis in PQ-treated mice and human lung fibroblasts, and dissect the responsible underlying mechanisms. BALB/C mice were divided into control group, PQ group, PQ + low-dose APN group, and PQ + high-dose APN group. Mice were sacrificed 3, 7, 14, and 21 days after PQ treatment. We compared pulmonary histopathological changes among different groups on the basis of fibrosis scores, TGF-β1, CTGF and α-SMA pulmonary content via Western blot and real-time quantitative fluorescence-PCR (RT-PCR. Blood levels of MMP-9 and TIMP-1 were determined by ELISA. Human lung fibroblasts WI-38 were divided into control group, PQ group, APN group, and APN receptor (AdipoR 1 small-interfering RNA (siRNA group. Fibroblasts were collected 24, 48, and 72 hours after PQ exposure for assay. Cell viability and apoptosis were determined via Kit-8 (CCK-8 and fluorescein Annexin V-FITC/PI double labeling. The protein and mRNA expression level of collagen type III, AdipoR1, and AdipoR2 were measured by Western blot and RT-PCR. APN treatment significantly decreased the lung fibrosis scores, protein and mRNA expression of pulmonary TGF-β1, CTGF and α-SMA content, and blood MMP-9 and TIMP-1 in a dose-dependent manner (p<0.05. Pretreatment with APN significantly attenuated the reduced cell viability and up-regulated collagen type III expression induced by PQ in lung fibroblasts, (p<0.05. APN pretreatment up-regulated AdipoR1, but not AdipoR2, expression in WI-38 fibroblasts. AdipoR1 siRNA abrogated APN-mediated protective effects in PQ-exposed fibroblasts. Taken together, our data suggests APN protects against PQ-induced pulmonary fibrosis in a

  6. Rac2 is required for alternative macrophage activation and bleomycin induced pulmonary fibrosis; a macrophage autonomous phenotype.

    Directory of Open Access Journals (Sweden)

    Shweta Joshi

    Full Text Available Idiopathic pulmonary fibrosis (IPF is a chronic lung disease characterized by cellular phenotype alterations and deposition of extracellular matrix proteins. The alternative activation of macrophages in the lungs has been associated as a major factor promoting pulmonary fibrosis, however the mechanisms underlying this phenomenon are poorly understood. In the present study, we have defined a molecular mechanism by which signals transmitted from the extracellular matrix via the α4β1 integrin lead to the activation of Rac2 which regulates alternative macrophage differentiation, a signaling axis within the pulmonary macrophage compartment required for bleomycin induced pulmonary fibrosis. Mice deficient in Rac2 were protected against bleomycin-induced fibrosis and displayed diminished collagen deposition in association with lower expression of alternatively activated profibrotic macrophage markers. We have demonstrated a macrophage autonomous process by which the injection of M2 and not M1 macrophages restored the bleomycin induced pulmonary fibrosis susceptibility in Rac2-/- mice, establishing a critical role for a macrophage Rac2 signaling axis in the regulation of macrophage differentiation and lung fibrosis in vivo. We also demonstrate that markers of alternative macrophage activation are increased in patients with IPF. Taken together, these studies define an important role for an integrin-driven Rac2 signaling axis in macrophages, and reveal that Rac2 activation is required for polarization of macrophages towards a profibrotic phenotype and progression of pulmonary fibrosis in vivo.

  7. Rac2 is required for alternative macrophage activation and bleomycin induced pulmonary fibrosis; a macrophage autonomous phenotype

    Science.gov (United States)

    Zulcic, Muamera; Jiang, Min; Pardo, Annie; Selman, Moises; Hagood, James S.

    2017-01-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by cellular phenotype alterations and deposition of extracellular matrix proteins. The alternative activation of macrophages in the lungs has been associated as a major factor promoting pulmonary fibrosis, however the mechanisms underlying this phenomenon are poorly understood. In the present study, we have defined a molecular mechanism by which signals transmitted from the extracellular matrix via the α4β1 integrin lead to the activation of Rac2 which regulates alternative macrophage differentiation, a signaling axis within the pulmonary macrophage compartment required for bleomycin induced pulmonary fibrosis. Mice deficient in Rac2 were protected against bleomycin-induced fibrosis and displayed diminished collagen deposition in association with lower expression of alternatively activated profibrotic macrophage markers. We have demonstrated a macrophage autonomous process by which the injection of M2 and not M1 macrophages restored the bleomycin induced pulmonary fibrosis susceptibility in Rac2-/- mice, establishing a critical role for a macrophage Rac2 signaling axis in the regulation of macrophage differentiation and lung fibrosis in vivo. We also demonstrate that markers of alternative macrophage activation are increased in patients with IPF. Taken together, these studies define an important role for an integrin-driven Rac2 signaling axis in macrophages, and reveal that Rac2 activation is required for polarization of macrophages towards a profibrotic phenotype and progression of pulmonary fibrosis in vivo. PMID:28817691

  8. Modifying effects of preexisting pulmonary fibrosis on biological responses of rats to inhaled 239PuO2

    Energy Technology Data Exchange (ETDEWEB)

    Lundgren, D.L.; Mauderly, J.L.; Rebar, A.H.; Gillett, N.A.; Hahn, F.F. (Lovelace Biomedical and Environmental Research Institute, Albuquerque, NM (USA))

    1991-03-01

    We investigated the modifying effects of preexisting, bleomycin-induced pulmonary fibrosis on the deposition, retention, and biological effects of inhaled 239PuO2 in the rat. Among rats exposed to similar airborne concentrations of 239PuO2, initial lung burdens of 239Pu per kilogram body mass were similar whether or not pulmonary fibrosis was present. However, clearance of 239Pu from the lungs was significantly decreased in the rats with preexisting pulmonary fibrosis. The incidence of lung lesions (epithelial hyperplasia, diffuse macrophage increases and aggregation, and loose and dense connective tissue) was significantly greater among rats with preexisting pulmonary fibrosis than among the exposed controls. Rats with preexisting fibrosis had shorter life spans than 239PuO2-exposed control rats. When groups of rats with similar alpha doses to the lungs were compared, the incidences of neoplastic lesions in the lung, the times to death of rats with lung neoplasms, and the risk of lung tumors per unit of alpha dose to the lungs in rats with or without pulmonary fibrosis were similar. The results of this study suggest that humans with uncomplicated pulmonary fibrosis may not be more sensitive to the carcinogenic effects of inhaled 239PuO2 than are individuals with normal lungs, assuming that the total alpha doses to the lungs are similar.

  9. Detection of epithelial to mesenchymal transition in airways of a bleomycin induced pulmonary fibrosis model derived from an α-smooth muscle actin-Cre transgenic mouse

    Directory of Open Access Journals (Sweden)

    Yang Xiao

    2007-01-01

    Full Text Available Abstract Background Epithelial to mesenchymal transition (EMT in alveolar epithelial cells (AECs has been widely observed in patients suffering interstitial pulmonary fibrosis. In vitro studies have also demonstrated that AECs could convert into myofibroblasts following exposure to TGF-β1. In this study, we examined whether EMT occurs in bleomycin (BLM induced pulmonary fibrosis, and the involvement of bronchial epithelial cells (BECs in the EMT. Using an α-smooth muscle actin-Cre transgenic mouse (α-SMA-Cre/R26R strain, we labelled myofibroblasts in vivo. We also performed a phenotypic analysis of human BEC lines during TGF-β1 stimulation in vitro. Methods We generated the α-SMA-Cre mouse strain by pronuclear microinjection with a Cre recombinase cDNA driven by the mouse α-smooth muscle actin (α-SMA promoter. α-SMA-Cre mice were crossed with the Cre-dependent LacZ expressing strain R26R to produce the double transgenic strain α-SMA-Cre/R26R. β-galactosidase (βgal staining, α-SMA and smooth muscle myosin heavy chains immunostaining were carried out simultaneously to confirm the specificity of expression of the transgenic reporter within smooth muscle cells (SMCs under physiological conditions. BLM-induced peribronchial fibrosis in α-SMA-Cre/R26R mice was examined by pulmonary βgal staining and α-SMA immunofluorescence staining. To confirm in vivo observations of BECs undergoing EMT, we stimulated human BEC line 16HBE with TGF-β1 and examined the localization of the myofibroblast markers α-SMA and F-actin, and the epithelial marker E-cadherin by immunofluorescence. Results βgal staining in organs of healthy α-SMA-Cre/R26R mice corresponded with the distribution of SMCs, as confirmed by α-SMA and SM-MHC immunostaining. BLM-treated mice showed significantly enhanced βgal staining in subepithelial areas in bronchi, terminal bronchioles and walls of pulmonary vessels. Some AECs in certain peribronchial areas or even a small

  10. CCN5 overexpression inhibits profibrotic phenotypes via the PI3K/Akt signaling pathway in lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis and in an in vivo model of lung fibrosis.

    Science.gov (United States)

    Zhang, Lin; Li, Yingna; Liang, Chunlian; Yang, Weilin

    2014-02-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease with unknown etiology and undefined treatment modality. Fibroblasts are regarded as the major cell type that mediates the onset and progression of lung fibrosis by secreting large amounts of extracellular matrix (ECM) proteins, such as connective tissue growth factor (CTGF/CCN2). Current knowledge confers a crucial role of CCN2 in lung fibrosis. CCN5, another member of the CCN family, has been suggested to play an inhibitory role in some fibrotic diseases, such as cardiac fibrosis. However, the role of CCN5 in the process of IPF remains unknown. In the present study, using western blot analysis, we demonstrate that CCN2 is highly expressed in fibroblasts derived from IPF tissue, but is only slightly expressed in normal human lung fibroblasts. However, CCN5 was weakly expressed in all the above cells. qRT-PCR revealed that transforming growth factor (TGF)-β1 stimulation increased CCN2 expression in the IPF-derived cultures of primary human lung fibroblasts (PIFs) in a time- and concentration-dependent manner, but only slightly affected the expression of CCN5. The overexpression of CCN5 induced by the transfection of PIFs with recombinant plasmid did not affect cell viability, proliferation and apoptosis; however, it significantly suppressed the expression of CCN2, α-smooth muscle actin (α-SMA) and collagen type I. The TGF-β1-induced upregulation of the phosphorylation of Akt was reversed by CCN5 overexpression. Our results also demonstrated that adenovirus-mediated CCN5 overexpression in a mouse model of bleomycin-induced IPF significantly decreased the hydroxyproline content in the lungs, as well as TGF-β1 expression in bronchoalveolar lavage fluid. Taken together, our data demonstrate that CCN5 exerts an inhibitory effect on the fibrotic phenotypes of pulmonary fibroblasts in vitro and in vivo, and as such may be a promising target for the treatment of IPF.

  11. Treatment of giant pulmonary interstitial emphysema by ipsilateral bronchial occlusion with a Swan-Ganz catheter

    International Nuclear Information System (INIS)

    Rastogi, Shantanu; Gupta, Archana; Wung, Jen-Tien; Berdon, Walter E.

    2007-01-01

    Unilateral giant pulmonary interstitial emphysema (PIE) can be seen as a complication of chronic ventilation in extremely low-birth-weight babies. Many can be managed by conventional pulmonary care which includes positioning, suctioning, chest physiotherapy, gentle conventional ventilation and high-frequency ventilation. Some may need invasive procedures such as lung puncture, pleurotomies and excisional surgery. This is the group in which single-lung ventilation may be beneficial and circumvent the need for an invasive procedure. We describe the technique of single-lung ventilation using a Swan-Ganz catheter to block the main stem bronchus on the diseased side in air-leak syndromes. A retrospective chart review was done on 17 newborns undergoing single-lung ventilation using this technique at the Children's Hospital of New York, Columbia University, from 1986 to 2000. The technique was successful in the management of severe, neonatal unilateral lung disease not responsive to conventional modes of therapy in all but two neonates as seen by a significant improvement in pH and a decrease in PaCO 2 levels. In one neonate malpositioning of the Swan-Ganz catheter balloon could have contributed to the development of pneumothorax. The described technique of single-lung ventilation provides a safe, minimally invasive and economically feasible method of management of unilateral giant PIE in newborns not responsive to conventional modes of therapy with minimal complications. (orig.)

  12. Influence of chest background on pulmonary 99m Tc-DTPA clearance in interstitial lung disease

    International Nuclear Information System (INIS)

    Ishizaka, Akitoshi; Kanazawa, Minoru; Suzuki, Yukio; Hasegawa, Naoki; Kubo, Atsushi; Kawashiro, Takeo

    1992-01-01

    The authors examined the effect of chest extracellular 99m T c -diethylenetriamine pentaacetate (DTPA) as a background in the measurement of pulmonary 99m T c -DTPA clearance in patients with interstitial lung disease (ILD). Eight healthy nonsmokers (HN) and eight patients with ILD were studied. They monitored changes in gamma counts after the inhalation of 99m T c -DTPA aerosol by using a gamma camera placed over the anterior chest. The rate constant of pulmonary 99m T c -DTPA clearance (k; %/min) was assessed by calculating the slope of the decrease in the gamma counts. The chest background, estimated by 99m T c -DTPA intravenous injection, was subtracted from the original data to obtain the corrected DTPA clearance (k c ; %/min). In patients with ILD, k was significantly greater [2.19 ± 1.03 (SD) %/min; n = 8] compared with HN (0.86 ± 0.17%/min; n = 8; P c was also greater (2.80 ± 1.15%/min; n = 8; P c among all subjects (r = 0.987, P 99m T c -DTPA clearance. 16 refs., 2 figs., 2 tabs

  13. Treatment of giant pulmonary interstitial emphysema by ipsilateral bronchial occlusion with a Swan-Ganz catheter

    Energy Technology Data Exchange (ETDEWEB)

    Rastogi, Shantanu [College of Physicians and Surgeons, Columbia University, Division of Neonatology, Department of Pediatrics, The Children' s Hospital of New York, New York, NY (United States); Maimonides Medical Center, Department of Pediatrics, Brooklyn, NY (United States); Gupta, Archana; Wung, Jen-Tien [College of Physicians and Surgeons, Columbia University, Division of Neonatology, Department of Pediatrics, The Children' s Hospital of New York, New York, NY (United States); Berdon, Walter E. [College of Physicians and Surgeons, Columbia University, Pediatric Radiology, The Children' s Hospital of New York, New York, NY (United States)

    2007-11-15

    Unilateral giant pulmonary interstitial emphysema (PIE) can be seen as a complication of chronic ventilation in extremely low-birth-weight babies. Many can be managed by conventional pulmonary care which includes positioning, suctioning, chest physiotherapy, gentle conventional ventilation and high-frequency ventilation. Some may need invasive procedures such as lung puncture, pleurotomies and excisional surgery. This is the group in which single-lung ventilation may be beneficial and circumvent the need for an invasive procedure. We describe the technique of single-lung ventilation using a Swan-Ganz catheter to block the main stem bronchus on the diseased side in air-leak syndromes. A retrospective chart review was done on 17 newborns undergoing single-lung ventilation using this technique at the Children's Hospital of New York, Columbia University, from 1986 to 2000. The technique was successful in the management of severe, neonatal unilateral lung disease not responsive to conventional modes of therapy in all but two neonates as seen by a significant improvement in pH and a decrease in PaCO{sub 2} levels. In one neonate malpositioning of the Swan-Ganz catheter balloon could have contributed to the development of pneumothorax. The described technique of single-lung ventilation provides a safe, minimally invasive and economically feasible method of management of unilateral giant PIE in newborns not responsive to conventional modes of therapy with minimal complications. (orig.)

  14. Quantification of Pulmonary Fibrosis in a Bleomycin Mouse Model Using Automated Histological Image Analysis.

    Directory of Open Access Journals (Sweden)

    Jean-Claude Gilhodes

    Full Text Available Current literature on pulmonary fibrosis induced in animal models highlights the need of an accurate, reliable and reproducible histological quantitative analysis. One of the major limits of histological scoring concerns the fact that it is observer-dependent and consequently subject to variability, which may preclude comparative studies between different laboratories. To achieve a reliable and observer-independent quantification of lung fibrosis we developed an automated software histological image analysis performed from digital image of entire lung sections. This automated analysis was compared to standard evaluation methods with regard to its validation as an end-point measure of fibrosis. Lung fibrosis was induced in mice by intratracheal administration of bleomycin (BLM at 0.25, 0.5, 0.75 and 1 mg/kg. A detailed characterization of BLM-induced fibrosis was performed 14 days after BLM administration using lung function testing, micro-computed tomography and Ashcroft scoring analysis. Quantification of fibrosis by automated analysis was assessed based on pulmonary tissue density measured from thousands of micro-tiles processed from digital images of entire lung sections. Prior to analysis, large bronchi and vessels were manually excluded from the original images. Measurement of fibrosis has been expressed by two indexes: the mean pulmonary tissue density and the high pulmonary tissue density frequency. We showed that tissue density indexes gave access to a very accurate and reliable quantification of morphological changes induced by BLM even for the lowest concentration used (0.25 mg/kg. A reconstructed 2D-image of the entire lung section at high resolution (3.6 μm/pixel has been performed from tissue density values allowing the visualization of their distribution throughout fibrotic and non-fibrotic regions. A significant correlation (p<0.0001 was found between automated analysis and the above standard evaluation methods. This correlation

  15. Pulmonary fibrosis secondary to siderosis causing symptomatic respiratory disease: a case report

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    McCormick Liam M

    2008-08-01

    Full Text Available Abstract Introduction Pulmonary siderosis secondary to the inhalation of iron compounds is a rare condition which, despite striking radiological and histopathological features, has not traditionally been associated with symptoms or functional impairment. Although not the first of its kind, we present an unusual case of pulmonary siderosis with symptomatic respiratory disease, most likely secondary to associated fibrosis. Case presentation A 66-year-old Caucasian man was referred to the outpatient clinic with a 2-year history of exertional breathlessness. He had worked as an engineer for 20 years where he did a significant amount of welding but always wore a face shield. Clinical, radiological and histological features were consistent with a diagnosis of pulmonary siderosis, with associated fibrosis, most likely related to his occupational welding history. Conclusion Our report illustrates that symptomatic respiratory disease due to mild peribronchiolar fibrosis can occur with pulmonary siderosis despite wearing a mask. Furthermore, it reinforces the need for all clinicians to compile a detailed occupational history in individuals presenting with breathlessness.

  16. Effects of CTGF Blockade on Attenuation and Reversal of Radiation-Induced Pulmonary Fibrosis.

    Science.gov (United States)

    Bickelhaupt, Sebastian; Erbel, Christian; Timke, Carmen; Wirkner, Ute; Dadrich, Monika; Flechsig, Paul; Tietz, Alexandra; Pföhler, Johanna; Gross, Wolfgang; Peschke, Peter; Hoeltgen, Line; Katus, Hugo A; Gröne, Hermann-Josef; Nicolay, Nils H; Saffrich, Rainer; Debus, Jürgen; Sternlicht, Mark D; Seeley, Todd W; Lipson, Kenneth E; Huber, Peter E

    2017-08-01

    Radiotherapy is a mainstay for the treatment of lung cancer that can induce pneumonitis or pulmonary fibrosis. The matricellular protein connective tissue growth factor (CTGF) is a central mediator of tissue remodeling. A radiation-induced mouse model of pulmonary fibrosis was used to determine if transient administration of a human antibody to CTGF (FG-3019) started at different times before or after 20 Gy thoracic irradiation reduced acute and chronic radiation toxicity. Mice (25 mice/group; 10 mice/group in a confirmation study) were examined by computed tomography, histology, gene expression changes, and for survival. In vitro experiments were performed to directly study the interaction of CTGF blockade and radiation. All statistical tests were two-sided. Administration of FG-3019 prevented (∼50%-80%) or reversed (∼50%) lung remodeling, improved lung function, improved mouse health, and rescued mice from lethal irradiation ( P radiation-induced gene expression changes, and reduced myofibroblast abundance and Osteopontin expression. These results indicate that blocking CTGF attenuates radiation-induced pulmonary remodeling and can reverse the process after initiation. CTGF has a central role in radiation-induced fibrogenesis, and FG-3019 may benefit patients with radiation-induced pulmonary fibrosis or patients with other forms or origin of chronic fibrotic diseases. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  17. Alveolar type II cell transplantation restores pulmonary surfactant protein levels in lung fibrosis.

    Science.gov (United States)

    Guillamat-Prats, Raquel; Gay-Jordi, Gemma; Xaubet, Antoni; Peinado, Victor I; Serrano-Mollar, Anna

    2014-07-01

    Alveolar Type II cell transplantation has been proposed as a cell therapy for the treatment of idiopathic pulmonary fibrosis. Its long-term benefits include repair of lung fibrosis, but its success partly depends on the restoration of lung homeostasis. Our aim was to evaluate surfactant protein restoration after alveolar Type II cell transplantation in an experimental model of bleomycin-induced lung fibrosis in rats. Lung fibrosis was induced by intratracheal instillation of bleomycin. Alveolar Type II cells were obtained from healthy animals and transplanted 14 days after bleomycin was administered. Furthermore, one group transplanted with alveolar macrophages and another group treated with surfactant were established to evaluate the specificity of the alveolar Type II cell transplantation. The animals were euthanized at 21 days after bleomycin instillation. Lung fibrosis was confirmed by a histologic study and an evaluation of the hydroxyproline content. Changes in surfactant proteins were evaluated by mRNA expression, Western blot and immunofluorescence studies. The group with alveolar Type II cell transplantation was the only one to show a reduction in the degree of lung fibrosis and a complete recovery to normal levels of surfactant proteins. One of the mechanisms involved in the beneficial effect of alveolar Type II cell transplantation is restoration of lung surfactant protein levels, which is required for proper respiratory function. Copyright © 2014 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

  18. Pulmonary toxicity in radiotherapy for lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Shikaura, Sachiko (Kansai Medical School, Kyoto (Japan). Rakusei New-Town Hospital); Harima, Keizo; Murata, Takashi; Kawa, Sokichi; Tanaka, Yoshimasa; Shikata, Nobuaki

    1994-01-01

    Among 158 lung cancer patients at our hospital during past six years, 9 patients developed pulmonary toxicity. Elderly patients, patients with high dose radiation, or inclusion of the hilar mediastinum in the radiation field were more likely develop pulmonary toxicity. There were no significant differences in baseline pulmonary function tests between the pulmonary toxicity group and the control group. On histological examination, lung specimens outside the radiation field demonstrated interstitial pneumonitis or fibrosis. (author).

  19. Clinical management and outcomes of patients with Hermansky-Pudlak syndrome pulmonary fibrosis evaluated for lung transplantation

    Science.gov (United States)

    El-Chemaly, Souheil; O’Brien, Kevin J.; Nathan, Steven D.; Weinhouse, Gerald L.; Goldberg, Hilary J.; Connors, Jean M.; Cui, Ye; Astor, Todd L.; Camp, Philip C.; Rosas, Ivan O.; Lemma, Merte; Speransky, Vladislav; Merideth, Melissa A.; Gahl, William A.

    2018-01-01

    Pulmonary fibrosis is a progressive, fatal manifestation of Hermansky-Pudlak syndrome (HPS). Some patients with advanced HPS pulmonary fibrosis undergo lung transplantation despite their disease-associated bleeding tendency; others die while awaiting donor organs. The objective of this study is to determine the clinical management and outcomes of a cohort with advanced HPS pulmonary fibrosis who were evaluated for lung transplantation. Six patients with HPS-1 pulmonary fibrosis were evaluated at the National Institutes of Health Clinical Center and one of two regional lung transplant centers. Their median age was 41.5 years pre-transplant. Three of six patients died without receiving a lung transplant. One of these was referred with end-stage pulmonary fibrosis and died before a donor organ became available, and donor organs were not identified for two other patients sensitized from prior blood product transfusions. Three of six patients received bilateral lung transplants; they did not have a history of excessive bleeding. One patient received peri-operative desmopressin, one was transfused with intra-operative platelets, and one received extracorporeal membrane oxygenation and intra-operative prothrombin complex concentrate, platelet transfusion, and desmopressin. One transplant recipient experienced acute rejection that responded to pulsed steroids. No evidence of chronic lung allograft dysfunction or recurrence of HPS pulmonary fibrosis was detected up to 6 years post-transplant in these three lung transplant recipients. In conclusion, lung transplantation and extracorporeal membrane oxygenation are viable options for patients with HPS pulmonary fibrosis. Alloimmunization in HPS patients is an important and potentially preventable barrier to lung transplantation; interventions to limit alloimmunization should be implemented in HPS patients at risk of pulmonary fibrosis to optimize their candidacy for future lung transplants. PMID:29547626

  20. Epimorphin expression in interstitial pneumonia

    Directory of Open Access Journals (Sweden)

    Suga Moritaka

    2005-01-01

    Full Text Available Abstract Epimorphin modulates epithelial morphogenesis in embryonic mouse organs. We previously suggested that epimorphin contributes to repair of bleomycin-induced pulmonary fibrosis in mice via epithelium-mesenchyme interactions. To clarify the role of epimorphin in human lungs, we evaluated epimorphin expression and localization in normal lungs, lungs with nonspecific interstitial pneumonia (NSIP, and lungs with usual interstitial pneumonia (UIP; we also studied the effect of recombinant epimorphin on cultured human alveolar epithelial cells in vitro. Northern and Western blotting analyses revealed that epimorphin expression in NSIP samples were significantly higher than those in control lungs and lungs with UIP. Immunohistochemistry showed strong epimorphin expression in mesenchymal cells of early fibrotic lesions and localization of epimorphin protein on mesenchymal cells and extracellular matrix of early fibrotic lesions in the nonspecific interstitial pneumonia group. Double-labeled fluorescent images revealed expression of matrix metalloproteinase 2 in re-epithelialized cells overlying epimorphin-positive early fibrotic lesions. Immunohistochemistry and metalloproteinase activity assay demonstrated augmented expression of metalloproteinase induced by recombinant epimorphin in human alveolar epithelial cells. These findings suggest that epimorphin contributes to repair of pulmonary fibrosis in nonspecific interstitial pneumonia, perhaps partly by inducing expression of matrix metalloproteinase 2, which is an important proteolytic factor in lung remodeling.

  1. Type V collagen induced tolerance suppresses collagen deposition, TGF-β and associated transcripts in pulmonary fibrosis.

    Directory of Open Access Journals (Sweden)

    Ragini Vittal

    Full Text Available Idiopathic pulmonary fibrosis (IPF is a fatal interstitial lung disease characterized by progressive scarring and matrix deposition. Recent reports highlight an autoimmune component in IPF pathogenesis. We have reported anti-col(V immunity in IPF patients. The objective of our study was to determine the specificity of col(V expression profile and anti-col(V immunity relative to col(I in clinical IPF and the efficacy of nebulized col(V in pre-clinical IPF models.Col(V and col(I expression profile was analyzed in normal human and IPF tissues. C57-BL6 mice were intratracheally instilled with bleomycin (0.025 U followed by col(V nebulization at pre-/post-fibrotic stage and analyzed for systemic and local responses.Compared to normal lungs, IPF lungs had higher protein and transcript expression of the alpha 1 chain of col(V and col(I. Systemic anti-col(V antibody concentrations, but not of anti-col(I, were higher in IPF patients. Nebulized col(V, but not col(I, prevented bleomycin-induced fibrosis, collagen deposition, and myofibroblast differentiation. Col(V treatment suppressed systemic levels of anti-col(V antibodies, IL-6 and TNF-α; and local Il-17a transcripts. Compared to controls, nebulized col(V-induced tolerance abrogated antigen-specific proliferation in mediastinal lymphocytes and production of IL-17A, IL-6, TNF-α and IFN-γ. In a clinically relevant established fibrosis model, nebulized col(V decreased collagen deposition. mRNA array revealed downregulation of genes specific to fibrosis (Tgf-β, Il-1β, Pdgfb, matrix (Acta2, Col1a2, Col3a1, Lox, Itgb1/6, Itga2/3 and members of the TGF-β superfamily (Tgfbr1/2, Smad2/3, Ltbp1, Serpine1, Nfkb/Sp1/Cebpb.Anti-col(V immunity is pathogenic in IPF, and col(V-induced tolerance abrogates bleomycin-induced fibrogenesis and down regulates TGF- β-related signaling pathways.

  2. Idiopathic Pulmonary Fibrosis: Gender-Age-Physiology Index Stage for Predicting Future Lung Function Decline.

    Science.gov (United States)

    Salisbury, Margaret L; Xia, Meng; Zhou, Yueren; Murray, Susan; Tayob, Nabihah; Brown, Kevin K; Wells, Athol U; Schmidt, Shelley L; Martinez, Fernando J; Flaherty, Kevin R

    2016-02-01

    Idiopathic pulmonary fibrosis is a progressive lung disease with variable course. The Gender-Age-Physiology (GAP) Index and staging system uses clinical variables to stage mortality risk. It is unknown whether clinical staging predicts future decline in pulmonary function. We assessed whether the GAP stage predicts future pulmonary function decline and whether interval pulmonary function change predicts mortality after accounting for stage. Patients with idiopathic pulmonary fibrosis (N = 657) were identified retrospectively at three tertiary referral centers, and baseline GAP stages were assessed. Mixed models were used to describe average trajectories of FVC and diffusing capacity of the lung for carbon monoxide (Dlco). Multivariable Cox proportional hazards models were used to assess whether declines in pulmonary function ≥ 10% in 6 months predict mortality after accounting for GAP stage. Over a 2-year period, GAP stage was not associated with differences in yearly lung function decline. After accounting for stage, a 10% decrease in FVC or Dlco over 6 months independently predicted death or transplantation (FVC hazard ratio, 1.37; Dlco hazard ratio, 1.30; both, P ≤ .03). Patients with GAP stage 2 with declining pulmonary function experienced a survival profile similar to patients with GAP stage 3, with 1-year event-free survival of 59.3% (95% CI, 49.4-67.8) vs 56.9% (95% CI, 42.2-69.1). Baseline GAP stage predicted death or lung transplantation but not the rate of future pulmonary function decline. After accounting for GAP stage, a decline of ≥ 10% over 6 months independently predicted death or lung transplantation. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

  3. Pirfenidone attenuates bleomycin-induced pulmonary fibrosis in mice by regulating Nrf2/Bach1 equilibrium.

    Science.gov (United States)

    Liu, Yuan; Lu, Fuai; Kang, Lirong; Wang, Zhihua; Wang, Yongfu

    2017-04-18

    Oxidative stress is one of the important factors involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The equilibrium of Nuclear factor-erythroid-related factor 2 (Nrf2)/[BTB (broad-complex, tramtrack and bric-a-brac) and CNC (cap'n'collar protein) homology 1, Bach1] determines the expression level of antioxidant factors, further regulating the function of oxidation/antioxidation capacity. Pirfenidone (PFD) is one of two currently for IPF therapy approved drugs. PFD regulates intracellular antioxidants, inhibits secretion of inflammatory cytokines and collagen synthesis. However the mechanisms of its antioxidant effects remain elusive. Effects of PFD treatment were studied in mouse lung fibroblasts (MLF) following induction by transforming-growth factor beta 1 (TGF-β1) and in mice following bleomycin-induced lung fibrosis. The mRNA and protein levels of oxidative stress-related factors Nrf2/Bach1 and their downstream antioxidant factors heme oxygenase-1 (Ho-1) and glutathione peroxidase 1 (Gpx1) were determined by RT-PCR and Western blot. Fibrosis-related cytokines interleukin-6 (IL-6) and myofibroblast markers type 1 collagen α1 (COL1A1) levels in supernate of MLF, serum, and bronchoalveolar lavage fluid (BALF) as well as malondialdehyde (MDA) in serum and BALF were detected by ELISA, reactive oxygen species (ROS) generation was measured by 2',7'- dichlorofluorescin diacetate (DCFH-DA) assay and lung pathological/morphological alterations in mice were observed by HE and Masson to assess the antioxidant mechanism and therapeutic effects on pulmonary fibrosis induced by bleomycin. PFD inhibited Bach1 mRNA and protein expressions in mouse lung fibroblasts induced by TGF-β1 and lung tissues with pulmonary fibrosis induced by bleomycin. Furthermore, it improved Nrf2, Ho-1 and Gpx1 mRNA and protein expressions. After PFD treatment, COL1A1and IL-6 levels in supernate of MLF, serum, and BALF as well as ROS in lung tissues and MDA in serum and BALF from

  4. The Lung Microbiome in Idiopathic Pulmonary Fibrosis: A Promising Approach for Targeted Therapies

    Directory of Open Access Journals (Sweden)

    Fastrès Aline

    2017-12-01

    Full Text Available This review focuses on the role of the lung microbiome in idiopathic pulmonary fibrosis. Although historically considered sterile, bacterial communities have now been well documented in lungs both in healthy and pathological conditions. Studies in idiopathic pulmonary fibrosis (IPF suggest that increased bacterial burden and/or abundance of potentially pathogenic bacteria may drive disease progression, acute exacerbations, and mortality. More recent work has highlighted the interaction between the lung microbiome and the innate immune system in IPF, strengthening the argument for the role of both host and environment interaction in disease pathogenesis. Existing published data suggesting that the lung microbiome may represent a therapeutic target, via antibiotic administration, immunization against pathogenic organisms, or treatment directed at gastroesophageal reflux. Taken altogether, published literature suggests that the lung microbiome might serve in the future as a prognostic biomarker, a therapeutic target, and/or provide an explanation for disease pathogenesis in IPF.

  5. Amelioration of bleomycin-induced pulmonary fibrosis by chlorogenic acid through endoplasmic reticulum stress inhibition.

    Science.gov (United States)

    Wang, Yi-Chun; Dong, Jing; Nie, Jing; Zhu, Ji-Xiang; Wang, Hui; Chen, Qiong; Chen, Jun-Yi; Xia, Jia-Mei; Shuai, Wei

    2017-09-01

    To investigate the inhibitory effects of chlorogenic acid on pulmonary fibrosis and the internal mechanisms in vivo and in vitro. 30 male BALB/C mice were randomized into 5 groups: control group, pulmonary fibrosis model group, low, middle and high dose of chlorogenic acid groups. Mice in pulmonary fibrosis model group were administered 5.0 mg/kg bleomycin with intracheal instillation and mice in 3 chlorogenic acid groups were treated with chlorogenic acid every day for 28 days after bleomycin administration. Lung tissue histology was observed using HE staining. Primary pulmonary fibroblasts were isolated and cultured. The expressions of fibrosis related factors (α-SMA and collagen I), as well as ER stress markers (CHOP and GRP78) were determined by both real-time PCR assay and Western blotting, while the expressions of other ER stress signaling pathway factors PERK, IRE-1, ATF-6 and protein levels of caspase-12, caspase-9, caspase-3, PARP were determined by Western blotting. RLE-6TN cell line induced by TGF-β1 was also used to verify the amelioration effects in vitro study. In both in vivo and in vitro studies, TUNEL staining was used to evaluate cell apoptosis. Expressions of collagen I, α-SMA, GRP78, and CHOP were significantly inhibited by chlorogenic acid in dose-dependent manner. Similarly, decreasing levels of cleaved caspase-12, caspase-9, caspase-3 and increasing level of uncleaved PARP were observed in chlorogenic acid groups compared with those in the fibrosis group both in vivo and in vitro. Chlorogenic acid could also significantly down-regulate the level of phosphorylation of PERK and cleaved ATF-6 in vivo study. Moreover, MTT assay demonstrated chlorogenic acid could enhance proliferation of RLE-6TN cells induced by TGFβ1 in vitro. And the apoptosis assays indicated that chlorogenic acid could significantly inhibit cell apoptosis both in vivo and in vitro studies. Chlorogenic acid could inhibit the pulmonary fibrosis through endoplasmic

  6. Clinically Promising Biomarkers in Cystic Fibrosis Pulmonary Exacerbations.

    Science.gov (United States)

    Scott, L Keith; Toner, Robert

    2017-08-01

    Cystic fibrosis is a complex genetic disease hallmarked by repetitive infectious exacerbations that leads to destruction of airway architecture, acute on chronic inflammatory changes, and deterioration in lung function. Predicting an exacerbation may help preempt some of these changes by the initiation of swift antibiotic and anti-inflammatory therapy. A search for biomarkers that could predict exacerbations or help guide duration of antibiotic therapy is being aggressively sought. In this review, we discuss the most recent and promising biomarkers that hopefully will assist in the future management of the CF patient.

  7. Idiopathic pulmonary fibrosis in Sweden: report from the first year of activity of the Swedish IPF-Registry.

    Science.gov (United States)

    Ferrara, Giovanni; Carlson, Lisa; Palm, Andreas; Einarsson, Jonas; Olivesten, Cecilia; Sköld, Magnus

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is an emerging problem in the western world, being related to increasing age and implying significant costs for the diagnosis and management of affected patients. The epidemiology of IPF is not well understood. To allow estimates of the problem and eventually to evaluate quality of the care of IPF patients in Sweden, a national IPF Registry was started in the autumn of 2014. Data on criteria used to diagnose IPF, demographics, lung function, and quality of life (measured with the King's Brief Interstitial Lung Disease Questionnaire, K-BILD) were reported directly to the registry, based at the coordinating centre (Karolinska University Hospital, Stockholm, Sweden) via a web-based platform. During the first year, the registry was implemented in 11 (33%) of the 33 respiratory units in the country. Seventy-one patients were registered between October 2014 and October 2015, 50 (70.4%) males and 21 (29.6%) females. Median age was 70 (range 47-86). The mean K-BILD score at the first inclusion in the registry was 54.3+9.5. The main features of IPF patients in this first Swedish cohort were consistent with data published in the literature in main multinational randomized controlled trials. The K-BILD questionnaire showed that quality of life of patients with IPF and their perception of the disease are quite poor at the time of inclusion in the registry.

  8. A Systematic Review of the Role of Dysfunctional Wound Healing in the Pathogenesis and Treatment of Idiopathic Pulmonary Fibrosis

    Directory of Open Access Journals (Sweden)

    Alan Betensley

    2016-12-01

    Full Text Available Idiopathic pulmonary fibrosis (IPF is a chronic, progressive interstitial lung disorder showcasing an interaction between genetic predisposition and environmental risks. This usually involves the coaction of a mixture of cell types associated with abnormal wound healing, leading to structural distortion and loss of gas exchange function. IPF bears fatal prognosis due to respiratory failure, revealing a median survival of approximately 2 to 3 years. This review showcases the ongoing progress in understanding the complex pathophysiology of IPF and it highlights the latest potential clinical treatments. In IPF, various components of the immune system, particularly clotting cascade and shortened telomeres, are highly involved in disease pathobiology and progression. This review also illustrates two US Food and Drug Administration (FDA-approved drugs, nintedanib (OFEV, Boehringer Ingelheim, Ingelheim am Rhein, Germany and pirfenidone (Esbriet, Roche, Basel, Switzerland, that slow IPF progression, but unfortunately neither drug can reverse the course of the disease. Although the mechanisms underlying IPF remain poorly understood, this review unveils the past and current advances that encourage the detection of new IPF pathogenic pathways and the development of effective treatment methods for the near future.

  9. Acute adaptive immune response correlates with late radiation-induced pulmonary fibrosis in mice.

    Science.gov (United States)

    Paun, Alexandra; Kunwar, Amit; Haston, Christina K

    2015-02-20

    The lung response to radiation exposure can involve an immediate or early reaction to the radiation challenge, including cell death and an initial immune reaction, and can be followed by a tissue injury response, of pneumonitis or fibrosis, to this acute reaction. Herein, we aimed to determine whether markers of the initial immune response, measured within days of radiation exposure, are correlated with the lung tissue injury responses occurring weeks later. Inbred strains of mice known to be susceptible (KK/HIJ, C57BL/6J, 129S1/SvImJ) or resistant (C3H/HeJ, A/J, AKR/J) to radiation-induced pulmonary fibrosis and to vary in time to onset of respiratory distress post thoracic irradiation (from 10-23 weeks) were studied. Mice were untreated (controls) or received 18 Gy whole thorax irradiation and were euthanized at 6 h, 1d or 7 d after radiation treatment. Pulmonary CD4+ lymphocytes, bronchoalveolar cell profile & cytokine level, and serum cytokine levels were assayed. Thoracic irradiation and inbred strain background significantly affected the numbers of CD4+ cells in the lungs and the bronchoalveolar lavage cell differential of exposed mice. At the 7 day timepoint greater numbers of pulmonary Th1 and Th17 lymphocytes and reduced lavage interleukin17 and interferonγ levels were significant predictors of late stage fibrosis. Lavage levels of interleukin-10, measured at the 7 day timepoint, were inversely correlated with fibrosis score (R=-0.80, p=0.05), while serum levels of interleukin-17 in control mice significantly correlated with post irradiation survival time (R=0.81, p=0.04). Lavage macrophage, lymphocyte or neutrophil counts were not significantly correlated with either of fibrosis score or time to respiratory distress in the six mouse strains. Specific cytokine and lymphocyte levels, but not strain dependent lavage cell profiles, were predictive of later radiation-induced lung injury in this panel of inbred strains.

  10. Effects of puberty on cystic fibrosis related pulmonary exacerbations in women versus men.

    Science.gov (United States)

    Sutton, Shelby; Rosenbluth, Daniel; Raghavan, Deepa; Zheng, Jie; Jain, Raksha

    2014-01-01

    Epidemiologic data from studies of airway diseases, such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis indicate a gender disparity where women have worse outcomes. The explanation for this is largely unknown. We hypothesize that female sex hormones play a role in this gender disparity, predisposing women to more exacerbations and decreased lung function post-puberty. In Cystic Fibrosis, to determine if puberty marks a point of increasing exacerbations and decreasing lung function in women relative to men. Using the United States Cystic Fibrosis Foundation Patient Registry, we used linear regression to compare lung function and rate of pulmonary exacerbations in men versus women before and after puberty. Of 5,137 subjects who met inclusion criteria, 2,689 were male and 2,448 were female. Average age of puberty was found to be 13.2 ± 2.2 years in men and 11.2 ± 2.0 years of age in women. Percent predicted FEV1 pre- and post-puberty were no different between males versus females (P = 0.44 pre-puberty and P = 0.16 post-puberty). In contrast, women had a significantly higher rate of pulmonary exacerbations post-puberty than men (1.17 ± 1.35 exacerbations per year in women versus 0.95 ± 1.27 in men; P puberty, the rate of pulmonary exacerbations increased in adolescent women relative to men with cystic fibrosis, supporting a role for sex hormones in the disease process. Further understanding of the mechanisms that modulate sex hormone receptors in airway disease may serve as future targets for therapy. © 2013 Wiley Periodicals, Inc.

  11. Osthole Alleviates Bleomycin-Induced Pulmonary Fibrosis via Modulating Angiotensin-Converting Enzyme 2/Angiotensin-(1-7) Axis and Decreasing Inflammation Responses in Rats.

    Science.gov (United States)

    Hao, Yuewen; Liu, Yan

    2016-01-01

    Studies have shown that angiotensin-converting enzyme 2 (ACE2) plays modulating roles in lung pathophysiology, including pulmonary fibrosis (PF) and acute lung injury. Pulmonary fibrosis is a common complication in these interstitial lung diseases, and PF always has a poor prognosis and short survival. To date, there are few promising methods for treating PF, and they are invariably accompanied by severe side effects. Recent studies have showed that the traditional Chinese herbal extract, osthole, had beneficial effects on lipopolysaccharide (LPS) induced acute lung injury (ALI) via an ACE2 pathway. Here we further investigated the protective effects of osthole on bleomycin induced pulmonary fibrosis and attempted to determine the underlying mechanism. PF mode rats were induced by bleomycin (BLM) and then subsequently administered osthole. Histopathological analyses were employed to identify PF changes. The results showed that BLM resulted in severe PF and diffuse lung inflammation, together with significant elevation of inflammatory factors and a marked increase in expression of angiotensin II (ANG II) and transforming growth factor-beta 1 (TGF-β1). ACE2 and angiotensin-(1-7) [ANG-(1-7)] were both greatly reduced after BLM administration. Meanwhile, osthole treatment attenuated BLM induced PF and inflammation, decreased the expression of these inflammatory mediators, ANG II, and TGF-β1, and reversed ACE2 and ANG-(1-7) production in rat lungs. We conclude that osthole may exert beneficial effects on BLM induced PF in rats, perhaps via modulating the ACE2/ANG-(1-7) axis and inhibiting lung inflammation pathways.

  12. Secreted Phosphoprotein 1 and Sex-Specific Differences in Silica-Induced Pulmonary Fibrosis in Mice.

    Science.gov (United States)

    Latoche, Joseph D; Ufelle, Alexander Chukwuma; Fazzi, Fabrizio; Ganguly, Koustav; Leikauf, George D; Fattman, Cheryl L

    2016-08-01

    Fibrotic lung diseases occur predominantly in males, and reports describe better survival in affected females. Male mice are more sensitive to silica-induced lung fibrosis than silica-treated female mice. Secreted phosphoprotein 1 (SPP1, also known as osteopontin) increases in pulmonary fibrosis, and Spp1 transcription may be regulated by estrogen or estrogen receptor-related receptors. We determined whether differences in silica-induced SPP1 levels contribute to sex differences in lung fibrosis. Male and female mice were treated with 0.2 g/kg intratracheal silica, and lung injury was assessed 1, 3, or 14 days post-exposure. Gene-targeted (Spp1-/-) mice, control Spp1+/+ (C57BL/6J) mice, ovariectomized (OVX) female mice, and estrogen-treated male mice were treated with silica, and lung injury was assessed. Silica-induced SPP1 in lung tissue, bronchoalveolar lavage, and serum increased more in male than in female mice. Following silica treatment, bronchoalveolar lavage cell infiltrates decreased in female Spp1-/- mice compared with female Spp1+/+ mice, and lung hydroxyproline decreased in male Spp1-/- mice compared with male Spp1+/+ mice. OVX female mice had increased lung SPP1 expression in response to silica compared with silica-treated sham female mice. Silica-induced lung collagen and hydroxyproline (markers of fibrosis), and SPP1 levels decreased in estrogen-treated males compared with untreated males. These findings suggest that sex-specific differences in SPP1 levels contribute to the differential sensitivity of male and female mice to the development of silica-induced fibrosis. Latoche JD, Ufelle AC, Fazzi F, Ganguly K, Leikauf GD, Fattman CL. 2016. Secreted phosphoprotein 1 and sex-specific differences in silica-induced pulmonary fibrosis in mice. Environ Health Perspect 124:1199-1207; http://dx.doi.org/10.1289/ehp.1510335.

  13. Description and validation of a scoring system for tomosynthesis in pulmonary cystic fibrosis

    International Nuclear Information System (INIS)

    Vult von Steyern, Kristina; Bjoerkman-Burtscher, Isabella M.; Bozovic, Gracijela; Wiklund, Marie; Geijer, Mats; Hoeglund, Peter

    2012-01-01

    To design and validate a scoring system for tomosynthesis (digital tomography) in pulmonary cystic fibrosis. A scoring system dedicated to tomosynthesis in pulmonary cystic fibrosis was designed. Three radiologists independently scored 88 pairs of radiographs and tomosynthesis examinations of the chest in 60 patients with cystic fibrosis and 7 oncology patients. Radiographs were scored according to the Brasfield scoring system and tomosynthesis examinations were scored using the new scoring system. Observer agreements for the tomosynthesis score were almost perfect for the total score with square-weighted kappa >0.90, and generally substantial to almost perfect for subscores. Correlation between the tomosynthesis score and the Brasfield score was good for the three observers (Kendall's rank correlation tau 0.68, 0.77 and 0.78). Tomosynthesis was generally scored higher as a percentage of the maximum score. Observer agreements for the total score for Brasfield score were almost perfect (square-weighted kappa 0.80, 0.81 and 0.85). The tomosynthesis scoring system seems robust and correlates well with the Brasfield score. Compared with radiography, tomosynthesis is more sensitive to cystic fibrosis changes, especially bronchiectasis and mucus plugging, and the new tomosynthesis scoring system offers the possibility of more detailed and accurate scoring of disease severity. (orig.)

  14. Description and validation of a scoring system for tomosynthesis in pulmonary cystic fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Vult von Steyern, Kristina; Bjoerkman-Burtscher, Isabella M.; Bozovic, Gracijela; Wiklund, Marie; Geijer, Mats [Skaane University Hospital, Lund University, Centre for Medical Imaging and Physiology, Lund (Sweden); Hoeglund, Peter [Skaane University Hospital, Competence Centre for Clinical Research, Lund (Sweden)

    2012-12-15

    To design and validate a scoring system for tomosynthesis (digital tomography) in pulmonary cystic fibrosis. A scoring system dedicated to tomosynthesis in pulmonary cystic fibrosis was designed. Three radiologists independently scored 88 pairs of radiographs and tomosynthesis examinations of the chest in 60 patients with cystic fibrosis and 7 oncology patients. Radiographs were scored according to the Brasfield scoring system and tomosynthesis examinations were scored using the new scoring system. Observer agreements for the tomosynthesis score were almost perfect for the total score with square-weighted kappa >0.90, and generally substantial to almost perfect for subscores. Correlation between the tomosynthesis score and the Brasfield score was good for the three observers (Kendall's rank correlation tau 0.68, 0.77 and 0.78). Tomosynthesis was generally scored higher as a percentage of the maximum score. Observer agreements for the total score for Brasfield score were almost perfect (square-weighted kappa 0.80, 0.81 and 0.85). The tomosynthesis scoring system seems robust and correlates well with the Brasfield score. Compared with radiography, tomosynthesis is more sensitive to cystic fibrosis changes, especially bronchiectasis and mucus plugging, and the new tomosynthesis scoring system offers the possibility of more detailed and accurate scoring of disease severity. (orig.)

  15. The Effects of Silymarin in Bleomycin-Induced Pulmonary Fibrosis in Mice

    Directory of Open Access Journals (Sweden)

    L. Safaeian

    2009-08-01

    Full Text Available AbstractBackground and Objectives: Silymarin, the active principle of Silybum marianum, has antifibrotic effects in hepatic fibrosis by several mechanisms. Since the pathogenesis of fibroproliferative diseases is similar, the effect of silymarin in bleomycin-induced pulmonary fibrosis was evaluated in this study.Methods: Silymarin (50 mg/kg, i.p. was administered two days before the bleomycin instillation (3 U/kg and throughout the test interval in mice. After two weeks, lung tissues of mice were evaluated for fibrosis by biochemical measurement of collagen deposition and histological analysis of pathological lung changes. Data were evaluated by one-way ANOVA and Dunnett analysis. P<0.05 was considered as significant. Results: Pretreatment with Silymarin significantly (P<0.05 prevented the increase in lung collagen content and also partially inhibited the histologic changes induced by bleomycin. The wet lung weight in silymarin group was similar to that of control group and significantly lower than bleomycin group (P<0.001. Conclusion: The results of this study indicate that silymarin may prevent the collagen deposition and inflammation and may be protective in fibrogenic effects of bleomycin on lung.Keywords: Silymarin; Bleomycin; Pulmonary Fibrosis; Hydroxyproline.

  16. Combined pulmonary fibrosis and emphysema: The many aspects of a cohabitation contract.

    Science.gov (United States)

    Papaioannou, Andriana I; Kostikas, Konstantinos; Manali, Effrosyni D; Papadaki, Georgia; Roussou, Aneza; Kolilekas, Likurgos; Borie, Raphaël; Bouros, Demosthenis; Papiris, Spyridon A

    2016-08-01

    Combined pulmonary fibrosis and emphysema (CPFE) is a clinical entity characterized by the coexistence of upper lobe emphysema and lower lobe fibrosis. Patients with this condition experience severe dyspnea and impaired gas exchange with preserved lung volumes. The diagnosis of the CPFE syndrome is based on HRCT imaging, showing the coexistence of emphysema and pulmonary fibrosis both in varying extent and locations within the lung parenchyma. Individual genetic background seem to predispose to the development of the disease. The risk of the development of pulmonary hypertension in patients with CPFE is high and related to poor prognosis. CPFE patients also present a high risk of lung cancer. Mortality is significant in patients with CPFE and median survival is reported between 2.1 and 8.5 years. Currently, no specific recommendations are available regarding the management of patients with CPFE. In this review we provide information on the existing knowledge on CPFE regarding the pathophysiology, clinical manifestations, imaging, complications, possible therapeutic interventions and prognosis of the disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Clinical analysis on Shengmai Injection in treating radiation pneumonia and pulmonary fibrosis

    International Nuclear Information System (INIS)

    Yao Chunxiao

    2004-01-01

    Objective: To study the effect of Shengmai Injection in treating radiation pneumonia and pulmonary fibrosis in the course of radiotherapy. Methods: Altogether 96 cases were randomly and equally allocated into a treatment group and a control group, 48 cases each, All patients were treated with radical radiotherapy. The initial radiotherapy was using 10 MV X-rays at conventionally fractionated dose of 60-70 Gy. Patients of the control group were given conventional radiotherapy, and those of the treatment group were given both conventional radiotherapy and Shengmai Injection 40-60 ml by iv drip for 3-5 courses, 10 days for each course. Results: In the treatment group, the incidences of radiation pneumonia and pulmonary fibrosis were 18.8%, 16.7%, respectively, whereas in the control group they were 37.5% and 35.4%, respectively. There were significant differences between the two groups (P<0.05). Conclusion: Shengmai Injection can decrease the incidences of radiation pneumonia and pulmonary fibrosis

  18. Therapeutic effect of glucocorticoid inhalation for pulmonary fibrosis in ARDS patients

    Directory of Open Access Journals (Sweden)

    Wen-biao ZHAO

    2014-10-01

    Full Text Available Objective To observe the effect of glucocorticoid inhalation on the clinical symptoms and pulmonary fibrosis index in ARDS patients. Methods Fifty-three ARDS patients admitted to ICU of Songjiang District Center Hospital of Shanghai from Dec. 2011 to Jun. 2013 were randomly divided into two groups. Group A (n=29 received conventional therapy, and group B (n=24 was given glucocorticoid inhalation treatment (budesonide, 2 mg, 1/12 h, for 12 days on the basis of the conventional therapy. The oxygenation index, time of extubation, changes in pulmonary fibrosis index, including collagen Ⅰ(Co Ⅰ, Ⅲ procollagen peptide (PⅢP and transforming growth factor (TGF-β1 were compared between the two groups, and the incidence of common adverse reactions were analyzed. Results The oxygenation index of patients in group B was significantly improved on the 15th day compared with group A (P0.05. Conclusion A small dose of glucocorticoids introduced by inhalation can improve the oxygenation index and pulmonary fibrosis level without increasing common adverse reactions, suggesting that the inhalation of corticosteroid may be a clinically safe and effective way in patients with ARDS. DOI: 10.11855/j.issn.0577-7402.2014.09.13

  19. Dietary Flaxseed Oil Protects against Bleomycin-Induced Pulmonary Fibrosis in Rats

    Directory of Open Access Journals (Sweden)

    Joshua Lawrenz

    2012-01-01

    Full Text Available Bleomycin, a widely used antineoplastic agent, has been associated with severe pulmonary toxicity, primarily fibrosis. Previous work has shown a reduction in bleomycin-induced lung pathology by long-chain omega-3 fatty acids. Treatment by short-chain omega-3 fatty acids, α-linolenic acid, found in dietary flaxseed oil may also reduce lung fibrosis, as previously evidenced in the kidney. To test this hypothesis, 72 rats were divided between diets receiving either 15% (w/w flaxseed oil or 15% (w/w corn oil (control. These groups were further divided to receive either bleomycin or vehicle (saline via an oropharyngeal delivery, rather than the traditional intratracheal instillation. Lungs were harvested at 2, 7, and 21 days after bleomycin or saline treatment. Animals receiving flaxseed oil showed a delay in edema formation (=0.025 and a decrease in inflammatory cell infiltrate and vasculitis (=0.04 and 0.007, resp.. At days 7 and 21, bleomycin produced a reduction in pulmonary arterial lumen patency (=0.01, but not in rats that were treated with flaxseed oil. Bleomycin-treated rats receiving flaxseed oil had reduced pulmonary septal thickness (=0.01, signifying decreased fibrosis. Dietary flaxseed oil may prove beneficial against the side effects of this highly effective chemotherapeutic agent and its known toxic effects on the lung.

  20. MnTBAP Inhibits Bleomycin-Induced Pulmonary Fibrosis by Regulating VEGF and Wnt Signaling

    Science.gov (United States)

    Venkatadri, Rajkumar; Krishnan V. Iyer, Anand; Ramesh, Vani; Wright, Clayton; Castro, Carlos A.; Yakisich, Juan S.; Azad, Neelam

    2017-01-01

    Cellular oxidative stress is implicated not only in lung injury but also in contributing to the development of pulmonary fibrosis. We demonstrate that a cell-permeable superoxide dismutase (SOD) mimetic and peroxynitrite scavenger, manganese (III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP) significantly inhibited bleomycin-induced fibrogenic effects both in vitro and in vivo. Further investigation into the underlying mechanisms revealed that MnTBAP targets canonical Wnt and non-canonical Wnt/Ca2+ signaling pathways, both of which were upregulated by bleomycin treatment. The effect of MnTBAP on canonical Wnt signaling was significant in vivo but inconclusive in vitro and the non-canonical Wnt/Ca2+ signaling pathway was observed to be the predominant pathway regulated by MnTBAP in bleomycin-induced pulmonary fibrosis. Furthermore, we show that the inhibitory effects of MnTBAP involve regulation of VEGF which is upstream of the Wnt signaling pathway. Overall, the data show that the superoxide scavenger MnTBAP attenuates bleomycin-induced pulmonary fibrosis by targeting VEGF and Wnt signaling pathways. PMID:27649046

  1. B-Lines in Assessment of Pulmonary Hypertension in Patients With Interstitial Lung Diseases: Feasibility of Transthoracic Lung Sonographic Signs.

    Science.gov (United States)

    Zheng, Xiao-Zhi; Zheng, Quan; Zhou, Jing; Yang, Bin

    2015-09-01

    This study was conducted to evaluate the value of sonographic B-lines (previously called "comet tail artifacts") in assessment of pulmonary hypertension in patients with interstitial lung diseases. One hundred thirty-four patients with clinically diagnosed interstitial lung diseases complicated by pulmonary hypertension underwent transthoracic lung sonography and Doppler echocardiography for assessment of the presence of B-lines, the distance between them, and the pulmonary artery (PA) systolic pressure. A correlation analysis and a receiver operating characteristic curve analysis were performed. All patients had diffuse bilateral B-lines. The maximum number of B-lines seen in any positive zone (not a summation) was significantly correlated with the severity of PA systolic pressure (r= 0.812; P30 mm Hg). The number of B-lines is useful in assessment of pulmonary hypertension, especially when tricuspid regurgitation and pulmonary valve regurgitation do not exist or cannot be satisfactorily measured by Doppler echocardiography. © 2015 by the American Institute of Ultrasound in Medicine.

  2. Pathophysiology of Pulmonary Hypertension in Chronic Parenchymal Lung Disease.

    Science.gov (United States)

    Singh, Inderjit; Ma, Kevin Cong; Berlin, David Adam

    2016-04-01

    Pulmonary hypertension commonly complicates chronic obstructive pulmonary disease and interstitial lung disease. The association of chronic lung disease and pulmonary hypertension portends a worse prognosis. The pathophysiology of pulmonary hypertension differs in the presence or absence of lung disease. We describe the physiological determinants of the normal pulmonary circulation to better understand the pathophysiological factors implicated in chronic parenchymal lung disease-associated pulmonary hypertension. This review will focus on the pathophysiology of 3 forms of chronic lung disease-associated pulmonary hypertension: idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and sarcoidosis. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Interstitial pneumonia and pulmonary hypertension associated with suspected ehrlichiosis in a dog

    NARCIS (Netherlands)

    Toom, Marjolein Lisette den; Dobak, Tetyda Paulina; Broens, Els Marion; Valtolina, Chiara

    2016-01-01

    BACKGROUND: In dogs with canine monocytic ehrlichiosis (CME), respiratory signs are uncommon and clinical and radiographic signs of interstitial pneumonia are poorly described. However, in human monocytic ehrlichiosis, respiratory signs are common and signs of interstitial pneumonia are well known.

  4. Long-term survival despite early loss of graft function after single lung transplantation for pulmonary fibrosis

    NARCIS (Netherlands)

    Ouwens, JP; van den Berg, JWK; van der Bij, W; Koeter, GH

    We report a patient who received a single, left lung transplantation for idiopathic pulmonary fibrosis. The effect of the graft on pulmonary improvement was only temporary, because the patient developed obliterative bronchiolitis (OB), resulting in complete destruction of the graft. The patient,

  5. Astragalus injection attenuates bleomycin-induced pulmonary fibrosis via down-regulating Jagged1/Notch1 in lungs.

    Science.gov (United States)

    Zhou, Yan; Liao, Shiping; Zhang, Zhongwei; Wang, Bo; Wan, Lihong

    2016-03-01

    Inhibition of Notch signalling is a potential therapeutic strategy for pulmonary fibrosis. This study was designed to investigate the antifibrosis effects and possible mechanism of astragalus injection (AI) on bleomycin (BLM)-induced pulmonary fibrosis in rats. Pulmonary fibrosis was induced by intratracheal instillation of bleomycin (5 mg/kg) in male SD rats. All rats received daily intraperitoneally administration of dexamethasone (DEX, 3 mg/kg), astragalus injection (AI, 8 g/kg) or saline 1 day after bleomycin instillation daily for 28 days. Histological changes in the lung were evaluated by haematoxylin and eosin and Masson's trichrome staining. The expression of α-smooth muscle protein (α-SMA) was assayed by immunohistochemical (IHC). The mRNA and protein level of Jagged1, Notch1 and transforming growth factor-β1 (TGF-β1) was analysed by qPCR and Western blot. BLM-induced severe alveolitis and pulmonary fibrosis; together with significant elevation of α-SMA, TGF-β1, Jagged1 and Notch1. Astragalus injection (AI, 8 g/kg) administration notably attenuated the degree of alveolitis and lung fibrosis, and markedly reduced the elevated levels of α-SMA, TGF-β1, Jagged1 and Notch1 in lungs. Astragalus injection (AI, 8 g/kg) may exert protective effects on bleomycin-induced pulmonary fibrosis via downregulating Jagged1/Notch1 in lung. © 2016 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology.

  6. The antifibrotic effects of alveolar macrophages 5-HT2C receptors blockade on bleomycin-induced pulmonary fibrosis in rats.

    Science.gov (United States)

    Elaidy, Samah M; Essawy, Soha S

    2016-12-01

    The most widespread chronic fibrosing lung disease is idiopathic pulmonary fibrosis. Lung serotonin (5-HT) content is increased during pulmonary fibrosis with the implication of 5-HT2 receptors in the pathogenesis. Serotonin plays important roles in alveolar macrophages function through 5-HT2C receptors activation. Numerous studies described the important role of 5-HT2A/B receptor blockers in suppressing different types of fibrosis as idiopathic pulmonary fibrosis. The current study pointed to examine the antifibrotic effects of RS-102221 and/or terguride through in vivo model of pulmonary fibrosis. Induction of pulmonary fibrosis was through a single dose of intra-tracheal bleomycin instillation (5mg/kg dissolved in phosphate buffer saline) in adult male albino Wistar rats. Next day of bleomycin instillation, intraperitoneal injection of RS-102221 (0.5mg/kg/d) and/or terguride (1.2mg/kg/d) were administered and continued for 14 days. Noticeable increase in 5-HT2C receptors expression was observed in fibrotic lung tissues with marked allocation belonging to alveolar macrophages. Either RS-102221 or terguride reduced the increments in lung water contents, grading of lung fibrosis, lung tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta1 (TGF- β1 ) and vascular endothelial growth factor (VEGF) levels in lung injury and fibrosis-induced by bleomycin. Moreover, collagen content and myofibroblasts-alpha smooth muscle actin (α-SМA) were significantly decreased. Additionally, the simultaneous administration of RS-102221 with terguride had a synergistic outcome compared to that obtained by individual monotherapy. These findings suggested the potential use of 5-HT2A/B/C antagonists as anti-fibrotic agents in lung fibrosis. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

  7. Patient factors associated with lung transplant referral and waitlist for patients with cystic fibrosis and pulmonary fibrosis.

    Science.gov (United States)

    Liu, Yuan; Vela, Monica; Rudakevych, Tanya; Wigfield, Christopher; Garrity, Edward; Saunders, Milda R

    2017-03-01

    Since 2005, the Lung Allocation Score (LAS) has prioritized patient benefit and post-transplant survival, reducing waitlist to transplant time to fibrosis (CF) and pulmonary fibrosis (PF). We analyzed the times from transplant eligibility to referral, work-up and waitlisting using Kaplan-Meier curves and log-rank tests. Overall, the referral rate for transplant-eligible patients was 64%. Of those referred, approximately 36% reach the lung transplant waitlist. Referred CF patients were significantly more likely to reach the transplant waitlist than PF patients (CF 60% vs PF 22%, p < 0.05). In addition, CF patients had a shorter wait from transplant eligibility to waitlist than PF patients (329 vs 2,369 days, respectively [25th percentile], p < 0.05). Patients with PF and CF both faced delays from eligibility to referral and waitlist. Quality improvement efforts are needed to better identify and refer appropriate patients for lung transplant evaluation. Targeted interventions may facilitate more efficient evaluation completion and waitlist appearance. Copyright © 2017 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

  8. A polymicrobial perspective of pulmonary infections exposes an enigmatic pathogen in cystic fibrosis patients.

    Science.gov (United States)

    Sibley, Christopher D; Parkins, Michael D; Rabin, Harvey R; Duan, Kangmin; Norgaard, Jens C; Surette, Michael G

    2008-09-30

    Lung disease is the leading cause of morbidity and mortality in cystic fibrosis (CF) patients. A modest number of bacterial pathogens have been correlated with pulmonary function decline; however, microbiological and molecular evidence suggests that CF airway infection is polymicrobial. To obtain a more complete assessment of the microbial community composition and dynamics, we undertook a longitudinal study by using culture-independent and microbiological approaches. In the process, we demonstrated that within complex and dynamic communities, the Streptococcus milleri group (SMG) can establish chronic pulmonary infections and at the onset of 39% of acute pulmonary exacerbations, SMG is the numerically dominant pathogen. We report the comprehensive polymicrobial community dynamics of a CF lung infection in a clinically relevant context. If a given organism, such as Pseudomonas aeruginosa, becomes resistant to antibiotic therapy, an alternative treatment avenue may mediate the desired clinical response by effectively managing the composition of the microbial community.

  9. A sigmoidal fit for pressure-volume curves of idiopathic pulmonary fibrosis patients on mechanical ventilation: clinical implications

    Directory of Open Access Journals (Sweden)

    Juliana C. Ferreira

    2011-01-01

    Full Text Available OBJECTIVE: Respiratory pressure-volume curves fitted to exponential equations have been used to assess disease severity and prognosis in spontaneously breathing patients with idiopathic pulmonary fibrosis. Sigmoidal equations have been used to fit pressure-volume curves for mechanically ventilated patients but not for idiopathic pulmonary fibrosis patients. We compared a sigmoidal model and an exponential model to fit pressure-volume curves from mechanically ventilated patients with idiopathic pulmonary fibrosis. METHODS: Six idiopathic pulmonary fibrosis patients and five controls underwent inflation pressure-volume curves using the constant-flow technique during general anesthesia prior to open lung biopsy or thymectomy. We identified the lower and upper inflection points and fit the curves with an exponential equation, V = A-B.e-k.P, and a sigmoid equation, V = a+b/(1+e-(P-c/d. RESULTS: The mean lower inflection point for idiopathic pulmonary fibrosis patients was significantly higher (10.5 ± 5.7 cm H2O than that of controls (3.6 ± 2.4 cm H2O. The sigmoidal equation fit the pressure-volume curves of the fibrotic and control patients well, but the exponential equation fit the data well only when points below 50% of the inspiratory capacity were excluded. CONCLUSION: The elevated lower inflection point and the sigmoidal shape of the pressure-volume curves suggest that respiratory system compliance is decreased close to end-expiratory lung volume in idiopathic pulmonary fibrosis patients under general anesthesia and mechanical ventilation. The sigmoidal fit was superior to the exponential fit for inflation pressure-volume curves of anesthetized patients with idiopathic pulmonary fibrosis and could be useful for guiding mechanical ventilation during general anesthesia in this condition.

  10. Regulatory T Cells Promote β-Catenin–Mediated Epithelium-to-Mesenchyme Transition During Radiation-Induced Pulmonary Fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Xiong, Shanshan; Pan, Xiujie; Xu, Long; Yang, Zhihua [Beijing Institute of Radiation Medicine, Beijing (China); Guo, Renfeng [Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan (United States); Gu, Yongqing; Li, Ruoxi; Wang, Qianjun; Xiao, Fengjun; Du, Li; Zhou, Pingkun [Beijing Institute of Radiation Medicine, Beijing (China); Zhu, Maoxiang, E-mail: zhumx@nic.bmi.ac.cn [Beijing Institute of Radiation Medicine, Beijing (China)

    2015-10-01

    Purpose: Radiation-induced pulmonary fibrosis results from thoracic radiation therapy and severely limits radiation therapy approaches. CD4{sup +}CD25{sup +}FoxP3{sup +} regulatory T cells (Tregs) as well as epithelium-to-mesenchyme transition (EMT) cells are involved in pulmonary fibrosis induced by multiple factors. However, the mechanisms of Tregs and EMT cells in irradiation-induced pulmonary fibrosis remain unclear. In the present study, we investigated the influence of Tregs on EMT in radiation-induced pulmonary fibrosis. Methods and Materials: Mice thoraxes were irradiated (20 Gy), and Tregs were depleted by intraperitoneal injection of a monoclonal anti-CD25 antibody 2 hours after irradiation and every 7 days thereafter. Mice were treated on days 3, 7, and 14 and 1, 3, and 6 months post irradiation. The effectiveness of Treg depletion was assayed via flow cytometry. EMT and β-catenin in lung tissues were detected by immunohistochemistry. Tregs isolated from murine spleens were cultured with mouse lung epithelial (MLE) 12 cells, and short interfering RNA (siRNA) knockdown of β-catenin in MLE 12 cells was used to explore the effects of Tregs on EMT and β-catenin via flow cytometry and Western blotting. Results: Anti-CD25 antibody treatment depleted Tregs efficiently, attenuated the process of radiation-induced pulmonary fibrosis, hindered EMT, and reduced β-catenin accumulation in lung epithelial cells in vivo. The coculture of Tregs with irradiated MLE 12 cells showed that Tregs could promote EMT in MLE 12 cells and that the effect of Tregs on EMT was partially abrogated by β-catenin knockdown in vitro. Conclusions: Tregs can promote EMT in accelerating radiation-induced pulmonary fibrosis. This process is partially mediated through β-catenin. Our study suggests a new mechanism for EMT, promoted by Tregs, that accelerates radiation-induced pulmonary fibrosis.

  11. Regulatory T Cells Promote β-Catenin–Mediated Epithelium-to-Mesenchyme Transition During Radiation-Induced Pulmonary Fibrosis

    International Nuclear Information System (INIS)

    Xiong, Shanshan; Pan, Xiujie; Xu, Long; Yang, Zhihua; Guo, Renfeng; Gu, Yongqing; Li, Ruoxi; Wang, Qianjun; Xiao, Fengjun; Du, Li; Zhou, Pingkun; Zhu, Maoxiang

    2015-01-01

    Purpose: Radiation-induced pulmonary fibrosis results from thoracic radiation therapy and severely limits radiation therapy approaches. CD4 + CD25 + FoxP3 + regulatory T cells (Tregs) as well as epithelium-to-mesenchyme transition (EMT) cells are involved in pulmonary fibrosis induced by multiple factors. However, the mechanisms of Tregs and EMT cells in irradiation-induced pulmonary fibrosis remain unclear. In the present study, we investigated the influence of Tregs on EMT in radiation-induced pulmonary fibrosis. Methods and Materials: Mice thoraxes were irradiated (20 Gy), and Tregs were depleted by intraperitoneal injection of a monoclonal anti-CD25 antibody 2 hours after irradiation and every 7 days thereafter. Mice were treated on days 3, 7, and 14 and 1, 3, and 6 months post irradiation. The effectiveness of Treg depletion was assayed via flow cytometry. EMT and β-catenin in lung tissues were detected by immunohistochemistry. Tregs isolated from murine spleens were cultured with mouse lung epithelial (MLE) 12 cells, and short interfering RNA (siRNA) knockdown of β-catenin in MLE 12 cells was used to explore the effects of Tregs on EMT and β-catenin via flow cytometry and Western blotting. Results: Anti-CD25 antibody treatment depleted Tregs efficiently, attenuated the process of radiation-induced pulmonary fibrosis, hindered EMT, and reduced β-catenin accumulation in lung epithelial cells in vivo. The coculture of Tregs with irradiated MLE 12 cells showed that Tregs could promote EMT in MLE 12 cells and that the effect of Tregs on EMT was partially abrogated by β-catenin knockdown in vitro. Conclusions: Tregs can promote EMT in accelerating radiation-induced pulmonary fibrosis. This process is partially mediated through β-catenin. Our study suggests a new mechanism for EMT, promoted by Tregs, that accelerates radiation-induced pulmonary fibrosis

  12. Validation of the 2nd Generation Proteasome Inhibitor Oprozomib for Local Therapy of Pulmonary Fibrosis.

    Directory of Open Access Journals (Sweden)

    Nora Semren

    Full Text Available Proteasome inhibition has been shown to prevent development of fibrosis in several organs including the lung. However, effects of proteasome inhibitors on lung fibrosis are controversial and cytotoxic side effects of the overall inhibition of proteasomal protein degradation cannot be excluded. Therefore, we hypothesized that local lung-specific application of a novel, selective proteasome inhibitor, oprozomib (OZ, provides antifibrotic effects without systemic toxicity in a mouse model of lung fibrosis. Oprozomib was first tested on the human alveolar epithelial cancer cell line A549 and in primary mouse alveolar epithelial type II cells regarding its cytotoxic effects on alveolar epithelial cells and compared to the FDA approved proteasome inhibitor bortezomib (BZ. OZ was less toxic than BZ and provided high selectivity for the chymotrypsin-like active site of the proteasome. In primary mouse lung fibroblasts, OZ showed significant anti-fibrotic effects, i.e. reduction of collagen I and α smooth muscle actin expression, in the absence of cytotoxicity. When applied locally into the lungs of healthy mice via instillation, OZ was well tolerated and effectively reduced proteasome activity in the lungs. In bleomycin challenged mice, however, locally applied OZ resulted in accelerated weight loss and increased mortality of treated mice. Further, OZ failed to reduce fibrosis in these mice. While upon systemic application OZ was well tolerated in healthy mice, it rather augmented instead of attenuated fibrotic remodelling of the lung in bleomycin challenged mice. To conclude, low toxicity and antifibrotic effects of OZ in pulmonary fibroblasts could not be confirmed for pulmonary fibrosis of bleomycin-treated mice. In light of these data, the use of proteasome inhibitors as therapeutic agents for the treatment of fibrotic lung diseases should thus be considered with caution.

  13. Comparison of Flutter device and chest physical therapy in the treatment of cystic fibrosis pulmonary exacerbation.

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    Gondor, M; Nixon, P A; Mutich, R; Rebovich, P; Orenstein, D M

    1999-10-01

    Chest physiotherapy (CPT) is recommended for the clearance of bronchial secretions in the management of patients with cystic fibrosis (CF). The Flutter valve (Scandipharm, Birmingham, AL) has been introduced as an alternative method to CPT for airway mucus clearance. The objective of this study was to compare the short-term effects of CPT and the Flutter valve on pulmonary function and exercise tolerance in patients with cystic fibrosis. Twenty-three patients, 5 to 21 years of age, were randomized to receive one of two interventions: CPT or the Flutter valve, upon admission to the hospital for a 2-week treatment of pulmonary exacerbation. Pulmonary function testing (PFTs) and the 6-min walk test were performed on admission, day 7, and day 14 of hospitalization. Data analysis indicated no significant differences between the two groups on admission. Both groups showed improvement in pulmonary function test results, but the Flutter group had a higher mean forced vital capacity (FVC) and forced expiratory volume in 1 sec (FEV(1)) compared to the CPT group after 1 week of intervention. Both groups continued to improve during the 2-week intervention, with no significant difference in FVC or FEV(1) between groups by the end of 2 weeks. Mean forced expiratory flow rate between 25-75% of vital capacity (FEF(25-75)), 6-min walk distance, and resting arterial oxyhemoglobin saturation (SaO(2)) showed little change by day 7, but improved significantly (P< 0.05) by day 14 of hospitalization in both groups, with no significant difference between groups. This study demonstrated that patients using the Flutter device had better pulmonary function after 1 week of therapy and similar improvement in pulmonary function and exercise tolerance compared to CPT after 2 weeks of therapy, suggesting that Flutter valve therapy is an acceptable alternative to standard CPT during in-hospital care of patients with CF. Copyright 1999 Wiley-Liss, Inc.

  14. [Comparison of LCD and CRT monitors for detection of pulmonary nodules and interstitial lung diseases on digital chest radiographs by using receiver operating characteristic analysis].

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    Ikeda, Ryuji; Katsuragawa, Shigehiko; Shimonobou, Toshiaki; Hiai, Yasuhiro; Hashida, Masahiro; Awai, Kazuo; Yamashita, Yasuyuki; Doi, Kunio

    2006-05-20

    Soft copy reading of digital images has been practiced commonly in the PACS environment. In this study, we compared liquid-crystal display (LCD) and cathode-ray tube (CRT) monitors for detection of pulmonary nodules and interstitial lung diseases on digital chest radiographs by using receiver operating characteristic (ROC) analysis. Digital chest images with a 1000x1000 matrix size and a 8 bit grayscale were displayed on LCD/CRT monitor with 2M pixels in each observer test. Eight and ten radiologists participated in the observer tests for detection of nodules and interstitial diseases, respectively. In each observer test, radiologists marked their confidence levels for diagnosis of pulmonary nodules or interstitial diseases. The detection performance of radiologists was evaluated by ROC analyses. The average Az values (area under the ROC curve) in detecting pulmonary nodules with LCD and CRT monitors were 0.792 and 0.814, respectively. In addition, the average Az values in detecting interstitial diseases with LCD and CRT monitors were 0.951 and 0.953, respectively. There was no statistically significant difference between LCD and CRT for both detection of pulmonary nodules (P=0.522) and interstitial lung diseases (P=0.869). Therefore, we believe that the LCD monitor instead of the CRT monitor can be used for the diagnosis of pulmonary nodules and interstitial lung diseases in digital chest images.

  15. Adrenomedullin in inflammatory process associated with experimental pulmonary fibrosis

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    Bramanti Placido

    2011-04-01

    Full Text Available Abstract Background Adrenomedullin (AM, a 52-amino acid ringed-structure peptide with C-terminal amidation, was originally isolated from human pheochromocytoma. AM are widely distributed in various tissues and acts as a local vasoactive hormone in various conditions. Methods In the present study, we investigated the efficacy of AM on the animal model of bleomycin (BLM-induced lung injury. Mice were subjected to intratracheal administration of BLM and were assigned to receive AM daily by an intraperitoneal injection of 200 ngr/kg. Results and Discussion Myeloperoxidase activity, lung histology, immunohistochemical analyses for cytokines and adhesion molecules expression, inducible nitric oxide synthase (iNOS, nitrotyrosine, and poly (ADP-ribose polymerase (PARP were performed one week after fibrosis induction. Lung histology and transforming growth factor beta (TGF-β were performed 14 and 21 days after treatments. After bleomycin administration, AM-treated mice exhibited a reduced degree of lung damage and inflammation compared with BLM-treated mice, as shown by the reduction of (1 myeloperoxidase activity (MPO, (2 cytokines and adhesion molecules expression, (3 nitric oxide synthase expression, (4 the nitration of tyrosine residues, (5 poly (ADP-ribose (PAR formation, a product of the nuclear enzyme poly (ADP-ribose polymerase (PARP (6 transforming growth factor beta (TGF-β (7and the degree of lung injury. Conclusions Our results indicate that AM administration is able to prevent bleomycin induced lung injury through the down regulation of proinflammatory factors.

  16. Netrin-1 Regulates Fibrocyte Accumulation in the Decellularized Fibrotic Sclerodermatous Lung Microenvironment and in Bleomycin-Induced Pulmonary Fibrosis.

    Science.gov (United States)

    Sun, Huanxing; Zhu, Yangyang; Pan, Hongyi; Chen, Xiaosong; Balestrini, Jenna L; Lam, TuKiet T; Kanyo, Jean E; Eichmann, Anne; Gulati, Mridu; Fares, Wassim H; Bai, Hanwen; Feghali-Bostwick, Carol A; Gan, Ye; Peng, Xueyan; Moore, Meagan W; White, Eric S; Sava, Parid; Gonzalez, Anjelica L; Cheng, Yuwei; Niklason, Laura E; Herzog, Erica L

    2016-05-01

    Fibrocytes are collagen-producing leukocytes that accumulate in patients with systemic sclerosis (SSc; scleroderma)-related interstitial lung disease (ILD) via unknown mechanisms that have been associated with altered expression of neuroimmune proteins. The extracellular matrix (ECM) influences cellular phenotypes. However, a relationship between the lung ECM and fibrocytes in SSc has not been explored. The aim of this study was to use a novel translational platform based on decellularized human lungs to determine whether the lung ECM of patients with scleroderma controls the development of fibrocytes from peripheral blood mononuclear cells. We performed biomechanical evaluation of decellularized scaffolds prepared from lung explants from healthy control subjects and patients with scleroderma, using tensile testing and biochemical and proteomic analysis. Cells obtained from healthy controls and patients with SSc-related ILD were cultured on these scaffolds, and CD45+pro-ColIα1+ cells meeting the criteria for fibrocytes were quantified. The contribution of the neuromolecule netrin-1 to fibrosis was assessed using neutralizing antibodies in this system and by administering bleomycin via inhalation to netrin-1(+/-) mice. Compared with control lung scaffolds, lung scaffolds from patients with SSc-related ILD showed aberrant anatomy, enhanced stiffness, and abnormal ECM composition. Culture of control cells in lung scaffolds from patients with SSc-related ILD increased production of pro-ColIα1+ cells, which was stimulated by enhanced stiffness and abnormal ECM composition. Cells from patients with SSc-related ILD demonstrated increased pro-ColIα1 responsiveness to lung scaffolds from scleroderma patients but not enhanced stiffness. Enhanced detection of netrin-1-expressing CD14(low) cells in patients with SSc-related ILD was observed, and antibody-mediated netrin-1 neutralization attenuated detection of CD45+pro-ColIα1+ cells in all settings. Netrin-1(+/-) mice were

  17. The exacerbating roles of CCAAT/enhancer-binding protein homologous protein (CHOP) in the development of bleomycin-induced pulmonary fibrosis and the preventive effects of tauroursodeoxycholic acid (TUDCA) against pulmonary fibrosis in mice.

    Science.gov (United States)

    Tanaka, Yuta; Ishitsuka, Yoichi; Hayasaka, Marina; Yamada, Yusei; Miyata, Keishi; Endo, Motoyoshi; Kondo, Yuki; Moriuchi, Hiroshi; Irikura, Mitsuru; Tanaka, Ken-ichiro; Mizushima, Tohru; Oike, Yuichi; Irie, Tetsumi

    2015-09-01

    The purpose of this study was to evaluate the role of CCAAT/enhancer-binding protein homologous protein (CHOP), an important transcription factor that regulates the inflammatory reaction during the endoplasmic reticulum (ER) stress response, in the development of pulmonary fibrosis induced by bleomycin (BLM) in mice. An intratracheal injection of BLM transiently increased the expression of CHOP mRNA and protein in an early phase (days 1 and 3) in mice lungs. BLM-induced pulmonary fibrosis was significantly attenuated in Chop gene deficient (Chop KO) mice, compared with wild-type (WT) mice. Furthermore, the inflammatory reactions evaluated by protein concentration, the total number of leucocytes and neutrophils in the bronchoalveolar lavage fluid (BALF), the mRNA expression of interleukin 1b and caspase 11, and the apoptotic cell death were suppressed in Chop KO mice compared with those in WT mice. In addition, administration of tauroursodeoxycholic acid (TUDCA), a pharmacological agent that can inhibit CHOP expression, inhibited the BLM-induced pulmonary fibrosis and inflammation, and the increase in Chop mRNA expression in WT mice in a dose-dependent manner. These results suggest that the ER stress-induced transcription factor, CHOP, at least in part, plays an important role in the development of BLM-induced pulmonary fibrosis in mice, and that the inhibition of CHOP expression by a pharmacological agent, such as TUDCA, may be a promising strategy for the prevention of pulmonary fibrosis. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Impact of a disease-management program on symptom burden and health-related quality of life in patients with idiopathic pulmonary fibrosis and their care partners.

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    Lindell, Kathleen Oare; Olshansky, Ellen; Song, Mi-Kyung; Zullo, Thomas G; Gibson, Kevin F; Kaminski, Naftali; Hoffman, Leslie A

    2010-01-01

    Patients were recruited from the Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, located within the University of Pittsburgh Medical Center. Idiopathic pulmonary fibrosis results in scarring of the lung and respiratory failure, and has a median survival of 3 to 5 years from the time of diagnosis. The purpose of this study was to determine whether patients with idiopathic pulmonary fibrosis and their care partners could be more optimally managed by a disease-management intervention entitled "Program to Reduce Idiopathic Pulmonary Fibrosis Symptoms and Improve Management," which nurses delivered using the format of a support group. We hypothesized that participation would improve perceptions of health-related quality of life (HRQoL) and decrease symptom burden. Subjects were 42 participants randomized to an experimental (10 patient/care partner dyads) or control (11 patient/care partner dyads) group. Experimental group participants attended the 6-week program, and controls received usual care. Before and after the program, all participants completed questionnaires designed to assess symptom burden and HRQoL. Patients and care partners in the intervention group were also interviewed in their home to elicit information on their experience after participating in the Program to Reduce Idiopathic Pulmonary Fibrosis Symptoms and Improve Management. After the intervention, experimental group patients rated their HRQoL less positively (P = .038) and tended to report more anxiety (P = .077) compared with controls. Care partners rated their stress at a lower level (P = .018) compared with controls. Course evaluations were uniformly positive. Post-study qualitative interviews with experimental group participants suggested benefits not exemplified by these scores. Patient participants felt less isolated, were able to put their disease into perspective, and valued participating in research and helping others. Further exploration of the impact of disease

  19. Pulmonary Bacterial Communities in Surgically Resected Noncystic Fibrosis Bronchiectasis Lungs Are Similar to Those in Cystic Fibrosis

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    Heather Maughan

    2012-01-01

    Full Text Available Background. Recurrent bacterial infections play a key role in the pathogenesis of bronchiectasis, but conventional microbiologic methods may fail to identify pathogens in many cases. We characterized and compared the pulmonary bacterial communities of cystic fibrosis (CF and non-CF bronchiectasis patients using a culture-independent molecular approach. Methods. Bacterial 16S rRNA gene libraries were constructed from lung tissue of 10 non-CF bronchiectasis and 21 CF patients, followed by DNA sequencing of isolates from each library. Community characteristics were analyzed and compared between the two groups. Results. A wide range of bacterial diversity was detected in both groups, with between 1 and 21 bacterial taxa found in each patient. Pseudomonas was the most common genus in both groups, comprising 49% of sequences detected and dominating numerically in 13 patients. Although Pseudomonas appeared to be dominant more often in CF patients than in non-CF patients, analysis of entire bacterial communities did not identify significant differences between these two groups. Conclusions. Our data indicate significant diversity in the pulmonary bacterial community of both CF and non-CF bronchiectasis patients and suggest that this community is similar in surgically resected lungs of CF and non-CF bronchiectasis patients.

  20. Radiological characteristics, histological features and clinical outcomes of lung cancer patients with coexistent idiopathic pulmonary fibrosis.

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    Khan, K A; Kennedy, M P; Moore, E; Crush, L; Prendeville, S; Maher, M M; Burke, L; Henry, M T

    2015-02-01

    Despite advances in diagnosis and management, the outcomes for both lung cancer and idiopathic pulmonary fibrosis (IPF) are still unfavourable. The pathophysiology and outcomes for patients with concomitant lung cancer and IPF remains unclear. A retrospective analysis was performed of all patients presenting with concomitant IPF and lung cancer to our centre over a 3-year period. Patients with connective tissue disease, asbestos exposure, sarcoidosis, previous thoracic radiation, radiological evidence of fibrosis but no histological confirmation of lung cancer, or the use of medications known to cause pulmonary fibrosis were excluded. We describe clinical, radiological and pathological characteristics of this group. We also report the response to standardized lung cancer therapy in this cohort. Of 637 lung cancer patients, 34 were identified with concomitant IPF (5.3 %) and all were smokers. 85 % had non-small cell lung cancer, 41 % were squamous cell cancers. The majority of tumours were located in the lower lobes, peripheral and present in an area of honeycombing. Despite the fact that approximately 2/3rds of the patients had localised or locally advanced lung cancer, the outcome of therapy for lung cancer was extremely poor regardless of tumour stage or severity of IPF. At our centre, 1/20 patients with lung cancer have concomitant IPF. The majority of these tumours are small in size, peripheral in location and squamous cell carcinoma; in an area of honey combing. The outcome for concomitant lung cancer and IPF regardless of stage or therapy is poor.

  1. Pathogenesis pathways of idiopathic pulmonary fibrosis in bleomycin-induced lung injury model in mice.

    Science.gov (United States)

    Shi, Keyun; Jiang, Jianzhong; Ma, Tieliang; Xie, Jing; Duan, Lirong; Chen, Ruhua; Song, Ping; Yu, Zhixin; Liu, Chao; Zhu, Qin; Zheng, Jinxu

    2014-01-01

    Our objective was to investigate the pathogenesis pathways of idiopathic pulmonary fibrosis (IPF). Bleomycin (BLM) induced animal models of experimental lung fibrosis were used. CHIP assay was executed to find the link between Smad3 and IL-31, and the expressions of TGF-β1, Smad3, IL-31 and STAT1 were detected to find whether they were similar with each other. We found that in the early injury or inflammation of the animal model, BLM promoted the development of inflammation, leading to severe pulmonary fibrosis. Then the expression of TGF-β1 and Smad3 increased. Activated Smad3 bound to the IL-31 promoter region, followed by the activation of JAK-STAT pathways. The inhibitor of TGF-β1 receptor decreased the IL-31 expression and knocking-down of IL-31 also decreased the STAT1 expression. We conclude that there is a pathway of pathogenesis in BLM-induced mouse model that involves the TGF-β, IL-31 and JAKs/STATs pathway. Copyright © 2013 Elsevier B.V. All rights reserved.

  2. Comparison of Active Drug Concentrations in the Pulmonary Epithelial Lining Fluid and Interstitial Fluid of Calves Injected with Enrofloxacin, Florfenicol, Ceftiofur, or Tulathromycin.

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    Derek M Foster

    Full Text Available Bacterial pneumonia is the most common reason for parenteral antimicrobial administration to beef cattle in the United States. Yet there is little information describing the antimicrobial concentrations at the site of action. The objective of this study was to compare the active drug concentrations in the pulmonary epithelial lining fluid and interstitial fluid of four antimicrobials commonly used in cattle. After injection, plasma, interstitial fluid, and pulmonary epithelial lining fluid concentrations and protein binding were measured to determine the plasma pharmacokinetics of each drug. A cross-over design with six calves per drug was used. Following sample collection and drug analysis, pharmacokinetic calculations were performed. For enrofloxacin and metabolite ciprofloxacin, the interstitial fluid concentration was 52% and 78% of the plasma concentration, while pulmonary fluid concentrations was 24% and 40% of the plasma concentration, respectively. The pulmonary concentrations (enrofloxacin + ciprofloxacin combined exceeded the MIC90 of 0.06 μg/mL at 48 hours after administration. For florfenicol, the interstitial fluid concentration was almost 98% of the plasma concentration, and the pulmonary concentrations were over 200% of the plasma concentrations, exceeding the breakpoint (≤ 2 μg/mL, and the MIC90 for Mannheimia haemolytica (1.0 μg/mL for the duration of the study. For ceftiofur, penetration to the interstitial fluid was only 5% of the plasma concentration. Pulmonary epithelial lining fluid concentration represented 40% of the plasma concentration. Airway concentrations exceeded the MIC breakpoint for susceptible respiratory pathogens (≤ 2 μg/mL for a short time at 48 hours after administration. The plasma and interstitial fluid concentrations of tulathromcyin were lower than the concentrations in pulmonary fluid throughout the study. The bronchial concentrations were higher than the plasma or interstitial concentrations

  3. Comparison of Active Drug Concentrations in the Pulmonary Epithelial Lining Fluid and Interstitial Fluid of Calves Injected with Enrofloxacin, Florfenicol, Ceftiofur, or Tulathromycin

    Science.gov (United States)

    Foster, Derek M.; Martin, Luke G.; Papich, Mark G.

    2016-01-01

    Bacterial pneumonia is the most common reason for parenteral antimicrobial administration to beef cattle in the United States. Yet there is little information describing the antimicrobial concentrations at the site of action. The objective of this study was to compare the active drug concentrations in the pulmonary epithelial lining fluid and interstitial fluid of four antimicrobials commonly used in cattle. After injection, plasma, interstitial fluid, and pulmonary epithelial lining fluid concentrations and protein binding were measured to determine the plasma pharmacokinetics of each drug. A cross-over design with six calves per drug was used. Following sample collection and drug analysis, pharmacokinetic calculations were performed. For enrofloxacin and metabolite ciprofloxacin, the interstitial fluid concentration was 52% and 78% of the plasma concentration, while pulmonary fluid concentrations was 24% and 40% of the plasma concentration, respectively. The pulmonary concentrations (enrofloxacin + ciprofloxacin combined) exceeded the MIC90 of 0.06 μg/mL at 48 hours after administration. For florfenicol, the interstitial fluid concentration was almost 98% of the plasma concentration, and the pulmonary concentrations were over 200% of the plasma concentrations, exceeding the breakpoint (≤ 2 μg/mL), and the MIC90 for Mannheimia haemolytica (1.0 μg/mL) for the duration of the study. For ceftiofur, penetration to the interstitial fluid was only 5% of the plasma concentration. Pulmonary epithelial lining fluid concentration represented 40% of the plasma concentration. Airway concentrations exceeded the MIC breakpoint for susceptible respiratory pathogens (≤ 2 μg/mL) for a short time at 48 hours after administration. The plasma and interstitial fluid concentrations of tulathromcyin were lower than the concentrations in pulmonary fluid throughout the study. The bronchial concentrations were higher than the plasma or interstitial concentrations, with over 900

  4. Hypoxia-preconditioned mesenchymal stem cells attenuate bleomycin-induced pulmonary fibrosis.

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    Lan, Ying-Wei; Choo, Kong-Bung; Chen, Chuan-Mu; Hung, Tsai-Hsien; Chen, Young-Bin; Hsieh, Chung-Hsing; Kuo, Han-Pin; Chong, Kowit-Yu

    2015-05-20

    Idiopathic pulmonary fibrosis is a progressive diffuse parenchymal lung disorder of unknown etiology. Mesenchymal stem cell (MSC)-based therapy is a novel approach with great therapeutic potential for the treatment of lung diseases. Despite demonstration of MSC grafting, the populations of engrafted MSCs have been shown to decrease dramatically 24 hours post-transplantation due to exposure to harsh microenvironments. Hypoxia is known to induce expression of cytoprotective genes and also secretion of anti-inflammatory, anti-apoptotic and anti-fibrotic factors. Hypoxic preconditioning is thought to enhance the therapeutic potency and duration of survival of engrafted MSCs. In this work, we aimed to prolong the duration of survival of engrafted MSCs and to enhance the effectiveness of idiopathic pulmonary fibrosis transplantation therapy by the use of hypoxia-preconditioned MSCs. Hypoxic preconditioning was achieved in MSCs under an optimal hypoxic environment. The expression levels of cytoprotective factors and their biological effects on damaged alveolar epithelial cells or transforming growth factor-beta 1-treated fibroblast cells were studied in co-culture experiments in vitro. Furthermore, hypoxia-preconditioned MSCs (HP-MSCs) were intratracheally instilled into bleomycin-induced pulmonary fibrosis mice at day 3, and lung functions, cellular, molecular and pathological changes were assessed at 7 and 21 days after bleomycin administration. The expression of genes for pro-survival, anti-apoptotic, anti-oxidant and growth factors was upregulated in MSCs under hypoxic conditions. In transforming growth factor-beta 1-treated MRC-5 fibroblast cells, hypoxia-preconditioned MSCs attenuated extracellular matrix production through paracrine effects. The pulmonary respiratory functions significantly improved for up to 18 days of hypoxia-preconditioned MSC treatment. Expression of inflammatory factors and fibrotic factor were all downregulated in the lung tissues of the

  5. Should vitamin K be supplemented instead of antagonised in patients with idiopathic pulmonary fibrosis?

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    De Brouwer, Bart; Piscaer, Ianthe; Von Der Thusen, Jan H; Grutters, Jan C; Schutgens, Roger Eg; Wouters, Emiel Fm; Janssen, Rob

    2018-03-01

    There is an ongoing need for additional interventions in idiopathic pulmonary fibrosis (IPF) as antifibrotic drugs currently available only inhibit and do not stall disease progression. Vitamin K is a co-factor for the activation of coagulation factors. However, it is also required to activate proteins with functions outside of the coagulation cascade, such as matrix Gla protein (MGP), a defender against soft tissue calcification. Vitamin K antagonists are anticoagulants that are, for unknown reasons, associated with increased mortality in IPF. Areas covered: We advance the hypothesis that modulation of vitamin K-dependent MGP activation in IPF patients by either vitamin K antagonism or administration may result in acceleration and deceleration of fibrosis progression, respectively. Furthermore, shortfall in vitamin K could be suspected in IPF based on the high prevalence of certain co-morbidities, such as vascular calcification and lung cancer. Expert commentary: We hypothesize that vitamin K status is reduced in IPF patients. This, in combination with studies suggesting that vitamin K may play a role in lung fibrosis pathogenesis, would provide a rationale for conducting a clinical trial assessing the potential mitigating effects of vitamin K administration on progression of lung fibrosis, prevention of co-morbidities and mortality in IPF.

  6. Essential role for the ATG4B protease and autophagy in bleomycin-induced pulmonary fibrosis

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    Cabrera, Sandra; Maciel, Mariana; Herrera, Iliana; Nava, Teresa; Vergara, Fabián; Gaxiola, Miguel; López-Otín, Carlos; Selman, Moisés; Pardo, Annie

    2015-01-01

    Autophagy is a critical cellular homeostatic process that controls the turnover of damaged organelles and proteins. Impaired autophagic activity is involved in a number of diseases, including idiopathic pulmonary fibrosis suggesting that altered autophagy may contribute to fibrogenesis. However, the specific role of autophagy in lung fibrosis is still undefined. In this study, we show for the first time, how autophagy disruption contributes to bleomycin-induced lung fibrosis in vivo using an Atg4b-deficient mouse as a model. Atg4b-deficient mice displayed a significantly higher inflammatory response at 7 d after bleomycin treatment associated with increased neutrophilic infiltration and significant alterations in proinflammatory cytokines. Likewise, we found that Atg4b disruption resulted in augmented apoptosis affecting predominantly alveolar and bronchiolar epithelial cells. At 28 d post-bleomycin instillation Atg4b-deficient mice exhibited more extensive and severe fibrosis with increased collagen accumulation and deregulated extracellular matrix-related gene expression. Together, our findings indicate that the ATG4B protease and autophagy play a crucial role protecting epithelial cells against bleomycin-induced stress and apoptosis, and in the regulation of the inflammatory and fibrotic responses. PMID:25906080

  7. Arctigenin suppresses renal interstitial fibrosis in a rat model of obstructive nephropathy.

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    Li, Ao; Zhang, Xiaoxun; Shu, Mao; Wu, Mingjun; Wang, Jun; Zhang, Jingyao; Wang, Rui; Li, Peng; Wang, Yitao

    2017-07-01

    Renal tubulointerstitial fibrosis (TIF) is commonly the final result of a variety of progressive injuries and leads to end-stage renal disease. There are few therapeutic agents currently available for retarding the development of renal TIF. The aim of the present study is to evaluate the role of arctigenin (ATG), a lignan component derived from dried burdock (Arctium lappa L.) fruits, in protecting the kidney against injury by unilateral ureteral obstruction (UUO) in rats. Rats were subjected to UUO and then administered with vehicle, ATG (1 and 3mg/kg/d), or losartan (20mg/kg/d) for 11 consecutive days. The renoprotective effects of ATG were evaluated by histological examination and multiple biochemical assays. Our results suggest that ATG significantly protected the kidney from injury by reducing tubular dilatation, epithelial atrophy, collagen deposition, and tubulointerstitial compartment expansion. ATG administration dramatically decreased macrophage (CD68-positive cell) infiltration. Meanwhile, ATG down-regulated the mRNA levels of pro-inflammatory chemokine monocyte chemoattractant protein-1 (MCP-1) and cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interferon-γ (IFN-γ), in the obstructed kidneys. This was associated with decreased activation of nuclear factor κB (NF-κB). ATG attenuated UUO-induced oxidative stress by increasing the activity of renal manganese superoxide dismutase (SOD2), leading to reduced levels of lipid peroxidation. Furthermore, ATG inhibited the epithelial-mesenchymal transition (EMT) of renal tubules by reducing the abundance of transforming growth factor-β1 (TGF-β1) and its type I receptor, suppressing Smad2/3 phosphorylation and nuclear translocation, and up-regulating Smad7 expression. Notably, the efficacy of ATG in renal protection was comparable or even superior to losartan. ATG could protect the kidney from UUO-induced injury and fibrogenesis by suppressing inflammation, oxidative

  8. Mounier-Kuhn Syndrome in an Elderly Female with Pulmonary Fibrosis

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    Panagiotis Boglou

    2016-01-01

    Full Text Available Mounier-Kuhn syndrome (MKS, or tracheobronchomegaly, is a rare clinical and radiologic condition characterized by pronounced tracheobronchial dilation and recurrent lower respiratory tract infections. Tracheobronchomegaly presents when the defect extends to the central bronchi. MKS can be diagnosed in adult women when the transverse and sagittal diameters of the trachea, right mainstem bronchus, and left mainstem bronchus exceed 21, 23, 19.8, and 17.4 mm, respectively. Its diagnosis is based on chest radiograph and chest computed tomography (CT. Patients, usually middle-aged men, may be asymptomatic or present with clinical manifestations ranging from minimal symptoms with preserved lung function to severe respiratory failure. Pulmonary function tests (PFTs typically reveal a restrictive pattern. This report presents an elderly woman with previously diagnosed pulmonary fibrosis with symptoms of increased sputum production and haemoptysis. High-resolution chest CT showed tracheal and main stem bronchi dilatation along with bronchial diverticulosis. PFTs indicated a restrictive pattern characteristic of the underlying pulmonary fibrosis. The patient is the oldest, referred to the female gender, at presentation of MKS hitherto reported. This case highlights the need to include MKS in the differential diagnosis of recurrent lower respiratory tract infections, even in older subjects.

  9. Clinical Insights into Pulmonary Exacerbations in Cystic Fibrosis from the Microbiome. What Are We Missing?

    Science.gov (United States)

    Whelan, Fiona J; Surette, Michael G

    2015-11-01

    Pulmonary exacerbations account for much of the decrease in lung function and consequently most of the morbidity and mortality in patients with cystic fibrosis. These events are driven by an acute inflammatory response to infection. Recent technological advancements in molecular profiling techniques have allowed for a proliferation of microbiome studies of the lower airways of patients with cystic fibrosis. But these methods may not provide a comprehensive and unbiased measure of the lung microbiota in these patients and molecular profiles do not always translate to quantitative microbiology. Furthermore, these studies have not yet been able to provide much in the way of mechanistic insights into exacerbations or to guide patient therapy. We propose a model in which pulmonary exacerbations may be driven by an active subpopulation of the lung microbiota, which may represent only a small portion of the microbiota measured in a clinical sample. Methodology should be focused on the ultimate goal, which is to use the best available approaches to provide accurate quantitative measures of the microbiome to inform clinical decisions and provide rapid assessment of treatment efficacy. These strategies would be relevant to other chronic lung diseases such as chronic obstructive pulmonary disease and neutrophilic asthma.

  10. The Pattern of Elastic Fiber Breakdown in Bleomycin-Induced Pulmonary Fibrosis May Reflect Microarchitectural Changes.

    Science.gov (United States)

    Liu, Xingjian; Ma, Shuren; Turino, Gerard; Cantor, Jerome

    2017-02-01

    Desmosine and isodesmosine (DID) are unique elastin crosslinks that may serve as biomarkers for elastic fiber degradation in chronic obstructive pulmonary disease. Previously, our laboratory found that the ratio of free to peptide-bound DID in bronchoalveolar lavage fluid (BALF) showed a significant positive correlation with the extent of airspace enlargement in an elastase model of pulmonary emphysema. To further evaluate this hypothesis, our laboratory measured this ratio in a bleomycin (BLM) model of pulmonary fibrosis, which involved different microarchitectural changes than those associated with pulmonary emphysema. Syrian hamsters were instilled intratracheally with 1.0 unit BLM in 0.2 ml of normal saline (controls received the vehicle alone), and BALF was analyzed for both free and total DID, using a combination of liquid chromatography and tandem mass spectrometry. Total BALF DID was significantly increased in hamsters receiving BLM at 1 week post-treatment (92 vs 13 pg/ml; p induced emphysema, free/bound DID was lower in BLM-treated animals compared to controls at both 1 week (0.76 vs 0.84) and 2 weeks post-treatment (0.69 vs 0.86), though the differences were not statistically significant. These results indicate that it may be possible to identify specific pulmonary microarchitecture changes, based on the ratio of free to peptide-bound DID. It is speculated that the proportionate decrease in free DID in BLM-induced fibrosis may be due to preservation of intact elastic fibers as the lung injury progresses.

  11. Fibroblast growth factor 2 is required for epithelial recovery, but not for pulmonary fibrosis, in response to bleomycin.

    Science.gov (United States)

    Guzy, Robert D; Stoilov, Ivan; Elton, Timothy J; Mecham, Robert P; Ornitz, David M

    2015-01-01

    The pathogenesis of pulmonary fibrosis involves lung epithelial injury and aberrant proliferation of fibroblasts, and results in progressive pulmonary scarring and declining lung function. In vitro, fibroblast growth factor (FGF) 2 promotes myofibroblast differentiation and proliferation in cooperation with the profibrotic growth factor, transforming growth factor-β1, but the in vivo requirement for FGF2 in the development of pulmonary fibrosis is not known. The bleomycin model of lung injury and pulmonary fibrosis was applied to Fgf2 knockout (Fgf2(-/-)) and littermate control mice. Weight loss, mortality, pulmonary fibrosis, and histology were analyzed after a single intranasal dose of bleomycin. Inflammation was evaluated in bronchoalveolar lavage (BAL) fluid, and epithelial barrier integrity was assessed by measuring BAL protein and Evans Blue dye permeability. Fgf2 is expressed in mouse and human lung epithelial and inflammatory cells, and, in response to bleomycin, Fgf2(-/-) mice have significantly increased mortality and weight loss. Analysis of BAL fluid and histology show that pulmonary fibrosis is unaltered, but Fgf2(-/-) mice fail to efficiently resolve inflammation, have increased BAL cellularity, and, importantly, deficient recovery of epithelial integrity. Fgf2(-/-) mice similarly have deficient recovery of club cell secretory protein(+) bronchial epithelium in response to naphthalene. We conclude that FGF2 is not required for bleomycin-induced pulmonary fibrosis, but rather is essential for epithelial repair and maintaining epithelial integrity after bleomycin-induced lung injury in mice. These data identify that FGF2 acts as a protective growth factor after lung epithelial injury, and call into question the role of FGF2 as a profibrotic growth factor in vivo.

  12. Fibroblast Growth Factor 2 Is Required for Epithelial Recovery, but Not for Pulmonary Fibrosis, in Response to Bleomycin

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    Guzy, Robert D.; Stoilov, Ivan; Elton, Timothy J.; Mecham, Robert P.

    2015-01-01

    The pathogenesis of pulmonary fibrosis involves lung epithelial injury and aberrant proliferation of fibroblasts, and results in progressive pulmonary scarring and declining lung function. In vitro, fibroblast growth factor (FGF) 2 promotes myofibroblast differentiation and proliferation in cooperation with the profibrotic growth factor, transforming growth factor-β1, but the in vivo requirement for FGF2 in the development of pulmonary fibrosis is not known. The bleomycin model of lung injury and pulmonary fibrosis was applied to Fgf2 knockout (Fgf2−/−) and littermate control mice. Weight loss, mortality, pulmonary fibrosis, and histology were analyzed after a single intranasal dose of bleomycin. Inflammation was evaluated in bronchoalveolar lavage (BAL) fluid, and epithelial barrier integrity was assessed by measuring BAL protein and Evans Blue dye permeability. Fgf2 is expressed in mouse and human lung epithelial and inflammatory cells, and, in response to bleomycin, Fgf2−/− mice have significantly increased mortality and weight loss. Analysis of BAL fluid and histology show that pulmonary fibrosis is unaltered, but Fgf2−/− mice fail to efficiently resolve inflammation, have increased BAL cellularity, and, importantly, deficient recovery of epithelial integrity. Fgf2−/− mice similarly have deficient recovery of club cell secretory protein+ bronchial epithelium in response to naphthalene. We conclude that FGF2 is not required for bleomycin-induced pulmonary fibrosis, but rather is essential for epithelial repair and maintaining epithelial integrity after bleomycin-induced lung injury in mice. These data identify that FGF2 acts as a protective growth factor after lung epithelial injury, and call into question the role of FGF2 as a profibrotic growth factor in vivo. PMID:24988442

  13. Serum amyloid P therapeutically attenuates murine bleomycin-induced pulmonary fibrosis via its effects on macrophages.

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    Lynne A Murray

    Full Text Available Macrophages promote tissue remodeling but few mechanisms exist to modulate their activity during tissue fibrosis. Serum amyloid P (SAP, a member of the pentraxin family of proteins, signals through Fcgamma receptors which are known to affect macrophage activation. We determined that IPF/UIP patients have increased protein levels of several alternatively activated pro-fibrotic (M2 macrophage-associated proteins in the lung and monocytes from these patients show skewing towards an M2 macrophage phenotype. SAP therapeutically inhibits established bleomycin-induced pulmonary fibrosis, when administered systemically or locally to the lungs. The reduction in aberrant collagen deposition was associated with a reduction in M2 macrophages in the lung and increased IP10/CXCL10. These data highlight the role of macrophages in fibrotic lung disease, and demonstrate a therapeutic action of SAP on macrophages which may extend to many fibrotic indications caused by over-exuberant pro-fibrotic macrophage responses.

  14. Suppression of von Hippel-Lindau Protein in Fibroblasts Protects against Bleomycin-Induced Pulmonary Fibrosis.

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    Zhou, Qiyuan; Chen, Tianji; Zhang, Wei; Bozkanat, Melike; Li, Yongchao; Xiao, Lei; van Breemen, Richard B; Christman, John W; Sznajder, Jacob I; Zhou, Guofei

    2016-05-01

    We have reported that von Hippel-Lindau protein (pVHL) expression is elevated in human and mouse fibrotic lungs and that overexpression of pVHL stimulates fibroblast proliferation. We sought to determine whether loss of pVHL in fibroblasts prevents injury and fibrosis in mice that are treated with bleomycin. We generated heterozygous fibroblast-specific pVHL (Fsp-VHL) knockdown mice (Fsp-VHL(+/-)) and homozygous Fsp-VHL knockout mice (Fsp-VHL(-/-)) by crossbreeding vhlh 2-lox mice (VHL(fl/fl)) with Fsp-Cre recombinase mice. Our data show that Fsp-VHL(-/-) mice, but not Fsp-VHL(+/-) mice, have elevated red blood cell counts, hematocrit, hemoglobin content, and expression of hypoxia-inducible factor (HIF) targets, indicating HIF activation. To examine the role of pVHL in bleomycin-induced lung injury and fibrosis in vivo, we administered PBS or bleomycin to age-, sex-, and strain-matched 8-week-old VHL(fl/fl), Fsp-VHL(+/-), and Fsp-VHL(-/-) mice. In Fsp-VHL(+/-) and Fsp-VHL(-/-) mice, bleomycin-induced collagen accumulation, fibroblast proliferation, differentiation, and matrix protein dysregulation were markedly attenuated. Suppression of pVHL also decreased bleomycin-induced Wnt signaling and prostaglandin E2 signaling but did not affect bleomycin-induced initial acute lung injury and lung inflammation. These results indicate that pVHL has a pivotal role in bleomycin-induced pulmonary fibrosis, possibly via an HIF-independent pathway. Paradoxically, pVHL does not affect bleomycin-induced lung injury and inflammation, indicating a separation of the mechanisms involved in injury/inflammation from those involved in pulmonary fibrosis.

  15. Impact of serum SP-A and SP-D levels on comparison and prognosis of idiopathic pulmonary fibrosis

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    Wang, Kai; Ju, Qing; Cao, Jing; Tang, Wenze; Zhang, Jian

    2017-01-01

    Abstract Background and objective: Idiopathic pulmonary fibrosis (IPF) has a poor prognosis in general; however, it is heterogeneous to detect relative biomarkers for predicting the disease progression. Serum biomarkers can be conveniently collected to detect and help to differentially diagnose IPF and predict IPF prognosis. This meta-analysis aimed to evaluate the use of serum surfactant proteins A and D (SP-A and SP-D) for differential diagnosis and prognosis of IPF. Methods: Relevant articles were searched in PubMed, Embase, and Chinese National Knowledge Infrastructure databases and reviewed by 2 independent readers. Standard mean difference (SMD) and 95% confidence interval (CI) were calculated to assess the difference in serum levels of SP-A/D among patients with IPF, when compared to patients with non-IPF interstitial lung disease (ILD), pulmonary infection, and healthy control. Hazard ratio (HR) and 95% CI were used to compare the relative risk of mortality. Results: Twenty-one articles (totalling 1289 IPF patients) were included in final meta-analysis. Serum SP-A levels were significantly higher in patients with IPF than in patients with non-IPF ILD (SMD: 1.108 [0.584, 1.632], P infection (SMD: 1.320 [0.999, 1.640], P SMD: 2.802 [1.901, 3.702], P SMD: 0.459 [−0.000, 0.919], P = .050). Serum SP-D levels were significantly higher in patients with IPF than in patients with pulmonary infection (SMD: 1.308 [0.813, 1.803], P SMD: 2.235 [1.739, 2.731], P < .001). Risk of death in patients with IPF and elevated serum SP-A was increased 39% compared to patients with low SP-A groups. Elevated SP-D increased risk by 111% when compared to low SP-D. In acute exacerbation of IPF, serum SP-A/D were higher than those in stable stage. The comparisons and prognosis might be different in Asian and Caucasian patients. Conclusions: Serum SP-A/D detection might be useful for differential diagnosis and prediction of survival in patients with IPF. PMID:28591049

  16. Serum Levels of Surfactant Proteins in Patients with Combined Pulmonary Fibrosis and Emphysema (CPFE.

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    Andriana I Papaioannou

    Full Text Available Emphysema and idiopathic pulmonary fibrosis (IPF present either per se or coexist in combined pulmonary fibrosis and emphysema (CPFE. Serum surfactant proteins (SPs A, B, C and D levels may reflect lung damage. We evaluated serum SP levels in healthy controls, emphysema, IPF, and CPFE patients and their associations to disease severity and survival.122 consecutive patients (31 emphysema, 62 IPF, and 29 CPFE and 25 healthy controls underwent PFTs, ABG-measurements, 6MWT and chest HRCT. Serum levels of SPs were measured. Patients were followed-up for 1-year.SP-A and SP-D levels differed between groups (p = 0.006 and p<0.001 respectively. In post-hoc analysis, SP-A levels differed only between controls and CPFE (p<0.05 and CPFE and emphysema (p<0.05. SP-D differed between controls and IPF or CPFE (p<0.001 for both comparisons. In IPF SP-B correlated to pulmonary function while SP-A, correlated to the Composite Physiological Index (CPI. Controls current smokers had higher SP-A and SP-D levels compared to non-smokers (p = 0.026 and p = 0.023 respectively. SP-D levels were higher in CPFE patients with extended emphysema (p = 0.042. In patients with IPF, SP-B levels at the upper quartile of its range (≥26 ng/mL presented a weak association with reduced survival (p = 0.05.In conclusion, serum SP-A and SP-D levels were higher where fibrosis exists or coexists and related to disease severity, suggesting that serum SPs relate to alveolar damage in fibrotic lungs and may reflect either local overproduction or overleakage. The weak association between high levels of SP-B and survival needs further validation in clinical trials.

  17. Lung collagens perpetuate pulmonary fibrosis via CD204 and M2 macrophage activation.

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    Mirjam Stahl

    Full Text Available Idiopathic pulmonary fibrosis is characterized by abundant collagen production and accumulation of alternatively activated macrophages (M2 in the lower respiratory tract. Mechanisms as to how alveolar macrophages are activated by collagen breakdown products are unknown. Alveolar macrophages were obtained by bronchoalveolar lavage from 30 patients with idiopathic pulmonary fibrosis (IPF and 37 healthy donors (HD. Alveolar macrophages were cultured in the presence of collagen type I, III, IV and V monomers w/wo a neutralizing antibody against scavenger receptor I class A (CD204. Culture supernatants were assayed for the M2 markers CCL18, CCL2, and interleukin-1 receptor antagonist (IL-1ra by ELISA. Furthermore, expression of phospho-Akt was measured using ELISA and expression of CD204 by RT-PCR and flow cytometry. Stimulation with collagen type I and III monomers significantly up-regulated CCL18, IL-1ra production of alveolar macrophages. Furthermore, expression of CCL2 and CD204 were up-regulated by collagen type I exposure. In addition, collagen type I stimulation increased pospho-Akt expression. Collagen type I effects were abrogated by neutralizing antiCD204 and a non-selective Phosphatidylinositide 3-kinase inhibitor (LY294002. Spontaneous CD204 expression of alveolar macrophages was significantly increased in patients with IPF. In conclusion, our findings demonstrate that monomeric collagen type I via CD204 induces phospho-Akt expression shifting alveolar macrophages to the profibrotic M2 type. Innate immune responses induced by collagen monomers might perpetuate pulmonary fibrosis.

  18. The absence of reactive oxygen species production protects mice against bleomycin-induced pulmonary fibrosis

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    Boichot Elisabeth

    2005-01-01

    Full Text Available Abstract Background Reactive oxygen species and tissue remodeling regulators, such as metalloproteinases (MMPs and their inhibitors (TIMPs, are thought to be involved in the development of pulmonary fibrosis. We investigated these factors in the fibrotic response to bleomycin of p47phox -/- (KO mice, deficient for ROS production through the NADPH-oxidase pathway. Methods Mice are administered by intranasal instillation of 0.1 mg bleomycin. Either 24 h or 14 days after, mice were anesthetized and underwent either bronchoalveolar lavage (BAL or lung removal. Results BAL cells from bleomycin treated WT mice showed enhanced ROS production after PMA stimulation, whereas no change was observed with BAL cells from p47phox -/- mice. At day 1, the bleomycin-induced acute inflammatory response (increased neutrophil count and MMP-9 activity in the BAL fluid was strikingly greater in KO than wild-type (WT mice, while IL-6 levels increased significantly more in the latter. Hydroxyproline assays in the lung tissue 14 days after bleomycin administration revealed the absence of collagen deposition in the lungs of the KO mice, which had significantly lower hydroxyproline levels than the WT mice. The MMP-9/TIMP-1 ratio did not change at day 1 after bleomycin administration in WT mice, but increased significantly in the KO mice. By day 14, the ratio fell significantly from baseline in both strains, but more in the WT than KO strains. Conclusions These results suggest that NADPH-oxidase-derived ROS are essential to the development of pulmonary fibrosis. The absence of collagen deposition in KO mice seems to be associated with an elevated MMP-9/TIMP-1 ratio in the lungs. This finding highlights the importance of metalloproteinases and protease/anti-protease imbalances in pulmonary fibrosis.

  19. Rac2 is involved in bleomycin-induced lung inflammation leading to pulmonary fibrosis.

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    Arizmendi, Narcy; Puttagunta, Lakshmi; Chung, Kerri L; Davidson, Courtney; Rey-Parra, Juliana; Chao, Danny V; Thebaud, Bernard; Lacy, Paige; Vliagoftis, Harissios

    2014-06-27

    Pulmonary fibrotic diseases induce significant morbidity and mortality, for which there are limited therapeutic options available. Rac2, a ras-related guanosine triphosphatase expressed mainly in hematopoietic cells, is a crucial molecule regulating a diversity of mast cell, macrophage, and neutrophil functions. All these cell types have been implicated in the development of pulmonary fibrosis in a variety of animal models. For the studies described here we hypothesized that Rac2 deficiency protects mice from bleomycin-induced pulmonary fibrosis. To determine the role of Rac2 in pulmonary fibrosis we used a bleomycin-induced mouse model. Anesthetized C57BL/6 wild type and rac2-/- mice were instilled intratracheally with bleomycin sulphate (1.25 U/Kg) or saline as control. Bronchoalveolar lavage (BAL) samples were collected at days 3 and 7 of treatment and analyzed for matrix metalloproteinases (MMPs). On day 21 after bleomycin treatment, we measured airway resistance and elastance in tracheotomized animals. Lung sections were stained for histological analysis, while homogenates were analyzed for hydroxyproline and total collagen content. BLM-treated rac2-/- mice had reduced MMP-9 levels in the BAL on day 3 and reduced neutrophilia and TNF and CCL3/MIP-1α levels in the BAL on day 7 compared to BLM-treated WT mice. We also showed that rac2-/- mice had significantly lower mortality (30%) than WT mice (70%) at day 21 of bleomycin treatment. Lung function was diminished in bleomycin-treated WT mice, while it was unaffected in bleomycin-treated rac2-/- mice. Histological analysis of inflammation and fibrosis as well as collagen and hydroxyproline content in the lungs did not show significant differences between BLM-treated rac2-/- and WT and mice that survived to day 21. Rac2 plays an important role in bleomycin-induced lung injury. It is an important signaling molecule leading to BLM-induced mortality and it also mediates the physiological changes seen in the airways

  20. Structural and functional correlations in a large animal model of bleomycin-induced pulmonary fibrosis.

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    Organ, Louise; Bacci, Barbara; Koumoundouros, Emmanuel; Barcham, Garry; Milne, Marjorie; Kimpton, Wayne; Samuel, Chrishan; Snibson, Ken

    2015-07-31

    Idiopathic pulmonary fibrosis (IPF) is a severe and progressive respiratory disease with poor prognosis. Despite the positive outcomes from recent clinical trials, there is still no cure for this disease. Pre-clinical animal models are currently largely limited to small animals which have a number of shortcomings. We have previously shown that fibrosis is induced in isolated sheep lung segments 14 days after bleomycin treatment. This study aimed to determine whether bleomycin-induced fibrosis and associated functional changes persisted over a seven-week period. Two separate lung segments in nine sheep received two challenges two weeks apart of either, 3U bleomycin (BLM), or saline (control). Lung function in these segments was assessed by a wedged-bronchoscope procedure after bleomycin treatment. Lung tissue, and an ex vivo CT analysis were used to assess for the persistence of inflammation, fibrosis and collagen content in this model. Fibrotic changes persisted up to seven weeks in bleomycin-treated isolated lung segments (Pathology scores: