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      Myofibroblast Differentiation and Enhanced Tgf-B Signaling in Cystic Fibrosis Lung Disease

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          Abstract

          Rationale

          TGF-β, a mediator of pulmonary fibrosis, is a genetic modifier of CF respiratory deterioration. The mechanistic relationship between TGF-β signaling and CF lung disease has not been determined.

          Objective

          To investigate myofibroblast differentiation in CF lung tissue as a novel pathway by which TGF-β signaling may contribute to pulmonary decline, airway remodeling and tissue fibrosis.

          Methods

          Lung samples from CF and non-CF subjects were analyzed morphometrically for total TGF-β 1, TGF-β signaling (Smad2 phosphorylation), myofibroblast differentiation (α-smooth muscle actin), and collagen deposition (Masson trichrome stain).

          Results

          TGF-β signaling and fibrosis are markedly increased in CF (p<0.01), and the presence of myofibroblasts is four-fold higher in CF vs. normal lung tissue (p<0.005). In lung tissue with prominent TGF-β signaling, both myofibroblast differentiation and tissue fibrosis are significantly augmented (p<0.005).

          Conclusions

          These studies establish for the first time that a pathogenic mechanism described previously in pulmonary fibrosis is also prominent in cystic fibrosis lung disease. The presence of TGF-β dependent signaling in areas of prominent myofibroblast proliferation and fibrosis in CF suggests that strategies under development for other pro-fibrotic lung conditions may also be evaluated for use in CF.

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          Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy.

          M. Selman, T E King, A. Pardo (2001)
          Idiopathic pulmonary fibrosis is a progressive and usually fatal lung disease characterized by fibroblast proliferation and extracellular matrix remodeling, which result in irreversible distortion of the lung's architecture. Although the pathogenetic mechanisms remain to be determined, the prevailing hypothesis holds that fibrosis is preceded and provoked by a chronic inflammatory process that injures the lung and modulates lung fibrogenesis, leading to the end-stage fibrotic scar. However, there is little evidence that inflammation is prominent in early disease, and it is unclear whether inflammation is relevant to the development of the fibrotic process. Evidence suggests that inflammation does not play a pivotal role. Inflammation is not a prominent histopathologic finding, and epithelial injury in the absence of ongoing inflammation is sufficient to stimulate the development of fibrosis. In addition, the inflammatory response to a lung fibrogenic insult is not necessarily related to the fibrotic response. Clinical measurements of inflammation fail to correlate with stage or outcome, and potent anti-inflammatory therapy does not improve outcome. This review presents a growing body of evidence suggesting that idiopathic pulmonary fibrosis involves abnormal wound healing in response to multiple, microscopic sites of ongoing alveolar epithelial injury and activation associated with the formation of patchy fibroblast-myofibroblast foci, which evolve to fibrosis. Progress in understanding the fibrogenic mechanisms in the lung is likely to yield more effective therapies.
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            Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis.

            Luca Richeldi, Ulrich Costabel, Moises Selman … (2011)
            Idiopathic pulmonary fibrosis is a progressive lung disease with a high mortality rate. Because the signaling pathways activated by several tyrosine kinase receptors have been shown to be involved in lung fibrosis, it has been suggested that the inhibition of these receptors may slow the progression of idiopathic pulmonary fibrosis. In a 12-month, phase 2 trial, we assessed the efficacy and safety of four different oral doses of the tyrosine kinase inhibitor BIBF 1120 as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Secondary end points included acute exacerbations, quality of life (measured with the St. George's Respiratory Questionnaire [SGRQ]), and total lung capacity. A total of 432 patients underwent randomization to receive one of four doses of BIBF 1120 (50 mg once a day, 50 mg twice a day, 100 mg twice a day, or 150 mg twice a day) or placebo. In the group receiving 150 mg of BIBF 1120 twice a day, FVC declined by 0.06 liters per year, as compared with 0.19 liters per year in the placebo group, a 68.4% reduction in the rate of loss with BIBF 1120 (P = 0.06 with the closed testing procedure for multiplicity correction; P = 0.01 with the hierarchical testing procedure). This dose also resulted in a lower incidence of acute exacerbations, as compared with placebo (2.4 vs. 15.7 per 100 patient-years, P = 0.02) and a small decrease in the SGRQ score (assessed on a scale of 0 to 100, with lower scores indicating better quality of life) as compared with an increase with placebo (-0.66 vs. 5.46, P = 0.007). Gastrointestinal symptoms (which led to more discontinuations in the group receiving 150 mg twice a day than in the placebo group) and increases in levels of liver aminotransferases were more frequent in the group receiving 150 mg of BIBF 1120 twice daily than in the placebo group. In patients with idiopathic pulmonary fibrosis, BIBF 1120 at a dose of 150 mg twice daily, as compared with placebo, was associated with a trend toward a reduction in the decline in lung function, with fewer acute exacerbations and preserved quality of life. (Funded by Boehringer Ingelheim; ClinicalTrials.gov number, NCT00514683 .).
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              Antifibrotic activities of pirfenidone in animal models.

              Scott D. Seiwert, Irvin Pan, K Kossen … (2011)
              Pirfenidone is an orally active small molecule that has recently been evaluated in large clinical trials for the treatment of idiopathic pulmonary fibrosis, a fatal disease in which the uncontrolled deposition of extracellular matrix leads to progressive loss of lung function. This review describes the activity of pirfenidone in several well-characterised animal models of fibrosis in the lung, liver, heart and kidney. In these studies, treatment-related reductions in fibrosis are associated with modulation of cytokines and growth factors, with the most commonly reported effect being reduction of transforming growth factor-β. The consistent antifibrotic activity of pirfenidone in a broad array of animal models provides a strong preclinical rationale for the clinical characterisation of pirfenidone in pulmonary fibrosis and, potentially, other conditions with a significant fibrotic component.
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                Author and article information

                Contributors
                Rory Edward Morty: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2013
                Publication date (Electronic): 12 August 2013
                Volume: 8
                Issue: 8
                Electronic Location Identifier: e70196
                Affiliations
                [1 ]Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
                [2 ]Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
                [3 ]Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
                [4 ]Center for Metabolic Bone Disease Histomorphometry and Molecular Analyses Core Laboratory, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
                [5 ]Department of Pediatrics, University of California at San Diego and Rady Children's Hospital of San Diego, San Diego, California, United States of America
                [6 ]Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America
                University of Giessen Lung Center, Germany
                Author notes

                Competing Interests: Dr. Clancy serves on the Vertex Pharmaceuticals Global Advisory Board and the Gilead CF Scholars Program. However, neither Vertex nor Gilead had any role role in the study design, data collection/analysis, publication decisions or preparation of the manuscript. William T Harris also currently participates as site PI for several Vertex multi-center pediatric studies. His participation with Vertex has not influenced the design, data, or publication decisions regarding this manuscript. These affiliations do not alter the authors' adherence to all PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: WTH JSH JPC NA EJS. Wrote the paper: WTH JSH JPC NA EJS. Data collection, analysis, and interpretation: WTH DRK YZ DW MM NA EJS. Content guarantor: WTH.

                Article
                Publisher ID: PONE-D-13-16338
                DOI: 10.1371/journal.pone.0070196
                PMC ID: 3741283
                PubMed ID: 23950911
                SO-VID: 9e38b414-6f61-4d5c-a831-a2f1872a9633
                Copyright statement: Copyright @ 2013
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 22 April 2013
                Date accepted : 14 June 2013
                Page count
                Pages: 8
                Funding
                MM, DW, and DRK do not report any conflicts of interest. NA receives grant NIH grant support. WTH and EJS receive NIH and Cystic Fibrosis Foundation grant support. WTH is currently a site PI for CF clinical studies sponsored by Vertex Pharmaceuticals. JSH receives NIH grant support and support from both the Pulmonary Fibrosis Foundation and Children's Interstitial Lung Disease foundation. JPC is a member of the Vertex Pharmaceutical Global Advisory Board and the Gilead CF Scholars Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Anatomy and Physiology
                Subject: Respiratory System
                Subject: Developmental Biology
                Subject: Cell Differentiation
                Subject: Histology
                Subject: Molecular Cell Biology
                Subject: Extracellular Matrix
                Subject: Connective Tissue
                Subject: Extracellular Matrix Composition
                Subject: Signal Transduction
                Subject: Signaling Cascades
                Subject: TGF-beta signaling cascade
                Subject: Signaling Pathways
                Subject: Cellular Types
                Subject: Mathematics
                Subject: Statistics
                Subject: Biostatistics
                Subject: Medicine
                Subject: Anatomy and Physiology
                Subject: Respiratory System
                Subject: Clinical Genetics
                Subject: Autosomal Recessive
                Subject: Cystic Fibrosis
                Subject: Pediatrics
                Subject: Pediatric Pulmonology
                Subject: Pulmonology

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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