αvβ6 integrin may be a potential prognostic biomarker in interstitial lung disease

Abstract

Idiopathic pulmonary fibrosis (IPF) and fibrotic nonspecific interstitial pneumonitis are progressive interstitial lung diseases (ILDs) with limited treatment options and poor survival. However, the rate of disease progression is variable, implying there may be different endotypes of disease. We hypothesised that immunophenotyping biopsies from ILD patients might reveal distinct endotypes of progressive fibrotic disease, which may facilitate stratification when undertaking clinical trials of novel therapies for IPF.43 paraffin-embedded, formalin-fixed lung tissue sections were immunostained for five molecules implicated in the pathogenesis of the fibrosis: α-smooth muscle actin (αSMA), αvβ6 integrin, pro-surfactant protein C (SP-C), hepatocyte growth factor (HGF) and tenascin-C (TenC). Levels of immunostaining and numbers of fibroblastic foci were quantified using operator-dependent and -independent methods. The relationship of all these markers to overall survival was analysed.Staining revealed high levels of αSMA, αvβ6 integrin, pro-SP-C, HGF and TenC, and fibroblastic foci. Immunostaining varied across samples for all molecules but only the extent of αvβ6 integrin immunostaining was associated with increased mortality. There was no association with the other markers measured.Our data suggest high levels of αvβ6 integrin may identify a specific endotype of progressive fibrotic lung disease. @ERSpublications High levels of αvβ6 integrin immunostaining on VATS biopsy predict worse survival than low levels of immunostaining http://ow.ly/IyCfH

3D pulmospheres serve as a personalized and predictive multicellular model for assessment of antifibrotic drugs

“…Current animal models, primarily those in rodents, have been disappointing (4), and many promising drugs have failed to demonstrate efficacy in human randomized clinical trials. An ideal preclinical model will need to recapitulate the multitude of factors responsible for the disease phenotype or endotype (1,5,6). Furthermore, it would more accurately predict drug responsiveness, while providing new insights into the pathobiology of the disease.…”

An Official American Thoracic Society Workshop Report: Use of Animal Models for the Preclinical Assessment of Potential Therapies for Pulmonary Fibrosis

“…Molecular imaging probes visualizing recently synthesized collagen, or the TGF-b-activating integrin avb6, have already been demonstrated to noninvasively track development of pulmonary fibrosis in the bleomycin mouse model by magnetic resonance imaging or SPECT, respectively (84,85). High levels of avb6 integrins, detected by immunohistochemistry, correlate with poor outcome in IPF (86). Using SPECT scanning, it is possible to identify up-regulated avb6 integrins in bleomycin-induced lung fibrosis, predict the development of fibrosis, and demonstrate target engagement using anti-avb6 integrin blocking antibodies (85).…”

Uncoupling of the profibrotic and hemostatic effects of thrombin in lung fibrosis

“…In response, the α v β 6 integrin, which binds latent TGF-β in the extracellular matrix, induces the release of active TGF-β from its latency-associated peptide, allowing it to interact with its receptors and exert its profibrotic effects (26). The α v β 6 integrin has been shown to be critical for the development of lung fibrosis in multiple animal models (27)(28)(29), and its expression is increased in human fibrotic lung tissue and correlates inversely with survival (28,30). Accordingly, an anti-α v β 6 antibody is currently being evaluated in a phase II clinical trial in IPF (clinicaltrials.gov identifier: NCT01371305).…”