Abstract

Transforming growth factor-{beta}1 (TGF{beta}1) is the key pro-fibrotic cytokine implicated in the interstitial lung diseases (ILD), including idiopathic pulmonary fibrosis (IPF), but the primary source of TGF{beta}1 in these diseases is unknown. Platelets have abundant TGF{beta}1 stores, however their role in IPF is ill-defined. We sought to investigate whether platelets or platelet-derived TGF{beta}1 mediate IPF disease progression. ILD/IPF and non-ILD patients were recruited to determine platelet reactivity and followed for mortality. To study whether platelet-derived TGF{beta}1 modulates pulmonary fibrosis, mice with a targeted deletion of TGF{beta}1 in megakaryocytes and platelets (TGF{beta}1fl/fl.PF4-Cre) were used in the bleomycin-induced PF model. We found a significantly higher mortality in IPF patients with elevated platelet counts, along with significantly increased platelets, neutrophils, TGF{beta}1 and CCL5 in the lung and bronchoalveolar lavage (BAL) of ILD patients. Despite platelets being readily detected within the lungs of bleomycin-treated mice, neither the degree of pulmonary inflammation or fibrosis were significantly different between TGF{beta}1fl/fl.PF4-Cre and control mice. Our results demonstrate for the first-time that platelet-derived TGF{beta}1 is redundant in driving pulmonary fibrosis in an animal model. However, platelets can predict mortality in IPF implicating other platelet-derived mediators, such as CCL5, in promoting human IPF disease.