Investigating the role of platelets and platelet-derived transforming growth factor-β in idiopathic pulmonary fibrosis

Transforming growth factor-beta 1 (TGF beta 1) is the key profibrotic cytokine in idiopathic pulmonary fibrosis (IPF), but the primary source of this cytokine in this disease is unknown. Platelets have abundant stores of TGF beta 1, although the role of these cells in IPF is ill-defined. In this study, we investigated whether platelets, and specifically platelet-derived TGF beta 1, mediate IPF disease progression. Patients with IPF and non-IPF patients were recruited to determine platelet reactivity, and separate cohorts of patients with IPF were followed for mortality. To study whether platelet-derived TGF beta 1 modulates pulmonary fibrosis (PF), mice with a targeted deletion of TGF beta 1 in megakaryocytes and platelets (TGF beta 1(fl/fl).PF4-Cre) were used in the well-characterized bleomycin-induced pulmonary fibrosis (PF) animal model. In a discovery cohort, we found significantly higher mortality in patients with IPF who had elevated platelet counts within the normal range. However, our validation cohort did not confirm this observation, despite significantly increased platelets, neutrophils, active TGF beta 1, and CCL5, a chemokine produced by inflammatory cells, in the blood, lung, and bronchoalveolar lavage (BAL) of patients with IPF. In vivo, we showed that despite platelets being readily detected within the lungs of bleomycin-treated mice, neither the degree of pulmonary inflammation nor fibrosis was significantly different between TGF beta 1(fl/fl).PF4-Cre and control mice. Our results demonstrate for the first time that platelet-derived TGF beta 1 does not significantly mediate inflammation or fibrosis in a PF animal model. Furthermore, our human studies revealed blood platelet counts do not consistently predict mortality in IPF but other platelet-derived mediators, such as C-C chemokine ligand 5 (CCL5), may promote neutrophil recruitment and human IPF.

Automated summary

This study investigates the role of platelets and platelet-derived TGF beta 1 in idiopathic pulmonary fibrosis (IPF). The study found that elevated platelet counts are associated with increased mortality in IPF patients, but this observation was not confirmed in a validation cohort. Additionally, platelet-derived TGF beta 1 does not significantly mediate inflammation or fibrosis in a bleomycin-induced pulmonary fibrosis animal model.