Chong, Deborah LW;
Mikolasch, Theresia A;
Sahota, Jagdeep;
Rebeyrol, Carine;
Garthwaite, Helen S;
Booth, Helen L;
Heightman, Melissa;
... Porter, Joanna C; + view all
(2023)
Investigating the role of platelets and platelet-derived transforming growth factor-β in idiopathic pulmonary fibrosis.
American Journal of Physiology: Lung Cellular and Molecular Physiology
10.1152/ajplung.00227.2022.
(In press).
Preview |
Text
_Merged_PDF.pdf - Accepted Version Download (21MB) | Preview |
Abstract
Transforming growth factor-β1 (TGFβ1) is the key pro-fibrotic cytokine in idiopathic pulmonary fibrosis (IPF), but the primary source of this cytokine in this disease is unknown. Platelets have abundant stores of TGFβ1, although the role of these cells in IPF is ill-defined. In this study, we investigated whether platelets, and specifically platelet-derived TGFβ1, mediate IPF disease progression. IPF and non-IPF patients were recruited to determine platelet reactivity and separate cohorts of IPF patients were followed for mortality. To study whether platelet-derived TGFβ1 modulates pulmonary fibrosis (PF), mice with a targeted deletion of TGFβ1 in megakaryocytes and platelets (TGFβ1fl/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 IPF patients with elevated platelet counts within the normal range. However, our validation cohort did not confirm this observation, despite significantly increased platelets, neutrophils, active TGFβ1 and CCL5, a chemokine produced by inflammatory cells, in the blood, lung and bronchoalveolar lavage (BAL) of IPF patients. In vivo, we showed that despite platelets being readily detected within the lungs of bleomycin-treated mice, neither the degree of pulmonary inflammation or fibrosis were significantly different between TGFβ1fl/fl.PF4-Cre and control mice. Our results demonstrate for the first-time that platelet-derived TGFβ1 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 CCL5, may promote neutrophil recruitment and human IPF.
Archive Staff Only
 |
View Item |
