Platelet counts predict prognosis in IPF, but are not the main source of pulmonary TGFβ1

Chong, D. L. W.; Mikolasch, T. A.; Sahota, J.; Rebeyrol, C.; Garthwaite, H. S.; Booth, H. L.; Heightman, M.; Jose, R.; Khawaja, A. A.; Labelle, M.; Scotton, C. J.; Porter, J. C.

doi:10.1101/2020.03.06.978874

bioRxiv · 10.1101/2020.03.06.978874

Platelet counts predict prognosis in IPF, but are not the main source of pulmonary TGFβ1

Chong, D. L. W.·Mikolasch, T. A.·Sahota, J.·Rebeyrol, C.·Garthwaite, H. S.·Booth, H. L.·Heightman, M.·Jose, R.·Khawaja, A. A.·Labelle, M.·Scotton, C. J.·Porter, J. C.

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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.

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Chong, D. L. W., Mikolasch, T. A., Sahota, J., Rebeyrol, C., Garthwaite, H. S., Booth, H. L., Heightman, M., Jose, R., Khawaja, A. A., Labelle, M., Scotton, C. J., Porter, J. C.. 2020-03-06. Platelet counts predict prognosis in IPF, but are not the main source of pulmonary TGFβ1. https://doi.org/10.1101/2020.03.06.978874

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