Background Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease which presents a grave prognosis for diagnosed patients. Nintedanib (a triple tyrosine kinase inhibitor) and pirfenidone (unclear mechanism of action) are the only approved therapies for IPF, but have limited efficacy. The pathogenic mechanisms of this disease are not fully elucidated; however, a role for mast cells (MCs) has been postulated.
Objectives The aim of this work was to investigate a role for MCs in IPF and to understand whether nintedanib or pirfenidone could impact MC function.
Methods and results MCs were significantly elevated in human IPF lung and negatively correlated with baseline lung function (FVC). Importantly, MCs were positively associated with the number of fibroblast foci, which has been linked to increased mortality. Furthermore, MCs were increased in the region immediately surrounding the fibroblast foci, and co-culture studies confirmed a role for MC–fibroblast crosstalk in fibrosis. Nintedanib but not pirfenidone inhibited recombinant stem cell factor (SCF)–induced MC survival. Further evaluation of nintedanib determined that it also inhibited human fibroblast-mediated MC survival. This was likely via a direct effect on ckit (SCF receptor) since nintedanib blocked SCF-stimulated ckit phosphorylation, as well as downstream effects on MC proliferation and cytokine release. In addition, nintedanib ablated the increase in lung MCs and impacted high tissue density frequency (HDFm) in a rat bleomycin model of lung fibrosis.
Conclusion Nintedanib inhibits MC survival and activation and thus provides a novel additional mechanism by which this drug may exert anti-fibrotic effects in patients with IPF.
- idiopathic pulmonary fibrosis
- hypersensitivity pneumonitis
- innate immunity
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Contributors CO-S designed and performed the research, analysed the data and wrote the manuscript; EM, RD, ELM, LB, DR, HP, AC, AC, SK and GG-G performed the research; EM provided critical input to histological assessments; HP and DR provided critical input to study cohort design; MK conducted bioinformatic analyses; AL co-ordinated histopathological assessments; LM, RM and DC planned the project and conceived the experiments. All authors read and approved the final manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests At the time of this study, all authors apart from DR, HP and SK were employees of MedImmune (part of the AstraZeneca group). DC is now an employee of Galapagos. CO-S, LM, AL, SK, GG-G and ELM are current AstraZeneca employees and have stock/stock options in AstraZeneca, and CO-S and LM are developing drugs for IPF.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. Additional gene expression data are available on reasonable request.
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