Details

Autor(en) / Beteiligte

• Overed-Sayer, Catherine
• Miranda, Elena
• Dunmore, Rebecca
• Liarte Marin, Elena
• Beloki, Lorea
• Rassl, Doris
• Parfrey, Helen
• Carruthers, Alan
• Chahboub, Amina
• Koch, Sofia
• Güler-Gane, Gülin
• Kuziora, Michael
• Lewis, Arthur
• Murray, Lynne
• May, Richard
• Clarke, Deborah

Titel

Inhibition of mast cells: a novel mechanism by which nintedanib may elicit anti-fibrotic effects

Ist Teil von

• Thorax, 2020-09, Vol.75 (9), p.754-763

Ort / Verlag

England

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. 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. 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. 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.