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

Abstract

BackgroundIdiopathic 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.ObjectivesThe 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 resultsMCs 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.ConclusionNintedanib 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.

Hypoxia Inducible Factor 1A Supports a Pro-Fibrotic Phenotype Loop in Idiopathic Pulmonary Fibrosis

“…TIMP1 was specifically observed in mast cells within the fibrotic areas. These findings correlate to a recent study by Overed-Sayer et al [ 20 ] that showed induction of mast cells in IPF and could explain the lack of positive staining in the HLFs. Moreover, this group showed that nintedanib inhibits mast cell survival and activation and thus provides a novel additional mechanism by which this drug may exert anti-fibrotic effects in patients with IPF.…”

“…exposure to the IPF-CM at the mRNA and the protein levels (p < 0.05, Figure 1D,E tionally, protein levels of plasminogen activator inhibitor-1 (PAI-1, encoded PINE1) were elevated (Figure 1E). 20) showed that IPF tissues expressed significantly higher HIF1A, TIMP1, SERPINE1 and VEGFA mRNA levels (p < 0.05, Figure 2A). IHC staining of paraffin tissue samples from patients with IPF and normal tissue samples revealed that HIF1α is abundant in the IPF tissue.…”

“…The pathogenesis of IPF is still incompletely understood, and is thought to involve recurrent injury to the alveolar epithelium inducing an aberrant wound healing response, characterized by activation and proliferation of fibroblasts and myofibroblasts [ 20 ]. With the aim to discover underlying mechanisms leading to myofibroblast differentiation, we used our established human IPF-CM in-vitro model, which is a platform that enables the investigation of fibroblast-ECM interactions.…”

The Role of Anti-angiogenesis in the Treatment Landscape of Non-small Cell Lung Cancer – New Combinational Approaches and Strategies of Neovessel Inhibition

“…In NSCLC the number of tryptase positive MCs linearly correlates with microvascular density, confirming the important role of this enzyme in regulating tumor angiogenesis (Ibaraki et al, 2005;Carlini et al, 2010). Inhibition of c-kit and its ligand SCF could hamper mast cell infiltration into the TME, preventing degranulation and thereby producing a synergizing anti-angiogenic effect (Huang et al, 2008;Overed-Sayer et al, 2020).…”

Regulatory Immune Cells in Idiopathic Pulmonary Fibrosis: Friends or Foes?

“…However, nintedanib alone only reduced the mobilization of MDSCs into peripheral blood (208). Overed-Sayer et al, 2020, found that the number of lung mast cells is increased in IPF and was found to be negatively correlated with baseline lung function in humans (209). Additionally, they found that nintedanib, but not pirfenidone, inhibited human fibroblast mediated mast cell survival through stem cell factor receptors and reduced the recruitment of mast cells into the lungs of BPF in rats (209).…”