The effect of mast cell stabilisation in a large animal model of pulmonary fibrosis

Introduction: While the involvement of mast cells in idiopathic pulmonary fibrosis has been documented, their precise role is not known. A better understanding of the role mast cells may play in IPF provides an opportunity for better anti-fibrotic drugs to be developed in future to treat this disease. Aims: This study aims to utilise an established large animal model of pulmonary fibrosis to investigate the effects of mast cell stabilising drug, cromolyn, and compare its efficacy with currently FDA approved drug pirfenidone. Methods: Fibrosis was induced in separate lung segments of 30 sheep with bleomycin. Sheep were assigned into 3 groups (n=10) and were treated orally twice daily with either: pirfenidone (30mg/kg); or vehicle (0.5%Methylcellulose); or twice weekly intrapulmonary cromolyn (2.4mg/sheep). Histopathology scores and collagen content were measured to assess the fibrosis. Results: In bleomycin-infused lung segments, sheep treated with pirfenidone had significantly less fibrosis compared to control sheep treated with vehicle (histopathology scores: 6.2±0.3 vs 13.5±0.9, P<0.0001; fibrosis fraction:33.1±3.7vs 20.5±1.1, P=0.002; collagen staining %: 0.63±0.9vs1.8±0.46, P=0.0001 pirfenidone vs vehicle respectively). Fibrotic changes in cromolyn treated lung segments did not significantly change compared to control group (histopathology scores:5.2±0.7 vs 6.4 ±0.6, P=0.19; fibrosis fraction:30.9±5.6 vs 27.1±3.3, P=0.73; collagen staining %: 1.2±0.3 vs 1.5±0.5, P=0.58 cromolyn vs vehicle respectively). Conclusion: In contrast to pirfenidone administration, mast cell stabilisation with cromolyn treatment did not contribute to controlling the pathological changes associated with pulmonary fibrosis.