Chiko Shimbori 1 , Chandak Upagupta 1 , Pierre-Simon Bellaye 1 , Ehab A Ayaub 1 , Seidai Sato 1 , Toyoshi Yanagihara 1 , Quan Zhou 1 , Alexander Ognjanovic 1 , Kjetil Ask 1 , Jack Gauldie 1 , Paul Forsythe 1,2 , Martin R J Kolb 1 Show Affiliations »
Abstract
BACKGROUND: The role of mast cells accumulating in idiopathic pulmonary fibrosis (IPF) lungs is unknown. OBJECTIVES: We investigated the effect of fibrotic extracellular matrix (ECM) on mast cells in experimental and human pulmonary fibrosis. RESULTS: In IPF lungs, mast cell numbers were increased and correlated with disease severity (control vs 60%<FVC<90%, mean difference=-222.7, 95% CI -386.3 to -59.2, p=0.004; control vs FVC<60%, mean difference=-301.7, 95% CI of difference -474.1 to -129.34, p=0.0001; FVC>90% vs 60%<FVC<90%, mean difference=-189.6, 95% CI of difference -353.1 to -26.03, p=0.017; FVC>90% vs FVC<60%, mean difference=-268.6, 95% CI of difference -441.0 to -96.17, p=0.0007). Plasma tryptase levels were increased in IPF and negatively correlated with FVC (control vs FVC<60%, mean difference=-17.12, 95% CI of difference -30.02 to -4.22, p=0.006: correlation curves R=-0.045, p=0.025). In a transforming growth factor (TGF)-β1-induced pulmonary fibrosis model, chymase-positive and tryptase-positive mast cells accumulated in fibrotic lung. Lung tissue was decellularised and reseeded with bone marrow or peritoneum-derived mast cells; cells on fibrotic ECM released more TGF-β1 compared with normal ECM (active TGF-β1: bone marrow-derived mast cell (BMMC)-DL vs BMMC-TGF-β1 p=0.0005, peritoneal mast cell (PMC)-DL vs PMC-TGF-β1 p=0.0003, total TGF-β1: BMMC-DL vs BMMC-TGF-β1 p=0.013, PMC-DL vs PMC-TGF-β1 p=0.001). Mechanical stretch of lungs caused mast cell degranulation; mast cell stabilisers inhibited degranulation (histamine: cont vs doxantrazole p=0.004, β-hexosaminidase: cont vs doxantrazole, mean difference=1.007, 95% CI of difference 0.2700 to 1.744, p=0.007) and TGF-β1 activation (pSmad2/Smad2: cont vs dox p=0.006). Cromoglycate attenuated pulmonary fibrosis in rats (collagen: phosphate-buffered saline (PBS) vs cromoglycate p=0.036, fibrotic area: PBS vs cromoglycate p=0.031). CONCLUSION: This study suggests that mast cells may contribute to the progression of pulmonary fibrosis. © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.
BACKGROUND: The role of mast cells accumulating in idiopathic pulmonary fibrosis (IPF) lungs is unknown. OBJECTIVES: We investigated the effect of fibrotic extracellular matrix (ECM) on mast cells in experimental and human pulmonary fibrosis . RESULTS: In IPF lungs, mast cell numbers were increased and correlated with disease severity (control vs 60%<FVC<90%, mean difference=-222.7, 95% CI -386.3 to -59.2, p=0.004; control vs FVC<60%, mean difference=-301.7, 95% CI of difference -474.1 to -129.34, p=0.0001; FVC>90% vs 60%<FVC<90%, mean difference=-189.6, 95% CI of difference -353.1 to -26.03, p=0.017; FVC>90% vs FVC<60%, mean difference=-268.6, 95% CI of difference -441.0 to -96.17, p=0.0007). Plasma tryptase levels were increased in IPF and negatively correlated with FVC (control vs FVC<60%, mean difference=-17.12, 95% CI of difference -30.02 to -4.22, p=0.006: correlation curves R=-0.045, p=0.025). In a transforming growth factor (TGF)-β1-induced pulmonary fibrosis model, chymase-positive and tryptase-positive mast cells accumulated in fibrotic lung . Lung tissue was decellularised and reseeded with bone marrow or peritoneum-derived mast cells; cells on fibrotic ECM released more TGF-β1 compared with normal ECM (active TGF-β1: bone marrow -derived mast cell (BMMC)-DL vs BMMC-TGF-β1 p=0.0005, peritoneal mast cell (PMC)-DL vs PMC-TGF-β1 p=0.0003, total TGF-β1: BMMC-DL vs BMMC-TGF-β1 p=0.013, PMC-DL vs PMC-TGF-β1 p=0.001). Mechanical stretch of lungs caused mast cell degranulation; mast cell stabilisers inhibited degranulation (histamine : cont vs doxantrazole p=0.004, β-hexosaminidase: cont vs doxantrazole , mean difference=1.007, 95% CI of difference 0.2700 to 1.744, p=0.007) and TGF-β1 activation (pSmad2/Smad2 : cont vs dox p=0.006). Cromoglycate attenuated pulmonary fibrosis in rats (collagen: phosphate-buffered saline (PBS) vs cromoglycate p=0.036, fibrotic area: PBS vs cromoglycate p=0.031). CONCLUSION: This study suggests that mast cells may contribute to the progression of pulmonary fibrosis . © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.
Entities: Chemical
Disease
Gene
Species
Keywords:
idiopathic pulmonary fibrosis; innate immunity; interstitial fibrosis
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Substances： See more »
Year: 2019
PMID： 30808717 DOI： 10.1136/thoraxjnl-2018-211516
Source DB: PubMed Journal: Thorax ISSN： 0040-6376 Impact factor: 9.139