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Original article
Mechanical stress-induced mast cell degranulation activates TGF-β1 signalling pathway in pulmonary fibrosis
  1. Chiko Shimbori1,
  2. Chandak Upagupta1,
  3. Pierre-Simon Bellaye1,
  4. Ehab A Ayaub1,
  5. Seidai Sato1,
  6. Toyoshi Yanagihara1,
  7. Quan Zhou1,
  8. Alexander Ognjanovic1,
  9. Kjetil Ask1,
  10. Jack Gauldie1,
  11. Paul Forsythe1,2,
  12. Martin R J Kolb1
  1. 1 St Joseph’s Healthcare and Department of Medicine, Firestone Institute for Respiratory Health, McMaster University Hamilton, Hamilton, Ontario, Canada
  2. 2 McMaster Brain-Body Institute, The Research Institute of St Joseph’s Hamilton, Hamilton, Ontario, Canada
  1. Correspondence to Dr Martin R J Kolb, Department of Medicine, McMaster University, Hamilton, ON L8N 4A6, Canada; kolbm{at}mcmaster.ca

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.

  • idiopathic pulmonary fibrosis
  • interstitial fibrosis
  • innate immunity
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Footnotes

  • Contributors CS conducted experiments and data analysis, prepared figures, advised on study design, and wrote and submitted the final manuscript approved by all authors. CU performed some of the experimental work and edited the manuscript. PSB, EAA, SS and TY contributed to data analysis and interpretation, and editing the manuscript. QZ and AO performed some experiment, data analysis and manuscript editing. KA, JG and PF advised on study design and edited the manuscript. MRJK designed the study and supervised the project, and edited the manuscript.

  • Funding CS was funded by the Pulmonary Fibrosis Foundation (IM Rosenzweig Junior Investigator Award) and the Canadian Pulmonary Fibrosis Foundation. PSB is funded by le Fonds de Dotation ’Recherche en Santé Respiratoire et de la Fondation du Souffle', the Canadian Pulmonary Fibrosis Foundation (CPFF), and the Research institute of St Joseph’s Hospital, Hamilton, ON, Canada (FSORC Award). The major funding for this work was from the Canadian Institute for Health Research (CIHR).

  • Competing interests None declared.

  • Ethics approval Hamilton Integrated Research Ethics Board (No 00-1839)

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Correction notice This article has been corrected since it was published Online First. A system error meant that information from the system was erroneously included in the Abstract. This has now been fixed.

  • Patient consent for publication Not required.

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