Mast cells contribute to bleomycin-induced lung inflammation and injury in mice through a chymase/mast cell protease 4-dependent mechanism.
Mast cells (MCs) are found in large numbers in lungs of patients with pulmonary fibrosis. However, the functions of MCs in lung fibrosis remain largely unknown. We assessed the role of MCs and MC protease 4 (MCPT4), the mouse counterpart of human MC chymase, in a mouse model of bleomycin (BLM)-induced lung injury. We found that levels of inflammation in the bronchoalveolar lavage and the lung, as well as levels of lung fibrosis, were reduced 7 d after intranasal delivery of BLM MC-deficient Kit(W-sh/W-sh) mice compared with wild-type (WT) mice. Confirming the implication of MCs in these processes, we report that the levels of inflammation and fibrosis observed in Kit(W-sh/W-sh) mice can be restored to those observed in WT mice after the adoptive transfer of bone marrow-derived cultured MCs into Kit(W-sh/W-sh) mice. Additionally, we show that levels of inflammation and fibrosis are also reduced in MC chymase MCPT4-deficient mice as compared with WT mice at day 7, suggesting a role for MC-derived MCPT4 in these processes. Our results support the conclusion that MCs can contribute to the initial lung injury induced by BLM through release of the MCPT4 chymase.
Laboratoire d'Innovation Thérapeutique, Unité Mixte de Recherche 7200, Centre National de la Recherche Scientifique-Université de Strasbourg, Laboratoire d'Excellence Medalis, Faculté de Pharmacie, 67401 Illkirch, France;
Laurent L
LL
Reber
François
F
Daubeuf
Gunnar
G
Pejler
Magnus
M
Abrink
Nelly
N
Frossard
D019264:Adoptive Transfer; D000818:Animals; D001761:Bleomycin; D001854:Bone Marrow Cells / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D053818:Chymases / Q000378:metabolism*; D004195:Disease Models, Animal; D008168:Lung / Q000276:immunology / Q000473:pathology; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology*; D011658:Pulmonary Fibrosis / Q000276:immunology*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*
D001761:Bleomycin; D012697:Serine Endopeptidases; C066932:mast cell protease 4; D053818:Chymases