Mast Cells Contribute to Bleomycin-Induced Lung Inflammation and Injury in Mice through a Chymase/Mast Cell Protease 4–Dependent Mechanism

Abstract

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 KitW-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 KitW-sh/W-sh mice can be restored to those observed in WT mice after the adoptive transfer of bone marrow–derived cultured MCs into KitW-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.

Chymase: a multifunctional player in pulmonary hypertension associated with lung fibrosis

“…Activated MCs release a variety of mediators, and among them chymase may have great importance in the context of PH and lung fibrosis development [5,[28][29][30]. There is evidence from the literature, although very limited, that chymase inhibition led to attenuation of lung fibrosis in bleomycin models of mice and hamsters and suppression of silica-induced PF in mice [16,[35][36][37]. It is worth mentioning that MC chymase has a potential role in the regulation of collagen synthesis, suggesting one of the possibilities to be involved in the pathology of fibrosis [7].…”

Potential effector and immunoregulatory functions of mast cells in mucosal immunity

“…However, MC numbers at mucosal sites can increase in both humans and mice in pathological settings such as inflammatory bowel disease (IBD) 46, 47 , food allergy 48, 49 , parasite infections 50, 51 , asthma 52–56 or various types of lung fibrosis 57–60 . Such increases in MC numbers could reflect, at least in part, the division of mature MCs at mucosal sites.…”

Platycodin D attenuates acute lung injury by suppressing apoptosis and inflammation in vivo and in vitro

“…Traditional Chinese medicine has been used by almost one-fifth of the world's population since ancient times, and it is an important source of pharmaceutical remedies [11,12]. Bleomycin (BLE) is a drug for the treatment of a variety of human malignancies [13]. Administration of BLE has been used to study the pathogenesis and intervention of ALI in mice [14].…”