Mouse Mast Cell Protease 4 Is the Major Chymase in Murine Airways and Has a Protective Role in Allergic Airway Inflammation

Abstract

It is widely established that mast cells (MCs) have a harmful role in asthma, for example by secreting various proinflammatory substances stored within their secretory granule. However, in this study, we show that one of the substances stored within MC granule, chymase, in fact has a protective role in allergic airway inflammation, indicating that MCs may possess both harmful and protective activities in connection with this type of disease. Wild-type (WT) mice and mice lacking mouse MC protease 4 (mMCP-4), a chymase that is functionally homologous to human chymase, were sensitized and challenged with OVA, followed by the assessment of airway physiology and inflammatory parameters. Our results show that the airway hyperresponsiveness was significantly higher in mMCP-4−/− as compared with WT mice. Moreover, the degree of lung tissue inflammation was markedly higher in mice lacking mMCP-4 than in WT controls. Histological analysis revealed that OVA sensitization/challenge resulted in a marked increased in the thickness of the smooth muscle cell (SMC) layer and, notably, that the degree of SMC layer thickening was more pronounced in mMCP-4−/− animals than in WT controls, thus indicating that chymase may have an effect on airway SMCs. In support of this, mMCP-4-positive MCs were located in the close vicinity of the SMC layer, mainly in the upper airways, and mMCP-4 was shown to be the major chymase expressed in these MCs. Taken together, our results indicate that chymase present in the upper airways protects against allergic airway responses, possibly by regulating SMCs.

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

“…However, the specificity of these inhibitors remains to be fully characterized in vivo. We report in the present study that mice deficient for MCPT4, the main chymase in murine airways (22) and closest homolog to human chymase (20,21), have reduced lung inflammation at day 7 and, to a lesser extent, at day 14 after i.n. administration of 0.1 mg BLM compared with WT mice.…”

“…Based on tissue distribution, heparin-binding properties, substrate, and cleavage specificity, the b-chymase MC protease 4 (MCPT4) appears as the main homolog to human chymase (20,21). Moreover, MCPT4 is the main chymase in murine airways (22). However, the role of MCPT4 in models of lung fibrosis has not been reported to date.…”

Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction

“…To examine the role of Mfge8 in allergic airway disease, we evaluated the response of Mfge8 −/− mice in two models (36-d and 70-d Ova protocols) of allergen-induced asthma (11,12). In both models, Ova-treated Mfge8 −/− mice developed significantly exaggerated increases in pulmonary resistance, a measure of AHR to acetylcholine ( Fig.…”

Expressão e caracterização das quimases recombinantes específicas de mastócitos de camundongos (mMCP4 e 5)

“…As proteases ativas são estocadas nos grânulos de mastócitos. Fonte: Pejler et al, 2010. As proteases específicas de mastócitos estão relacionadas com artrite, inflamação alérgica das vias aéreas, angiogênese tumoral, formação de aneurisma aórtico abdominal e glomerulonefrite e na defesa contra bactérias e parasitas MCNEIL et al, 2008;WAERN et al, 2009;SCANDIUZZI et al, 2010;SOUZA-JUNIOR et al, 2012). As proteases também possuem um papel modulador nas reações alérgicas, onde a β-triptase liberada durante a ativação dos mastócitos cliva a molécula de IgE limitando a inflamação alérgica (RAUTER et al, 2008).…”

“…Estudos com modelos animais mostraram que a quimase mMCP-4 possui uma função protetora na alergia, inflamação das vias aéreas e durante a hiper-reatividade brônquica (WAERN et al, 2009 A função protetora da quimase nas respostas alérgicas das vias aéreas é demonstrada pela clínica, onde se observa que a quimase está relacionada com a preservação da função pulmonar em pacientes asmáticos (BALZAR et al, 2005). O mecanismo associado a quimase com a preservação da função pulmonar ainda é desconhecido.…”