Serine protease inhibitors nafamostat mesilate and gabexate mesilate attenuate allergen-induced airway inflammation and eosinophilia in a murine model of asthma

Chen, Chih Lung; Wang, Shulhn Der; Zeng, Zhao Ying; Lin, Kuo-Juei; Kao, Shung Te; Tani, Thoru; Yu, Chun Keung; Wang, Jiu Yao

doi:10.1016/j.jaci.2006.02.047

Cited by 65 publications

(58 citation statements)

References 34 publications

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“…There was also a decrease in the cellular infiltrate in the bronchovascular bundles and in goblet cell hyperplasia and mucus secretion. In a model using mice sensitized and challenged with intratracheal house dust mite extract, DerP, systemic administrations of inhibitors of limited selectively decreased the numbers of eosinophils and neutrophils in BAL (43). Furthermore, Krishna et al (44) using a selective tryptase inhibitor found decreased late-phase bronchoconstriction in allergen-challenged atopic asthmatics.…”

Section: Discussionmentioning

confidence: 99%

Protease phenotype of constitutive connective tissue and of induced mucosal mast cells in mice is regulated by the tissue

Xing

Austen

Gurish

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

113

115

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Mouse mast cells (MCs) express a large number of serine proteases including tryptases, mouse mast cell protease (mMCP)-6 and -7; chymases, mMCP-1, -2, and -4; and an elastase, mMCP-5; along with carboxypeptidase-A3 (CPA3). In helminth-infected mouse intestine, distinct protease phenotypes are observed for connective tissue MCs (CTMCs) (mMCP-4 + -7 + , and CPA3 + ) and mucosal MCs (MMCs) (mMCP-1 + and 2 + ). To determine whether the protease phenotype was regulated by the tissue, we compared the phenotype of constitutive CTMCs and induced MMCs in trachea and large airways in antigen-sensitized unchallenged and challenged mice to MCs in skin and helminthic-infected intestine. We found that in the trachea, unlike in skin and intestine, CTMCs and MMCs both express all six serine proteases and CPA3 (mMCP-1 ). This phenotype also holds for the lung CTMCs in the proximal bronchi, whereas the induced MMCs express only four proteases, mMCP-1, -2, -6, and -7. Thus, the T-cell-dependent induction of MMCs in trachea, large bronchi, and small intestine provides numbers but does not determine the protease phenotype. Furthermore, the CTMCs, which are constitutive, also show striking differences at these tissue sites, supporting the view that the differences in expression are tissue directed and not dependent on inflammation.

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Section: Discussionmentioning

confidence: 99%

Protease phenotype of constitutive connective tissue and of induced mucosal mast cells in mice is regulated by the tissue

Xing

Austen

Gurish

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

113

115

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“…Previous studies showed increased IL-6 levels in bronchial epithelial cells, induced sputum, bronchoalveolar lavage (BAL), and peripheral blood of asthmatic patients [12][13][14][15]. Increased IL-6 levels have also been described in mouse models of allergic asthma [16,17]; however, the role of IL-6 in aeroallergeninduced airway inflammation and AHR remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Critical role of IL-6 in dendritic cell-induced allergic inflammation of asthma

2015

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“…Thus, nafamostat mesilate appears to be useful for research into the pathophysiological roles of tryptase, especially allergic airway inflammation, using animal models. Recently, Chen et al demonstrated that nafamostat mesilate inhibited antigen-induced airway eosinophilia, IgE production, and interleukin (IL)-4 and proinflammatory cytokines such as IL-6 and tumor necrosis factor (TNF)-α in BALF, but it augmented the production of IL-12, which is critical for the induction of Th1 responses, in BALF (22). However, it is still unclear whether nafamostat mesilate can modulate antigeninduced T helper type 2 / 1 (Th2 / Th1) imbalance and airway remodeling and whether it can attenuate these phenotypes through the inhibition of serine protease activation.…”

Section: Introductionmentioning

confidence: 99%

Nafamostat Mesilate, a Potent Serine Protease Inhibitor, Inhibits Airway Eosinophilic Inflammation and Airway Epithelial Remodeling in a Murine Model of Allergic Asthma

Ishizaki¹,

Tanaka²,

Kajiwara³

et al. 2008

J Pharmacol Sci

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Abstract. To clarify the involvement of serine proteases in the development of allergic airway inflammation, we investigated the effect of nafamostat mesilate, a serine protease inhibitor, in a murine model of allergic asthma. Mice were sensitized to ovalbumin (OA) with alum and then exposed to 1% OA for 30 min, three times every 4th day. Nafamostat mesilate was administered orally for 10 days during the allergen challenge. In sensitized mice, repeated allergen challenge induced an increase in tryptase proteolytic activity in bronchoalveolar lavage fluid (BALF). In addition, marked increases in the numbers of inflammatory cells, levels of T helper type 2 (Th2) cytokines and eotaxin in BALF, numbers of goblet cells in the epithelium, and level of OAspecific IgE in serum were observed after repetitive allergen inhalation. Treatment with nafamostat mesilate significantly inhibited not only increased proteolytic activities, but also increases in the numbers of eosinophils and lymphocytes in the BALF. Nafamostat mesilate also dose-dependently inhibited increases in the levels of interleukin-13 and eotaxin in BALF and goblet cell hyperplasia. These findings suggest that increased serine protease activity in the airways is involved in the development of antigen-induced allergic eosinophilic inflammation and epithelial remodeling in bronchial asthma.

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Serine protease inhibitors nafamostat mesilate and gabexate mesilate attenuate allergen-induced airway inflammation and eosinophilia in a murine model of asthma

Cited by 65 publications

References 34 publications

Protease phenotype of constitutive connective tissue and of induced mucosal mast cells in mice is regulated by the tissue

Protease phenotype of constitutive connective tissue and of induced mucosal mast cells in mice is regulated by the tissue

Critical role of IL-6 in dendritic cell-induced allergic inflammation of asthma

Nafamostat Mesilate, a Potent Serine Protease Inhibitor, Inhibits Airway Eosinophilic Inflammation and Airway Epithelial Remodeling in a Murine Model of Allergic Asthma

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