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

Abstract

Serine proteases such as mast cell tryptase and certain allergens are important in the pathogenesis of allergic inflammation of asthma. We sought to investigate the effects of serine protease inhibitors nafamostat mesilate (FUT), gabexate mesilate (FOY), and ulinastatin (UTI) on airway inflammation in a mouse model of allergic asthma. BALB/c mice were sensitized to Dermatophagoides pteronyssinus (Der p) and intratracheally challenged with Der p (0.5 mg/mL). Therapeutic doses of FUT (0.0625 mg/kg), FOY (20 mg/kg), and UTI (10,000 U/kg) were intra-peritoneally injected into 3 corresponding sensitized mice during the sensitization phase (protocol 1) or 24 hours after allergen challenge (protocol 2). Both FUT-treated and FOY-treated sensitized mice had reduced mast cells activation, airway hyperresponsiveness, attenuated eosinophils infiltrations, and decreased Der p-induced IL-4 and TNF-alpha, but increased IL-12 cytokine production in bronchoalveolar lavage fluid compared with nontreated mice. Furthermore, FUT treatment downregulated the expression of IL-1beta, TNF-alpha, IL-6, eotaxin, inducible NO synthase, CD86, and nuclear factor-kappaB activation, but enhanced the expression of IL-12 and IL-10 in Der p-stimulated alveolar macrophages. UTI-treated mice have no significant change of the aforementioned measurements compared with nontreated sensitized mice. Nafamostat mesilate and FOY exerting the therapeutic effect in allergen-induced airway inflammation was a result not only of their inhibitory action in the early phase of mast cells activation but also of immunoregulatory function in the late phase of allergic inflammation. Such properties of FUT and FOY might be a potential therapeutic approach for asthma. The clinical used of serine protease inhibitors FUT and FOY may also have implications for treating airway inflammation of asthma.