Effects of the serine protease inhibitor rBmTI-A in an experimental mouse model of chronic allergic pulmonary inflammation

Abstract

To evaluate whether a recombinant serine protease inhibitor (rBmTI-A) modulates inflammation in an experimental model of chronic allergic lung inflammation. Balb/c mice were divided into four groups: SAL (saline), OVA (sensitized with ovalbumin), SAL + rBmTI-A (control treated with rBmTI-A) and OVA + rBmTI-A (sensitized with ovalbumin and treated with rBmTI-A). The animals received an intraperitoneal injection of saline or ovalbumin, according to the group. The groups received inhalation with saline or ovalbumin and were treated with rBmTI-A or saline by nasal instillation. After 29 days, we evaluated the respiratory mechanics; bronchoalveolar lavage fluid (BALF); cytokines; MMP-9, TIMP-1; eosinophils; collagen and elastic fibre expression in the airways; and the trypsin- like , MMP-1, and MMP-9 lung tissue proteolytic activity. Treatment with rBmTI-A reduced the trypsin- like proteolytic activity, the elastance and resistance maximum response, the polymorphonuclear cells, IL-5, IL-10, IL-13 and IL-17A in the BALF, the expression of IL-5, IL-13, IL-17, CD4+, MMP-9, TIMP-1, eosinophils, collagen and elastic fibres in the airways of the OVA + rBmTI-A group compared to the OVA group (p < 0.05). rBmTI-A attenuated bronchial hyperresponsiveness, inflammation and remodelling in this experimental model of chronic allergic pulmonary inflammation. This inhibitor may serve as a potential therapeutic tool for asthma treatment.

Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2

“…camostat mesylate, nafamostat mesylate, gabexate mesylate, ulinastatin), used for the treatment of pancreatitis, disseminated intravascular coagulation, and anticoagulant for hemodialysis, 55,56 have been found to inhibit viral replication 57,58 and to attenuate inflammatory processes in different pathological contexts, such as asthma, chronic allergic pulmonary inflammation, and inflammatory myocardial injury. [59][60][61][62] For instance, nafamostat mesylate and gabexate mesylate have been demonstrated to attenuate allergen-induced airway inflammation and eosinophilia in mouse model of allergic asthma, 61 thus reducing mast cell activation, eosinophils infiltrations in the lung, and Dermatophagoides pteronyssinus-driven IL-4 and TNFα production in bronchoalveolar lavage fluid. 61 Furthermore, treatment with nafamostat mesylate downregulated the expression of IL-1β, TNFα, IL-6, eotaxin, inducible NO synthase (iNOS), CD86, and NF-κB activation, but enhanced the expression of IL-12 and IL-10 in Dermatophagoides pteronyssinus-driven IL-4 and TNFα production in bronchoalveolar lavage fluid.…”

Molecular docking between human TMPRSS2 and the serine protease Kunitz-type inhibitor rBmTI-A

“…The structure and thermostability of the rBmTI-A inhibitor were demonstrated by Bomediano Camillo et al [31]. rBmTI-A has been studied by different groups with positive results regarding its effects on chronic obstructive pulmonary disease (COPD), pulmonary emphysema development, chronic allergic pulmonary inflammation and vessel formation [27][28][29].…”

“…These results indicate that TMPRSS2 is greatly expressed in lung tissue inflammation processes and, therefore, COPD contributes to aggravate COVID-19 severity. Since rBmTI-A treatment has shown positive outcome in COPD and lung tissue inflammation [26][27][28][29], the study of the interaction and inhibition of TMPRSS2 by rBmTI-A is an important first step in the development of a drug candidate for COVID-19 treatment.…”

“…The serine protease inhibitor rBmTI-A has shown important experimental results in the context of pulmonary emphysema and lung tissue inflammation [27–29]. Given the health emergency imposed by SARS-CoV-2, responsible for a disease that mainly affects the lung tissue and the relationship between the interaction of its protein S with the ACE2 receptor through an initialization of protein S by the serine protease TMPRSS2, the study of the interaction of TMPRSS2 and serine protease inhibitor rBmTI-A can lead to development of a therapeutic potential drug against COVID-19 disease.…”

“…The serine protease inhibitor rBmTI-A has shown important experimental results in the context of pulmonary emphysema and lung tissue inflammation [27][28][29].…”