Unveiling the potential therapeutic role of nifuroxazide and liraglutide combination in mitigating LPS-induced acute lung injury through modulation of AT1R/JAK-2/STAT-3 by ACE2/ Ang1-7/MasR signaling in male albino rats: in vivo and in silico study

Abstract

The current study investigated the possible therapeutic role of a combination of liraglutide and nifuroxazide in ameliorating the JAK2/STAT3/NFĸB signaling pathway by augmenting the counter-regulatory ACE2/Ang1-7/MAS receptor axis of the renin angiotensin system (RAS). This therapeutic potential was further verified through molecular dynamic simulation studies. Seventy-five male Wistar albino rats were randomly allocated into 5 groups. The groups included normal control, LPS-induced ALI, ALI + NIF treated group, ALI + LIR-treated group, and ALI + LIR + NIF-treated group.The study revealed the promising therapeutic role of the liraglutide and nifuroxazide combination in significantly improving 7-day survival rates, ameliorating metabolic acidosis, and dampening the inflammatory response (IL-6, TNFα, iNOS, MPO, IL-1β) in bronchoalveolar lavage fluid (BALF). This was supported by the effective alleviation of pulmonary leakage, as evidenced by a remarkable decrease in wet lung weight/body weight ratio and wet/dry lung ratio. Additionally, the combination restored the redox balance by enhancing levels of SOD, catalase, and GSH. The combination regimen also improved the inflammatory score in histopathological examination, increased Nrf2 expression, and reduced iNOS immunoreactivity. These effects were attributed to the downregulation of total and phosphorylated protein expression of JAK2/STAT3/NFβB, and the upregulation of mRNA expression of ACE2 receptor, MAS receptors, and pulmonary lung surfactant B. Our study, which combined molecular dynamic simulation and experimental validation, provides a comprehensive perspective on managing septic acute lung injury, positioning the liraglutide and nifuroxazide combination regimen as a promising candidate for the management of septic acute lung injury (S-ALI).

Keywords: Acute lung injury; JAK2; Lipopolysaccharide; Liraglutide; Nifuroxazide; STAT3.