Mitsugumin 53 protects against smoke inhalation lung injury via suppressing the proinflammatory response in a rat model.

Abstract

OBJECTIVES: This study investigates the therapeutic potential of recombinant human Mitsugumin 53 (rhMG53) in a rodent model of smoke-induced acute lung injury (SI-ALI). We hypothesize that administration of rhMG53 will improve pulmonary function and attenuate inflammation following SI-ALI. METHODS: Sprague Dawley rats (n&#xa0;=&#xa0;6-9/group, 300-400&#xa0;g) underwent smoke inhalation or sham. Smoke-exposed rats received intravenous rhMG53 or saline. Arterial blood gases were obtained at baseline and 2, 6, and 24&#xa0;h post smoke inhalation. Lung tissue collected at 24&#xa0;h was analyzed via histopathology, immunofluorescence, bulk RNA sequencing, quantitative PCR, and western blotting. RESULTS: Six hours after smoke exposure, saline-treated rats exhibited dampened partial pressure of oxygen, whereas the rhMG53 group showed significant improvement (62.67&#xa0;&#xb1;&#xa0;15.81 vs. 75.83&#xa0;&#xb1;&#xa0;12.16&#xa0;mmHg, P&#xa0;<&#xa0;.01). By 24&#xa0;h, saline-treated animals remained significantly hypoxemic (79.33&#xa0;mmHg, P&#xa0;<&#xa0;.01 vs. baseline), while rhMG53-treated rats recovered to baseline (87.17&#xa0;mmHg), trending toward significantly higher oxygenation versus saline (P&#xa0;=&#xa0;0.0503). Smoke-exposed saline-treated rats exhibited increased overall histopathological scores, which were reduced with rhMG53 (0.60&#xa0;&#xb1;&#xa0;0.17 vs. 0.37&#xa0;&#xb1;&#xa0;0.05, P&#xa0;<&#xa0;.01). Gene ontology analysis revealed rhMG53 mitigated smoke-induced upregulation of inflammatory response pathways. Induction of pro-inflammatory genes and elevation of NLRP3 inflammasome expression observed in smoke-exposed saline-treated lungs was significantly suppressed by rhMG53, as corroborated by qPCR and western blotting. CONCLUSIONS: This study provides preclinical evidence for rhMG53 as a potential therapeutic for SI-ALI. RhMG53 improved oxygenation, reduced neutrophilic inflammation, and suppressed NLRP3 inflammasome activation. Further investigations in diverse models of ALI are warranted to define the therapeutic scope and translational potential of rhMG53.