Lung Dysfunction and Systemic Inflammation: A Role for HO-1 and NLRP3 in a COVID-19 Murine Model

RATIONALE. The COVID-19 (C19) pandemic caused significant mortality often due to lung injury and systemic inflammation, but there is significant heterogeneity in severity and the pathobiology is not well understood. We examined COVID-19-induced pulmonary and inflammatory sequelae using a murine noninfectious model to further define the models utility and to also understand the role of mediators such as heme oxgenase-1. METHODS. k18-hACE2 male mice oropharyngeally aspirated C19-spike or equal volume control. After 72 hours, we collected: pulmonary mechanics, bronchoalveolar lavage(BAL) and plasma, snap-froze right lung, and fixed/stained left lung for histologic injury assessment(Qupath). Cytokine elaboration in BAL and plasma was quantified(Luminex), and lung homogenates were probed for HO-1 and NLRP3 (Western). Statistical (SPSS and R) and pathways comparisons(Ingenuity Pathway Analysis) were made between control and C19. RESULTS Lung Mechanics. C19 exposure significantly reduced inspiratory capacity and static lung compliance;tissue elastance and airway hyperreactivity were increased. Histology: C19 exposure caused significant inflammation and thickened alveolar septae. Cytokines: C19 exposure led to inflammatory response in BAL and plasma with simultaneous activation of Type 1 and Type 2 pathways. Pathways. NLRP3 and HO-1 protein expression is significantly induced by C19. Regulator networks show involvement of multiple cell lines and lung damage. CONCLUSION: A noninfectious C19 murine model showed worsened lung parameters and increased inflammation. HO-1 and NLRP3 may be key mediators in the inflammatory process and induce both inflammatory and counter-regulatory effects. Further studies will focus on targeted therapeutic pathways that probe into the mechanistic relationship of HO-1 and NLRP3 in C19-related disease.