HO-1 and NLRP3-associated lung dysfunction and systemic inflammation in a noninfectious COVID-19 spike protein murine model

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 C19-induced pulmonary and inflammatory sequelae using a murine noninfectious model to further define the model’s utility and to also understand the role of mediators such as heme oxgenase-1 (HO-1). K18-hACE2 male mice oropharyngeally aspirated C19-spike protein(SP) or equal volume control. After 72 h, pulmonary mechanics, bronchoalveolar lavage (BAL), plasma, snap-frozen right lung, and fixed/stained left lung for histologic injury assessment (Qupath) was collected. 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-SP. C19-SP exposure significantly reduced inspiratory capacity and static lung compliance; tissue elastance and airway bronchoconstriction were increased. C19-SP exposure caused significant inflammation and thickened alveolar septae on histology. C19-SP exposure also led to inflammatory response in BAL and plasma with simultaneous activation of Type 1 and Type 2 pathways. NLRP3 and HO-1 protein expression is significantly increased after C19-SP. A noninfectious C19-SP murine model showed worsened lung parameters and increased inflammation. Increased expression of HO-1 and NLRP3 were associated with the inflammatory process after exposure to C19, consistent with findings in human cohorts. Further studies may focus on targeted knock in/knock down experiments and dose/time-course studies that probe the mechanistic relationship of HO-1 and NLRP3 in C19-related disease.