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

TL;DR

This study explores how a noninfectious mouse model of COVID-19 causes lung damage and inflammation, highlighting the roles of HO-1 and NLRP3 proteins in the disease process.

Contribution

The study identifies HO-1 and NLRP3 as key mediators in the inflammatory response to COVID-19 using a noninfectious murine model.

Findings

C19 exposure in mice caused worsened lung mechanics and increased inflammation.

C19 exposure led to simultaneous activation of Type 1 and Type 2 inflammatory pathways.

NLRP3 and HO-1 protein expression was significantly increased in response to C19 exposure.

Abstract

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.

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.

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.

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.

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