HO-1 and NLRP3-associated lung dysfunction and systemic inflammation in a noninfectious COVID-19 spike protein murine model
- 1Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, New York University Grossman School of Medicine (NYUGSoM), 462 1st Avenue, New York, NY 10016 USA
- 2Division of Environmental Medicine, Department of Medicine, NYUGSoM, New York, NY 10010 USA
- 3Division of Biostatistics, Department of Population Health, NYUGSoM, New York, NY USA
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 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.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1038/s41598-026-58934-9.
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BibTeX
@article{kwon2026nlrp3associated,
title = {{HO-1 and NLRP3-associated lung dysfunction and systemic inflammation in a noninfectious COVID-19 spike protein murine model}},
author = {Sophia Kwon and Joanna Zhou and Jamie Antelo Rivero and Hailey Bernier and Arul Veerappan and Mengling Liu and Gabriele Grunig and George Crowley and Anna Nolan},
journal = {Scientific Reports},
year = {2026},
month = aug,
doi = {10.1038/s41598-026-58934-9},
url = {https://doi.org/10.1038/s41598-026-58934-9},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - HO-1 and NLRP3-associated lung dysfunction and systemic inflammation in a noninfectious COVID-19 spike protein murine model
AU - Sophia Kwon
AU - Joanna Zhou
AU - Jamie Antelo Rivero
AU - Hailey Bernier
AU - Arul Veerappan
AU - Mengling Liu
AU - Gabriele Grunig
AU - George Crowley
AU - Anna Nolan
PY - 2026
DA - 2026/08/01
JO - Scientific Reports
DO - 10.1038/s41598-026-58934-9
UR - https://doi.org/10.1038/s41598-026-58934-9
AB - 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. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1038/s41598-026-58934-9.
SN - 2045-2322
ER -