HU308, A Selective Cannabinoid Type-2 Receptor Agonist, Mitigates SARS-CoV-2 Spike Protein–Induced Acute Lung Injury in Mice

Abstract Introduction The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to pose major health challenges despite effective vaccination efforts. The sustained occurrence of breakthrough infections and emerging variants of the virus highlights the need for additional therapeutic strategies. Given the anti-inflammatory role of the cannabinoid type 2 receptor (CB2R), we examined the effect of CB2R activation in SARS-CoV-2 spike protein subunit 1 (S1SP)-induced acute lung injury (ALI). Methods ALI was induced in mice by intratracheal (i.t.) administration of S1SP, followed by treatment with the CB2R agonist HU308 (5 mg/kg, intraperitoneal: i.p.) 1 h post-S1SP and every 24 h thereafter. Lung function, bronchoalveolar lavage fluid (BALF) parameters, cytokine levels, and inflammatory signaling were assessed at 48 h following S1SP exposure. Results HU308 treatment significantly reduced S1SP-induced pulmonary dysfunction, immune cell infiltration, neutrophil activation, and proinflammatory cytokine production, while suppressing NF-κB and STAT3 activation. HU308 treatment restored the Nrf2 expression in the lung. Conclusion CB2R activation ameliorates S1SP-induced lung inflammation and injury, suggesting its therapeutic potential against COVID-19-related ALI.