Administration of Δ8-tetrahydrocannabinol enhances lung function and attenuates neutrophiles infiltration in a preclinical model of acute respiratory distress syndrome

Abstract

Abstract Acute respiratory distress syndrome ARDS, characterized by severe hypoxemia, is an inflammatory response leads to high mortality rate. Patients with ARDS, such as some COVID-19 patients, suffer from pulmonary alveolar damage and major oedema due to diffuse infiltration of immune cells. Neutrophils are predominantly elevated in the bronchoalveolar lavage fluids of ARDS patients. Our laboratory already reported that Δ9-tetrahydrocannabinol (THC) administration effectively attenuated lung inflammation, cytokine storm, and prevents mortality in ARDS. In current study, we tested the effect of Δ8-THC, a cannabinoid which is less psychoactive than Δ9-THC, in lipopolysaccharide-endotoxin (LPS)-induced model of ARDS. Our data showed that Δ8-THC exhibited improvement of pulmonary function tests and decreased bronchoconstriction index in freely conscious-tested animals accompanied with significant decreasing in immune cells infiltration, specifically neutrophiles, and decreasing of serum tumor necrosis factor alpha (TNFα) level. Interestingly, Single cell RNA sequencing analysis of pulmonary cell tSNE clusters showed that Δ8-THC dramatically reduced neutrophils clusters and dysregulates certain genes involved in movement of neutrophils and chemokines production such as CCl6, CCl9, Cxcl3, Cxcl10, and CCl5. Together, these findings suggest that Δ8-THC mitigates ARDS by preventing neutrophiles trafficking into the lungs, and thus, may serve as a therapeutic agent to treat ARDS. This work was supported in parts by NIH grants R01ES030144, P01AT003961, P20GM103641, and R01AI123947, R01AI160896