?9-Tetrahydrocannabinol (THC) is a cannabinoid in Cannabis sativa. THC may be anti-inflammatory, but the effects of cannabis smoke on lung inflammation are unknown. This is relevant as inhaling cannabis smoke is the most common way that cannabis is consumed. THC interacts with CB1 and CB2 receptors, but may also interact with the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor highly expressed in the lungs that controls inflammation. We hypothesize that the AhR is a key regulator of inflammation from cannabis smoke exposure.

Heterozygous (Ahr+/?) and knock-out (Ahr?/?) mice were exposed to THC-dominant cannabis smoke. Nose-only inhalation exposures were performed twice per day in groups of two joints for 3 days. THC ELISA was performed on the plasma. Extracellular vesicles (EVs) were extracted from the bronchoaveolar lavage (BAL) fluid. Proteins from lungs, EVs, and BAL fluid were assessed through LC-MS/MS. Immune cells of the lung were assessed by flow cytometry.

Cannabis smoke activated the AhR in Ahr+/- mice as indicated by increased CYP1A1 mRNA expression. Cannabis smoke exposed Ahr-/- mice had a decrease in percent of viable cells and total immune cells but an increase in neutrophils. Lung compartments show distinct protein profiles as well as inflammatory pathway enrichment from cannabis smoke treatments which is further exacerbated in Ahr-/- mice.

Cannabis smoke activates the AhR and increases lung inflammation in the absence of AhR expression. Overall, this work investigates the consequences of cannabis smoke on lung inflammation and its therapeutic potential in lung health, pointing toward a pivotal role for the AhR.