The <scp>AhR</scp> Is a Critical Regulator of the Pulmonary Response to Cannabis Smoke

Cannabis use is prevalent worldwide, with smoking being the most common method of consumption. When smoking cannabis, users are exposed to both harmful combustion products and cannabinoids. The aryl hydrocarbon receptor (AhR), a transcription factor activated by both cannabinoids and combustion products, is known to regulate pulmonary responses to environmental insults. Therefore, we hypothesized that AhR activation would reduce susceptibility to the harmful effects of inhaled cannabis smoke. To investigate this hypothesis, Ahr^+/- and Ahr^-/- mice were exposed to air or cannabis smoke using a controlled puff regimen over a three-day period. In the first study to characterize the effects of cannabis smoke on lung tissue and the pulmonary secretome, we show that cannabis smoke activates AhR in lung tissue, leading to distinct immunological and proteomic responses across lung tissue, extracellular vesicles (EVs), and bronchoalveolar lavage fluid (BALF). AhR deficiency exacerbated neutrophilic inflammation, epithelial barrier disruption, and caused systemic cytokine elevation. Proteomic profiling revealed that AhR drives the activation of detoxification and metabolic pathways in lung tissue while suppressing cytoskeletal and adhesion proteins in response to cannabis smoke. In contrast, AhR loss shifted the proteomic response in EVs and BALF, altering coagulation, protease regulation, and metabolic stability. These findings demonstrate that AhR coordinates compartment-specific responses to cannabis smoke and plays a central role in preserving lung homeostasis and restraining inflammatory injury following cannabis exposure. These findings highlight not only the detrimental effects of cannabis smoke on lung health but also the pivotal role of the AhR as a key regulator of the pulmonary response to cannabis smoke exposure.