The AhR is a Critical Regulator of the Pulmonary Response to Cannabis Smoke

Abstract

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 as well as cannabinoids such as tetrahydrocannabinol (THC) and cannabidiol (CBD). THC and CBD have purported anti-inflammatory effects through activation of cannabinoid receptors; however, the minimal expression of these receptors in lung tissue suggests that respiratory effects of cannabis may be mediated through alternative pathways. One potential mediator of these effects is the aryl hydrocarbon receptor (AhR), a transcription factor involved in xenobiotic metabolism. Notably, the AhR is activated by both combustion products and cannabinoids. This receptor is also known to dampen lung inflammation induced by tobacco smoke or air pollution. 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, including extracellular vesicles and secreted proteins, we found that acute exposure induced neutrophilia, vascular leakage, and activation of tissue remodeling pathways, all of which were regulated by AhR. 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.