Marijuana is widely used in the U.S. and worldwide as an inhaled substance of abuse and also as a medicinal agent. Despite the common perception that marijuana poses little health risk, there are well-documented effects on the lungs, including the development of chronic airway inflammation, bronchitis, epithelial dysregulation and suppression of host defenses. In a recent characterizion by our group of the biological impact of marijuana smoke and delta9-tetrahydrocannabinol (THC) on lung cells, a novel injury pathway involving mitochondrial dysfunction and disruption of cellular energetics was discovered. Such mitochondrial injury does not occur with exposure to tobacco smoke, suggesting profound implications for short as well as long-term marijuana usage. Revelation of the unique mechanisms of action and biological consequences of marijuana smoke would significantly impact public and medical perception of health risks and would provide insight for formulating and interpreting biomedical research studies involving cannabinoids. In Phase I of this CEBRA application, our first aim will be to characterize receptor and nonreceptor mechanisms by which THC regulates mitochondrial membrane potential. In aim one of these studies, the role of cannabinoid and arylhydrocarbon receptors in the THC-induced mitochondrial injury will be determined. Having observed ten-fold higher concentrations of THC in the lung compared with blood, direct targeting of pulmonary mitochondria by THC is also a possibiltiy that will be explored mechanistically. The second aim will be to identify specific lung functions adversely impacted by marijuana smoke exposure in vivo using a rat inhalation model. This investigation will focus on interactions between epithelial cells and alveolar macrophages that modulate host defense. The results of these studies will provide the necessary background for a planned Phase II project which will identify specific mitochondrial targets of THC action and extensively characterize the role of marijuana-induced mitochondrial injury in host-defense activation, microbial killing and DNA damage. [unreadable] [unreadable] [unreadable]