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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DA021580-02
Application #
7244138
Study Section
Special Emphasis Panel (ZDA1-MXS-M (20))
Program Officer
Purohit, Vishnudutt
Project Start
2006-06-01
Project End
2009-05-31
Budget Start
2007-06-01
Budget End
2009-05-31
Support Year
2
Fiscal Year
2007
Total Cost
$150,020
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Sarafian, Theodore A; Montes, Cindy; Imura, Tetsuya et al. (2010) Disruption of astrocyte STAT3 signaling decreases mitochondrial function and increases oxidative stress in vitro. PLoS One 5:e9532
Sarafian, Theodore; Montes, Cindy; Harui, Airi et al. (2008) Clarifying CB2 receptor-dependent and independent effects of THC on human lung epithelial cells. Toxicol Appl Pharmacol 231:282-90