title: Gene expression changes in human small airway epithelial cells exposed to Delta9-tetrahydrocannabinol.
abstract: Marijuana smoking is associated with inflammation, cellular atypia, and molecular dysregulation of the tracheobronchial epithelium. While marijuana smoke shares many components in common with tobacco, it also contains a high concentration of Delta9-tetrahydrocannabinol (THC). The potential contribution of THC to airway injury was assessed by exposing primary cultures of human small airway epithelial (SAE) cells to THC (0.1-10.0 microg/ml) for either 1 day or 7 days. THC induced a time- and concentration-dependent decrease in cell viability, ATP level, and mitochondrial membrane potential. Using a targeted gene expression array, we observed acute changes (24 h) in the expression of mRNA for caspase-8, catalase, Bax, early growth response-1, cytochrome P4501A1 (CYP1A1), metallothionein 1A, PLAB, and heat shock factor 1 (HSF1). After 7 days of exposure, decrease in expression of mRNA for heat shock proteins (HSPs) and the pro-apoptotic protein Bax was observed, while expression of GADD45A, IL-1A, CYP1A1, and PTGS-2 increased significantly. These findings suggest a contribution of THC to DNA damage, inflammation, and alterations in apoptosis. Treatment with selected prototypical toxicants, 2,3,7,8-tetrachlorodibenznzo-p-dioxin (TCDD) and carbonyl cyanide-p-(trifluoramethoxy)-phenyl hydrazone (FCCP), produced partially overlapping gene expression profiles suggesting some similarity in mechanism of action with THC. THC, delivered as a component of marijuana smoke, may induce a profile of gene expression that contributes to the pulmonary pathology associated with marijuana use.
authors.affiliation: Division of Pulmonary and Critical Care, Department of Medicine, 14-184 Warren Hall, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1690, USA. tsarafian@mednet.ucla.edu
authors.forename: Theodore
authors.initials: T
authors.lastname: Sarafian
authors.forename: Nancy
authors.initials: N
authors.lastname: Habib
authors.forename: Jenny T
authors.initials: JT
authors.lastname: Mao
authors.forename: I-Hsien
authors.initials: IH
authors.lastname: Tsu
authors.forename: Mitsuko L
authors.initials: ML
authors.lastname: Yamamoto
authors.forename: Erin
authors.initials: E
authors.lastname: Hsu
authors.forename: Donald P
authors.initials: DP
authors.lastname: Tashkin
authors.forename: Michael D
authors.initials: MD
authors.lastname: Roth
mesh_terms: D000255:Adenosine Triphosphate; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000633:toxicity*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects*; D006213:Hallucinogens / Q000633:toxicity*; D006801:Humans; D002189:Marijuana Abuse; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D006213:Hallucinogens; D012333:RNA, Messenger; D013759:Dronabinol; D000255:Adenosine Triphosphate