J Leukoc Biol. 2008 Mar;83(3):785-96. Epub 2007 Dec 11.
Targeted Deletion of Cannabinoid Receptors CB1 and CB2 Produced Enhanced Inflammatory Responses to Influenza A/PR/8/34 in the Absence and Presence of Δ9-Tetrahydrocannabinol.
Buchweitz JP, Karmaus PW, Williams KJ, Harkema JR, Kaminski NE.
Department of Pharmacology and Toxicology, and Center for Integrative Toxicology, Michigan State University, East Lansing, MI 48824-1317, USA.
We have previously reported that Δ9-tetrahydrocannabinol (Δ9-THC)-treated mice challenged with influenza virus A/PR/8/34 (PR8) developed increased viral hemagglutinin 1 (H1) mRNA levels and decreased monocyte and lymphocyte recruitment to the pulmonary airways when compared with mice challenged with PR8 alone. The objective of the present study was to examine the role of cannabinoid (CB(1)/CB(2)) receptors in mediating the effects of Δ9-THC on immune and epithelial cell responses to PR8. In the current study, Δ9-THC-treated CB(1)/CB(2) receptor null (CB(1)-/-/CB(2)-/-) and wild-type mice infected with PR8 had marked increases in viral H1 mRNA when compared with CB(1)-/-/CB(2)-/- and wild-type mice challenged with PR8 alone. However, the magnitude of the H1 mRNA levels was greatly reduced in CB(1)-/-/CB(2)-/- mice as compared with wild-type mice. In addition, Δ9-THC-treated CB(1)-/-/CB(2)-/- mice infected with PR8 had increased CD4+ T cells and IFN-gamma in bronchoalveolar lavage fluid with greater pulmonary inflammation when compared with Delta(9)-THC-treated wild-type mice infected with PR8. Δ9-THC treatment of CB(1)-/-/CB(2)-/- mice in the presence or absence of PR8 challenge also developed greater amounts of mucous cell metaplasia in the affected bronchiolar epithelium. Collectively, the immune and airway epithelial cell responses to PR8 challenge in Δ9-THC-treated CB(1)-/-/CB(2)-/- and wild-type mice indicated the involvement of CB(1)/CB(2) receptor-dependent and -independent mechanisms.
PMCID: 18073275 [PubMed - indexed for MEDLINE]
J Pharmacol Exp Ther. 2007 Nov;323(2):675-83. Epub 2007 Aug 28.
Modulation of Airway Responses to Influenza A/PR/8/34 by Δ9-Tetrahydrocannabinol in C57BL/6 Mice
Buchweitz JP, Karmaus PW, Harkema JR, Williams KJ, Kaminski NE.
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824-1317, USA.
Δ9-tetrahydrocannabinol (Δ9-THC) has been widely established as a modulator of host immune responses. Accordingly, the objective of the present study was to examine the effects of Δ9-THC on the immune response within the lungs and associated changes in the morphology of the bronchiolar epithelium after one challenge with a nonlethal dose of the influenza virus A/PR/8 (PR8). C57BL/6 mice were treated by oral gavage with Δ9-THC and/or vehicle (corn oil) for 5 consecutive days. On day 3, mice were instilled intranasally with 50 plaque-forming units of PR8 and/or vehicle (saline) 4 h before Δ9-THC exposure. Mice were subsequently killed 7 and 10 days postinfection (dpi). Viral hemagglutinin 1 (H1) mRNA levels in the lungs were increased in a dose-dependent manner with Δ9-THC treatment. Enumeration of inflammatory cell types in bronchoalveolar lavage fluid showed an attenuation of macrophages and CD4(+) and CD8(+) T cells in Δ9-THC-treated mice compared with controls. Likewise, the magnitude of inflammation and virus-induced mucous cell metaplasia, as assessed by histopathology, was reduced in Δ9-THC-treated mice by 10 dpi. Collectively, these results suggest that Δ9-THC treatment increased viral load, as assessed by H1 mRNA levels, through a decrease in recruitment of macrophages and lymphocytes, particularly CD4(+) and CD8(+) T cells, to the lung.
PMCID: 17726158 [PubMed - indexed for MEDLINE]