Targeted deletion of cannabinoid receptors CB sub(1) and CB sub(2) produced enhanced inflammatory responses to influenza A/PR/8/34 in the absence and presence of Delta super(9)-tetrahydrocannabinol

We have previously reported that Delta -9-tetrahydrocannabinol ( Delta super(9)-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 sub(1)/CB sub(2)) receptors in mediating the effects of Delta super(9)-THC on immune and epithelial cell responses to PR8. In the current study, Delta super(9)-THC-treated CB sub(1)/CB sub(2) receptor null (CB super(-) sub(1) super(/-)/CB super(-) sub(2) super(/-)) and wild-type mice infected with PR8 had marked increases in viral H1 mRNA when compared with CB super(-) sub(1) super(/-)/CB super(-) sub(2) super(/-) and wild-type mice challenged with PR8 alone. However, the magnitude of the H1 mRNA levels was greatly reduced in CB1 super(-/-)/CB super(-) sub(2) super(/-) mice as compared with wild-type mice. In addition, Delta super(9)-THC-treated CB super(-) sub(1) super(/-)CB super(-) sub(2) super(/-) mice infected with PR8 had increased CD4 super(+) T cells and IFN- gamma in bronchoalveolar lavage fluid with greater pulmonary inflammation when compared with Delta super(9)-THC-treated wild-type mice infected with PR8. Delta super(9)-THC treatment of CB super(-) sub(1) super(/-)CB super(-) sub(2) super(/-) 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 Delta super(9)-THC-treated CB super(-) sub(1) super(/-)CB super(-) sub(2) super(/-) and wild-type mice indicated the involvement of CB sub(1)/CB sub(2) receptor-dependent and -independent mechanisms.