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.

We have previously reported that Δ-9-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 (CB1 /CB2 ) receptors in mediating the effects of Δ9 -THC on immune and epithelial cell responses to PR8. In the current study, Δ9 -THC-treated CB1 /CB2 receptor null (CB1-/- /CB2-/- ) and wild-type mice infected with PR8 had marked increases in viral H1 mRNA when compared with CB1-/- /CB2-/- and wild-type mice challenged with PR8 alone. However, the magnitude of the H1 mRNA levels was greatly reduced in CB1-/- /CB2-/- mice as compared with wild-type mice. In addition, Δ9 -THC-treated CB1-/- /CB2-/- mice infected with PR8 had increased CD4+ T cells and IFN-γ in bronchoalveolar lavage fluid with greater pulmonary inflammation when compared with Δ9 -THC-treated wild-type mice infected with PR8. Δ9 -THC treatment of CB1-/- /CB2-/- 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 CB1-/- /CB2-/- and wild-type mice indicated the involvement of CB1 /CB2 receptor-dependent and -independent mechanisms.