GABA receptor α-subunit knockout enhances lung inflammation and airway reactivity in a murine asthma model.

Emerging evidence indicates that hypnotic anesthetics affect immune function. Many anesthetics potentiate γ-aminobutyric acid A receptor (GABAR) activation, and these receptors are expressed on multiple subtypes of immune cells, providing a potential mechanistic link. Like immune cells, airway smooth muscle (ASM) cells also express GABARs, particularly isoforms containing α-subunits, and activation of these receptors leads to ASM relaxation. We sought to determine if GABAR signaling modulates the ASM contractile and inflammatory phenotype of a murine allergic asthma model utilizing GABAR α-subunit global knockout (KO; ) mice. Wild-type (WT) and KO mice were sensitized with house dust mite (HDM) antigen or exposed to PBS intranasally 5 days/wk for 3 wk. Ex vivo tracheal rings from HDM-sensitized WT and KO mice exhibited similar magnitudes of acetylcholine-induced contractile force and isoproterenol-induced relaxation ( = not significant; = 4). In contrast, in vivo airway resistance (flexiVent) was significantly increased in KO mice ( < 0.05, = 8). Moreover, the KO mice demonstrated increased eosinophilic lung infiltration ( < 0.05; = 4) and increased markers of lung T-cell activation/memory (CD62L low, CD44 high; < 0.01, = 4). In vitro, KO CD4 cells produced increased cytokines and exhibited increased proliferation after stimulation of the T-cell receptor as compared with WT CD4 cells. These data suggest that the GABAR α-subunit plays a role in immune cell function during allergic lung sensitization. Thus GABAR α-subunit-specific agonists have the therapeutic potential to treat asthma via two mechanisms: direct ASM relaxation and inhibition of airway inflammation.