EFFECTS OF GABA A RECEPTOR ANTAGONISM WITH BICUCULLINE ON SMOKE INHALATION IN SHEEP

Abstract

S149 INTRODUCTION: Sensory nerves in the lower airways and lungs contain neuropeptides including substance P and neurokinin A, which released by a variety of irritant stimuli. This neuroinflammatory mechanism has been reported to contribute to the acute lung injury of smoke inhalation. [1] Sluka and colleagues have described a model of neuroinflammation in which a central neural reflex arc involving GABA A receptors and initiated by an injury in peripheral tissues produces antidromic impulses that feedback to sustain and amplify the initial injury by releasing neuropeptides from sensory nerves. [2] Intraspinal administration of the BABA A receptor antagonist, cicuculline reduced swelling and behavioral indicators of pain in an experimental model of peripheral inflammation. We examined the effect of bicuculline on the response to smoke inhalation in sheep. METHODS: Adult female sheep were prepared surgically for chronic study by placement of vascular catheters for hemodynamic monitoring and microsphere injection, placement of an inflatable cuff around the left pulmonary artery, and formation of a chronic lung lymph fistula. After 5 to 7 days for recovery from surgery the sheep were anesthetized with ketamine and a tracheostomy performed. Under deep halothane Anesthesia smoke inhalation injury was produced by insufflation of the lungs with cool smoke from burning cotton towels. Control animals received saline infusion while the treatment group received bicuculline 100 mg/24 hours beginning 30 minutes prior to smoke inhalation. These sheep received standard supportive treatment with mechanical ventilation and pulmonary toilet while data were collected. After 24 hours the animals were sacrificed and tissue samples obtained for analysis. RESULTS: Pulmonary gas exchange was impaired by smoke inhalation as indicated by decreases in the ration of PaO2 to FiO2 (P/F ratio). Sheep treated with bicuculline and high P/F ratios after 24 hours than the control animals (446 +/- 48 vs 309 +/- 47). Lymph flow increased in sheep with smoke insufflation. This was also reduced in sheep given bicuculline (13 +/- 4 ml/hr vs 29 +/- ml/hr at 24 hours). The wet to dry ration determined for a lung sample from a bicuculline animal was 2.36 compared to 3.5 in control animals. CONCLUSIONS: These data are consistent with central nervous system modulation of neuroinflammatory mechanisms during smoke inhalation injury in sheep.