Effects of endothelin receptor antagonism on acute lung injury induced by chlorine gas

• OBJECTIVE: To test the hypothesis that the endothelin system is involved in chlorine gas-induced lung injury.DESIGN: Experimental study.SETTING: Academic research laboratory.SUBJECTS: Twenty-four domestic juvenile pigs.INTERVENTIONS: Anesthetized, ventilated pigs were exposed to chlorine gas (400 parts per million in air) for 20 mins and then randomly allocated to four groups (n = 6 in each group). The tezosentan pretreatment group received the dual endothelin receptor antagonist tezosentan 20 mins before and hyperoxic gas (Fio2 0.6) after chlorine gas exposure. The tezosentan postinjury treatment group received hyperoxic gas after chlorine gas exposure and tezosentan 60 mins later. Animals in the oxygen group received hyperoxic gas after chlorine gas exposure. Pigs in the fourth group (air) were ventilated with room air (Fio2 0.21) throughout the experiment.MEASUREMENTS AND MAIN RESULTS: Hemodynamics, gas exchange, lung mechanics, and plasma endothelin-1 were evaluated for 6 hrs. Chlorine gas exposure induced an increase in circulating endothelin-1 by 90% (p < .05). The acute chlorine gas-induced rise in pulmonary vascular resistance was partly blocked by tezosentan pretreatment (p < .001). Tezosentan postinjury treatment also decreased pulmonary vascular resistance to levels significantly lower than in the air and oxygen groups (p < .001). Recovery of peak airway pressure was better in the tezosentan-treated groups than in the air group. There were significant linear relationships between circulating endothelin-1 and pulmonary vascular resistance (r = .47, p < .001) and endothelin-1 and peak airway pressure (r = .41, p < .001). These relationships were modified by tezosentan.CONCLUSIONS: Tezosentan modified chlorine gas-induced pulmonary dysfunction, indicating that the endothelin system is involved in this mode of acute lung injury.

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