Endothelin-1 and acute lung injury in sheep with smoke inhalation and burn injury

Smoke inhalation injury increases the morbidity and mortality of burn patients. Studies have shown that acute lung injury (ALI) following these insults is dependent in part on inflammatory processes including increased production of nitric oxide (NO). Also obstructive casts in the airways are common findings in patients with inhalation injury. Obstructive material is composed of mucus, inflammatory cells and plasma exudate, however, no studies have examined the extent of airway obstruction after injury. Recent studies have suggested that the vasoactive peptide endothelin-1 (ET-1) is involved in airway inflammation and mucous secretion. ET-1 is known to modulate NO production. The aims of this study are to; (1) measure the degree of airway obstruction in sheep after smoke inhalation and burn injuries, (2) assess the expression of ET-1 in the lungs of sheep after inhalation injury and (3) test the hypothesis that treatment of sheep with a dual ET-1 receptor antagonist following smoke inhalation and burn (S+B) injury will decrease airway obstruction and attenuate the development of ALI. Results of these studies showed that S+B injury causes the highest degree of airway obstruction. Bronchial obstruction was maximal at 24 hours after injury. Staining for mucin subtypes showed that obstructive material in the bronchi migrated into distal airways and parenchyma with time. Statistically, a strong correlation between the degree of airway obstruction and PaO₂/FiO₂ scores was evident, r = 0.72. Assessment of ET-1 expression with immunohistochemistry in sheep after smoke inhalation injury showed increased expression in airway basal and secretory cells and airway smooth muscle. Assessment of the effects of treatment with a dual ET-1 receptor antagonist in sheep with S+B injury showed that the treated group exhibited similar levels of airway obstruction and progression to ALI. Treated animals exhibited greater degrees of lung lymph flow, with increased nitric oxide metabolites in plasma and lung lymph. These results suggest that ET-1 may not be a significant mediator of ALI. In contrast, enhanced expression of ET-1 after injury may attenuate NO production. Further studies assessing the effect of ET-1 on nitric oxide synthase expression and activity in this injury model are warranted.