Effects of a dual endothelin-1 receptor antagonist on airway obstruction and acute lung injury in sheep following smoke inhalation and burn injury

Abstract

Studies have suggested that ET-1 (endothelin-1) is associated with lung injury, airway inflammation and increased vascular permeability. In the present study we have tested the hypothesis that treatment with a dual ET-1 receptor antagonist will decrease airway obstruction and improve pulmonary function in sheep with combined S+B (smoke inhalation and burn) injury. Twelve sheep received S+B injury using the following protocol: six sheep were treated with tezosentan, an ETA and ETB receptor antagonist, and six sheep received an equivalent volume of vehicle. Physiological and morphological variables were assessed during the 48 h study period and at the end of the study. There was no statistically significant difference in the PaO2/FiO2 (partial pressure of O2 in arterial blood/fraction of O2 in the inspired gas) ratio of the tezosentan-treated animals compared with controls; however, lung lymph flow was significantly higher (P<0.05) in the treated animals. PVRI (pulmonary vascular resistance index) was significantly reduced (P<0.05) in the tezosentan-treated animals. Assessment of NOx (nitric oxide metabolite) levels in plasma and lymph showed significantly elevated (P<0.05) levels in the tezosentan-treated animals compared with levels in untreated sheep. The degree of bronchial obstruction was similar in both treated and control sheep; however, bronchiolar obstruction was reduced in sheep treated with tezosentan. Histopathologically, no difference in the degree of parenchymal injury was detected. In conclusion, administration of a dual ET-1 receptor antagonist prevented an increase in PVRI after injury and reduced the degree of bronchiolar obstruction in sheep with S+B; however, treated sheep showed higher levels of NOx and increased lung lymph flow. Tezosentan treatment was ineffective in protecting against acute lung injury in this model.

Effect of the endothelin receptor antagonist tezosentan on alpha‐naphthylthiourea‐induced lung injury in rats

“…Similarly, Cox et al. [44] found that tezosentan does not provide clear protection against ALI that was induced by smoke inhalation or burns in sheep. This suggests that the timing of intervention is important in dynamic progressive processes such as ALI.…”

Endothelin-1 Impairs Alveolar Epithelial Function via Endothelial ETB Receptor

“…ET-1 increases pulmonary microvascular pressure, causing edema formation, and several studies have suggested that ET-1 receptor inhibition has a protective effect in models of acute lung injury (12,(38)(39)(40). ET-1 is a potent vasoactive peptide released by endothelial and epithelial cells during stimuli such as shear stress, hypoxia, and inflammation (11,18,19).…”

Effect of Bronchodilators on Bronchial Gland Cell Proliferation After Inhalation and Burn Injury in Sheep

“…24 Typically, in the ovine model of inhalation injury, arterial oxygen tension begins to decrease between 12 and 24 hours after injury, and virtually all animals are receiving 100% oxygen at 48 hours after injury. 25 Sham animals received instrumentation and anesthesia without burn or inhalation injury and were studied for 48 hours. Fluid resuscitation in the sham animals was 2 ml/kg/hr.…”