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

Robert A. Cox, Perenlei Enkhabaatar, Ann S. Burke, Jiro Katahira, Katahiro Shimoda, Abhijit Chandra, Lillian D. Traber, David N. Herndon, Hal K. Hawkins, Daniel L. Traber

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Abstract

Studies have suggested that ET-I (endothelin-I) 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-I 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 PaO 2/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-I 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.

Original languageEnglish (US)
Pages (from-to)265-272
Number of pages8
JournalClinical Science
Volume108
Issue number3
DOIs
StatePublished - Mar 1 2005

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Keywords

  • Acute lung injury
  • Airway obstruction
  • Endothelin-1
  • Inflammation
  • Mucous secretion
  • Nitric oxide
  • Tezosentan

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Cox, R. A., Enkhabaatar, P., Burke, A. S., Katahira, J., Shimoda, K., Chandra, A., Traber, L. D., Herndon, D. N., Hawkins, H. K., & Traber, D. L. (2005). Effects of a dual endothelin-I receptor antagonist on airway obstruction and acute lung injury in sheep following smoke inhalation and burn injury. Clinical Science, 108(3), 265-272. https://doi.org/10.1042/CS20040191