Phosphoramidon, an endothelin-converting enzyme inhibitor, attenuates lipopolysaccharide-induced acute lung injury.
Phosphoramidon blocks the formation of endothelin-1 (ET-1), a proinflammatory mediator implicated in the pathogenesis of a variety of lung diseases. To determine whether phosphoramidon can ameliorate pulmonary inflammation, our laboratory undertook a series of experiments involving treatment of hamsters with either intraperitoneal (i.p.) or aerosolized phosphoramidon prior to induction of acute lung injury by intratracheal administration of lipopolysaccharide (LPS). The results indicate that phosphoramidon significantly reduces LPS-induced pulmonary inflammation as measured by lung histology, neutrophil content of bronchoalveolar lavage (BAL) fluid, percent tumor necrosis factor receptor 1 (TNFR1)-labeled BAL macrophages, and alveolar septal cell apoptosis. In additional experiments, i.p. administration of a novel endothelin A receptor anatgonist (HJP272) similarly decreased BAL neutrophils, whereas i.p. administration of either ET-1, or its precursor peptide, "big" ET-1, had the opposite effect. These findings support further evaluation of phosphoramidon and other ET-1 suppressors as potential treatments for human inflammatory lung disease.
Bhavsar
Tapan M
TM
School of Pharmacy and Allied Health Sciences, St. John's University, New York, New York, USA.
Cerreta
Joseph M
JM
Liu
Ming
M
Reznik
Sandra E
SE
Cantor
Jerome O
JO
D000818:Animals; D017209:Apoptosis; D006224:Cricetinae; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D006020:Glycopeptides / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008647:Mesocricetus; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000032:analysis; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000188:drug therapy*
D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D006020:Glycopeptides; D008070:Lipopolysaccharides; D047888:Receptors, Tumor Necrosis Factor, Type I; C008890:phosphoramidon