Inhaled neutrophil elastase inhibitor reduces oleic acid-induced acute lung injury in rats.
BACKGROUND
Neutrophil elastases (NE) play an important role in the pathogenesis of acute lung injury (ALI). NE activities are significantly increased in serums and lungs of patients or animals with ALI. Intravenous infusion (IV) of Sivelestat, an NE inhibitor, can reduce ALI. Through inhalation, drugs reach lungs directly and in high concentration. We hypothesized that inhaled Sivelestat would alleviate oleic acid (OA)-induced ALI in rats.


METHODS
Rats were anesthetized and mechanically ventilated, and then ALI was induced by OA injection. One hour later, the animals were randomized to receive either Sivelestat (3 mg/kg/h) or saline inhalation. The effect of Sivelestat IV (3 mg/kg/h) was also investigated. All animals were ventilated and observed for 6 h.


RESULTS
OA injection increased NE activities in lung tissues and serums. The increase of NE activities in lung tissues and serums markedly reduced by 77%, and 29%, respectively, by the inhalation of Sivelestat; and 53.8%, and 80%, respectively, by Sivelestat IV. Additionally, inhaled Sivelestat resulted in ameliorated lung injury by reducing edema and infiltration of neutrophils in the lung, improved oxygenation and survival.


CONCLUSIONS
An over increased NE activity in lungs may play a vital effect in the pathogenesis of OA-induced ALI in rats. Topical application of nebulized Sivelestat, an NE inhibitor, may reduce OA-induced ALI in rats. Sivelestat inhalation can be developed as a novel treatment for ALI.
Department of Thoracic Surgery, Subei People's Hospital of Jiangsu province, Yangzhou 225001, Jiangsu, PR China.
Wei
W
Tao
Qian-Bing
QB
Miao
Ya-Bing
YB
Zhu
Yu-Sheng
YS
Shu
D055371:Acute Lung Injury / Q000139:chemically induced* / Q000188:drug therapy* / Q000201:enzymology; D000280:Administration, Inhalation; D000418:Albumins / Q000032:analysis / Q000378:metabolism; D000818:Animals; D001784:Blood Gas Analysis; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002452:Cell Count; D015633:Extravascular Lung Water / Q000187:drug effects; D005260:Female; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D007275:Injections, Intravenous; D007958:Leukocyte Count; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019301:Oleic Acid; D010047:Ovalbumin / Q000008:administration & dosage / Q000633:toxicity; D009195:Peroxidase / Q000378:metabolism; D053491:Proteinase Inhibitory Proteins, Secretory / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012710:Serum Albumin, Bovine / Q000008:administration & dosage / Q000633:toxicity; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D016019:Survival Analysis
D000418:Albumins; D053491:Proteinase Inhibitory Proteins, Secretory; D013449:Sulfonamides; D012710:Serum Albumin, Bovine; D019301:Oleic Acid; D010047:Ovalbumin; C069195:sivelestat; D009195:Peroxidase; D019272:Leukocyte Elastase; D005998:Glycine