Inhaled neutrophil elastase inhibitor reduces oleic acid-induced acute lung injury in rats

Abstract Rationale 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 inhalat...

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Published in:Pulmonary pharmacology & therapeutics 2012-02, Vol.25 (1), p.99-103
Main Authors: Tao, Wei, Miao, Qian-Bing, Zhu, Ya-Bing, Shu, Yu-Sheng
Format: Article
Language:English
Subjects:
Acute lung injury
Acute Lung Injury - chemically induced
Acute Lung Injury - drug therapy
Acute Lung Injury - enzymology
Administration, Inhalation
Albumins - analysis
Albumins - metabolism
Animals
Blood Gas Analysis
Bronchoalveolar Lavage Fluid - chemistry
Bronchoalveolar Lavage Fluid - cytology
Cell Count
Extravascular Lung Water - drug effects
Female
Glycine - administration & dosage
Glycine - analogs & derivatives
Glycine - pharmacology
Inhalation
Injections, Intravenous
Leukocyte Count
Leukocyte Elastase - antagonists & inhibitors
Leukocyte Elastase - metabolism
Medical Education
Neutrophil elastase
Oleic Acid
Ovalbumin - administration & dosage
Ovalbumin - toxicity
Peroxidase - metabolism
Proteinase Inhibitory Proteins, Secretory - administration & dosage
Proteinase Inhibitory Proteins, Secretory - pharmacology
Pulmonary/Respiratory
Rats
Rats, Sprague-Dawley
Serum Albumin, Bovine - administration & dosage
Serum Albumin, Bovine - toxicity
Sivelestat
Sulfonamides - administration & dosage
Sulfonamides - pharmacology
Survival Analysis
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Summary:Abstract Rationale 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.
ISSN:1094-5539
1522-9629
DOI:10.1016/j.pupt.2011.12.006