A Comparison of α1-Proteinase Inhibitor Methoxysuccinyl-Ala-Ala-Pro-Val-Chloromethylketone and Specific β-Lactam Inhibitors in an Acute Model of Human Polymorphonuclear Leukocyte Elastase-induced Lung Hemorrhage in the Hamster
| Autor: | Donald G. Osinga, Paul E. Finke, William K. Hagmann, Philip Davies, Daniel S. Fletcher, Pam S. Dellea, Karen M. Hand, Richard A. Mumford, James B. Doherty, R. J. Bonney, Bonnie M. Ashe |
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| Rok vydání: | 1990 |
| Předmět: |
Lung Diseases
Male Pulmonary and Respiratory Medicine Neutrophils Thermolysin Hamster Hemorrhage Pharmacology Lung injury beta-Lactams Amino Acid Chloromethyl Ketones Pharmacokinetics Cricetinae medicine Animals Humans Lung Mesocricetus Pancreatic Elastase medicine.diagnostic_test biology business.industry Elastase biology.organism_classification Anti-Bacterial Agents Trachea Disease Models Animal Instillation Drug Bronchoalveolar lavage medicine.anatomical_structure Enzyme inhibitor alpha 1-Antitrypsin Immunology biology.protein business Bronchoalveolar Lavage Fluid |
| Zdroj: | American Review of Respiratory Disease. 141:672-677 |
| ISSN: | 0003-0805 |
| DOI: | 10.1164/ajrccm/141.3.672 |
| Popis: | A pharmacokinetic model is described for testing of polymorphonuclear leukocyte (PMN) elastase inhibitors administered by intratracheal or aerosol dosing of hamsters. Acute lung injury, measured as hemorrhage occurring within hours after intratracheal instillation of human PMN elastase, correlated directly with the amount of active enzyme instilled. Hemorrhage began within minutes of elastase instillation, was maximal within 1 h, and remained constant for up to 5 h subsequently. Therefore, inhibition of hemorrhage was used as an assay of the effectiveness of various PMN elastase inhibitors given by the intratracheal route. Lung hemorrhage could also be induced by intratracheal instillation of other elastolytic enzymes, such as thermolysin, and inhibition of hemorrhage was seen only with inhibitors active against the type of elastase used. Methoxysuccinyl-alanyl-alanyl-prolyl-valine-chloromethylketone (MeOSuc-AAPV-CMK), as well as alpha 1-proteinase inhibitor (alpha 1PI) but not tosyl-lysine-chloromethylketone (tosyl-lysine-CMK), inhibited the hemorrhage caused by human PMN elastase, but the specific inhibitors of this enzyme had no effect on thermolysin-induced lung hemorrhage. The duration of activity of these compounds as elastase inhibitors in this model correlated directly with the extent of their persistence in lung lavage fluid as determined by HPLC analysis of compound recovered by bronchoalveolar lavage. (ABSTRACT TRUNCATED AT 250 WORDS) |
| Databáze: | OpenAIRE |
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