title: Alpha-2-macroglobulin as the major defence in acute pseudomonal septic shock in the guinea-pig model.
abstract: An intravenous injection of 1.2 mg/kg of Pseudomonas aeruginosa elastase induces immediate lethal shock in guinea-pigs. In the present study, alpha-2-macroglobulin (alpha 2M) was shown to be the major factor in guinea-pig plasma that inhibits the enzymatic activity of elastase in vitro. Depletion of circulating alpha 2M by injecting anti-guinea-pig alpha 2M rabbit IgG F(ab')2 rendered the animals sensitive to a dose of elastase of 0.05 mg/kg. When the alpha 2M-depleted guinea-pigs were reconstituted with human alpha 2M, this sensitivity was reversed. Lethal shock did not occur in alpha 2M-depleted animals even at an elastase dose of 0.2 mg/kg when Hageman factor was simultaneously depleted, indicating that elastase induces shock through activation of the Hageman factor-dependent system. Similar results were obtained when the culture supernatants of an elastase-producing strain, IFO-3455, were used instead of the purified elastase, whereas no cardiovascular changes occurred, even in the alpha 2M-depleted guinea-pigs, when the culture supernatants were pretreated with an elastase specific inhibitor (zincov) or when the culture supernatants of an elastase non-producing strain, PA-103 were used.
authors.affiliation: Department of Neuroscience and Immunology, Graduate School of Medical Sciences, Kumamoto University, Japan.
authors.forename: M M
authors.initials: MM
authors.lastname: Khan
authors.forename: Y
authors.initials: Y
authors.lastname: Shibuya
authors.forename: T
authors.initials: T
authors.lastname: Nakagaki
authors.forename: T
authors.initials: T
authors.lastname: Kambara
authors.forename: T
authors.initials: T
authors.lastname: Yamamoto
mesh_terms: D000208:Acute Disease; D000818:Animals; D002474:Cell-Free System; D004195:Disease Models, Animal; D005174:Factor XII / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D008297:Male; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D011552:Pseudomonas Infections / Q000097:blood*; D012772:Shock, Septic / Q000097:blood* / Q000139:chemically induced; D000511:alpha-Macroglobulins / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*
chemical_list: D000511:alpha-Macroglobulins; D005174:Factor XII; D010196:Pancreatic Elastase