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Induction of Vascular Leakage and Blood Pressure Lowering through Kinin Release by a Serine Proteinase from Aeromonas sobria¹

Takahisa Imamura^2,*, Hidemoto Kobayashi, Rasel Khan, Hidetoshi Nitta^*, and Keinosuke Okamoto

^* Department of Molecular Pathology and Department of Gastroenterological Surgery, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; and Faculty of Pharmaceutical Sciences, Okayama University, Okayama, Japan

Aeromonas sobria causes septic shock, a condition associated with high mortality. To study the mechanism of septic shock by A. sobria infection, we examined the vascular leakage (VL) activity of A. sobria serine proteinase (ASP), a serine proteinase secreted by this pathogen. Proteolytically active ASP induced VL mainly in a bradykinin (BK) B₂ receptor-, and partially in a histamine-H₁ receptor-dependent manner in guinea pig skin. The ASP VL activity peaked at 10 min to 1.8-fold of the initial activity with an increased BK B₂ receptor dependency, and attenuated almost completely within 30 min. ASP produced VL activity from human plasma apparently through kallikrein/kinin system activation, suggesting that ASP can generate kinin in humans. Consistent with the finding that a major part of the ASP-induced VL was reduced by a potent kallikrein inhibitor, soybean trypsin inhibitor that does not affect ASP enzymatic activity, ASP activated prekallikrein but not factor XII to generate kallikrein in a dose- and incubation time-dependent manner. ASP produced more VL activity directly from human low m.w. kininogen than high m.w. kininogen when both were used at their normal plasma concentrations. Intra-arterial injection of ASP into guinea pigs lowered blood pressure specifically via the BK B₂ receptor. These data suggest that ASP induces VL through prekallikrein activation and direct kinin release from kininogens, which is a previously undescribed mechanism of A. sobria virulence and could be associated with the induction of septic shock by infection with this bacterium. ASP-specific inhibitors, and kinin receptor antagonists, might prove useful for the treatment or prevention of this fatal disease.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by a grant from the Japanese Ministry of Education and Science (Grant 16590319; to T.I.).

² Address correspondence and reprint requests to Dr. Takahisa Imamura, Department of Molecular Pathology, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan. E-mail address: taka{at}kaiju.medic.kumamoto-u.ac.jp

³ Abbreviations used in this paper: BK, bradykinin; HK, high m.w. kininogen; VL, vascular leakage; LK, low m.w. kininogen; ASP, Aeromonas sobria serine proteinase; BP, blood pressure; SBTI, soybean trypsin inhibitor; DFP, diisopropyl fluorophosphate; ScpA, staphopain A.

This article has been cited by other articles:

				H. Nitta, T. Imamura, Y. Wada, A. Irie, H. Kobayashi, K. Okamoto, and H. Baba Production of C5a by ASP, a Serine Protease Released from Aeromonas sobria J. Immunol., September 1, 2008; 181(5): 3602 - 3608. [Abstract] [Full Text] [PDF]