Bradykinin Generation Triggered by Pseudomonas Proteases Facilitates Invasion of the Systemic Circulation by Pseudomonas aeruginosa

Abstract

To elucidate the mechanism of bacterial exoprotease in promotion of the intravascular dissemination of Pseudomonas aeruginosa, we examined the possible involvement of bradykinin (whose generation is induced by pseudomonal proteases in septic foci) in the invasion by bacteria, and in access of bacterial toxins to systemic blood circulation. P. aeruginosa 621 (PA 621), which produces very little protease, was injected intraperitoneally into mice together with pseudomonal exoproteases (elastase/alkaline protease). Dissemination of bacteria from the peritoneal septic foci to the blood was assessed by counting viable bacteria in the blood and spleen by use of the colony-forming assay. The results showed that pseudomonal proteases markedly enhanced (10-to 100-fold) intravascular dissemination of bacteria in mice. This enhancement was induced not only by pseudomonal proteases but also by bradykinin. More importantly, the increased spread of PA 621 induced by pseudomonal protease and bradykinin was significantly augmented by the addition of kininase inhibitors, indicating the direct involvement of bradykinin in bacterial dissemination. Similarly, bradykinin caused effective dissemination of pseudomonal toxins such as endotoxin (lipopolysaccharide) and exotoxin A when the toxins were injected into the peritoneal cavity with bradykinin. Furthermore, the lethality of the infection with PA 621 was strongly enhanced by pseudomonal proteases given i.p. simultaneously with PA 621. On the basis of these results, it is strongly suggested that pseudomonal proteases as well as bradykinin generated in infectious foci are involved in facilitation of bacterial dissemination in vivo.

Infection-Induced Kinin B1Receptors in Human Pulmonary Fibroblasts: Role of Intact Pathogens and p38 Mitogen-Activated Protein Kinase-Dependent Signaling

“…Several factors, including tissue damage and infection, activates the generation of BK in tissues and plasma, and this occurs in infections with both gram-negative and gram-positive pathogens (Khan et al, 1993;Sakata et al, 1996;Mattsson et al, 2001). The formation of B 1 agonist through degradation of B 2 agonists is likely to occur and has been demonstrated in models of inflammation (Raymond et al, 1995) and following long-term incubation of BK on pulmonary fibroblasts (Koyama et al, 2000).…”

“…Pathogens that are involved in serious lung diseases such as cystic fibrosis (CF) can promote the generation of BK (Khan et al, 1993;Mattsson et al, 2001), and furthermore kallikrein levels have been found to be increased in the saliva of these patients (Lieberman and Littenberg, 1969). BK is involved in the bacterial dissemination of pathogens in vivo (Sakata et al, 1996), and the use of kinin receptor antagonists may be beneficial in controlling infections (Ridings et al, 1995;Heitsch, 2000). Overall, these findings suggest an important role for kinins in the initiation and maintenance of inflammation in infection.…”

Purification and Characterization of a 43-Kilodalton Extracellular Serine Proteinase from Cryptococcus neoformans

“…The identification and characterization of the C. neoformans extracellular protein is important because proteinases, esterases, and lipases are associated with virulence in other pathogens (5,10,11,12,14,20,22). C. neoformans is usually considered to be nonproteolytic (21), but a few studies have focused interest on its proteolytic activity (2,16).…”

Activation of Human Matrix Metalloproteinases by Various Bacterial Proteinases

“…Destruction of the extracellular matrix is a pathological feature often observed in septic foci in bacterial infections (43). This suggested to us that extracellular proteinases produced by pathogenic microbes may induce disintegration of the tissue via direct degradation of the extracellular matrix (47,48).…”