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Vascular permeability enhancement by Vibrio mimicus protease and the mechanisms of action
M A Chowdhury1, S Miyoshi, S Shinoda
1Faculty of Pharmaceutical Sciences, Okayama University, Japan.
Abstract:
Vibrio mimicus, a causative agent of gastroenteritis, has also been reported to attribute to extraintestinal infections. Recently we have purified a metalloprotease produced by the pathogen: however, the role of the protease in V. mimicus infection has not been documented. The V. mimicus protease (VMP) was found to enhance vascular permeability and form edema when injected into the dorsal skin of guinea pig and rat. The permeability enhancement by VMP was observed in a dose-dependent manner in both guinea pig and rat skin. In guinea pig, an inhibitor of the angiotensin-converting enzyme was found to augment the permeability enhancement reaction. The permeability enhancement was significantly blocked by soybean trypsin inhibitor (SBTI), an inhibitor of plasma kallikrein reaction. In vitro conversion of plasma prekallikrein to kallikrein by VMP was also noted. In rat skin, the permeability enhancement reaction was not blocked by antihistamine or SBTI. However, the reaction was partially blocked when a mixture of antihistamine and SBTI was administered with VMP. It is apparent from the study that in guinea pig skin, VMP enhances vascular permeability through activation of plasma kallikrein-kinin system which generates bradykinin, whereas in addition to the activation of plasma kallikrein-kinin cascade in the case of rat, stimulation of histamine release from mast cells and other unknown mechanism seem to be also a cause of the permeability enhancement reaction. These results suggest that VMP may play a role in extraintestinal infections with edema caused by the pathogen.
Insights
The Vibrio mimicus protease (VMP) causes edema by increasing vascular permeability. In guinea pigs, VMP activates the plasma kallikrein-kinin system, while in rats, it activates this system and releases histamine.
Area of Science:
- Microbiology
- Pathogen Research
- Biochemistry
Background:
- Vibrio mimicus is a known cause of gastroenteritis and can lead to extraintestinal infections.
- A metalloprotease produced by V. mimicus (VMP) was recently purified.
- The specific role of VMP in V. mimicus infections, particularly in extraintestinal manifestations, remained uncharacterized.
Purpose of the Study:
- To investigate the role of the purified Vibrio mimicus protease (VMP) in vascular permeability and edema formation.
- To elucidate the mechanisms underlying VMP-induced vascular permeability in different animal models.
- To determine the potential contribution of VMP to the pathogenesis of extraintestinal Vibrio mimicus infections.
Main Methods:
- Intradermal injection of purified VMP into guinea pig and rat skin to assess vascular permeability and edema formation.
- Dose-response analysis of VMP's effect on vascular permeability.
- Administration of inhibitors, including angiotensin-converting enzyme inhibitor, soybean trypsin inhibitor (SBTI), and antihistamine, to investigate the mechanisms involved.
- In vitro assessment of VMP's ability to convert plasma prekallikrein to kallikrein.
Main Results:
- VMP significantly enhanced vascular permeability and induced edema in a dose-dependent manner in both guinea pig and rat skin.
- In guinea pigs, VMP-induced permeability was augmented by an angiotensin-converting enzyme inhibitor and blocked by SBTI, indicating plasma kallikrein-kinin system activation.
- In vitro studies confirmed VMP's capacity to activate plasma prekallikrein to kallikrein.
- In rats, VMP-induced permeability was not fully blocked by SBTI or antihistamine alone but was partially inhibited by a combination, suggesting both plasma kallikrein-kinin system activation and histamine release or other mechanisms.
Conclusions:
- Vibrio mimicus protease (VMP) plays a significant role in enhancing vascular permeability and causing edema.
- In guinea pigs, VMP primarily acts through the activation of the plasma kallikrein-kinin system, leading to bradykinin generation.
- In rats, VMP-induced permeability involves the activation of the plasma kallikrein-kinin system, alongside histamine release and potentially other pathways.
- These findings suggest that VMP is a key virulence factor contributing to edema formation in extraintestinal Vibrio mimicus infections.