Kinin generating cascade

Matsumra Y, Kimura M, Yamamoto T, et al. Involvement of the kinin-generating cascade in enhanced vascular permeability in tumor tissue. Jpn J Cancer Res 1988 79 1327-1334. 

Matsumura Y, Maruo K, Kimura M, Yamamoto T, Konno T, Maeda H. Kinin-generating cascade in advanced cancer patients and in vitro study. Jpn J Cancer Res 1991 82 732-741. 

Figure 4, Kinin generating cascade and various vascular mediators in cancer tissues affecting the EPR effect. Mediators, enzymes, and inhibitors are shown. See text for details. M, macrophage PMN, polymorphoneuclear cells COXs, cyclooxygenases PCs, prostaglandins. SBTl, soybean trypsin inhibitor (Kunitz type) ONOO", peroxynitrite NO, nitric oxid MMP, matrix metalloproteinases.

There were several data showing that vascular permeability occurred at the site of inflammation such as bacterial infection and was caused by bacterial proteases, which activate an endogenous kinin-generating cascade. Kinin is the most potent vascular permeability factor in the bodyl... 

Fig. 2. A diagrammatic representation of the piasma kinin-forming cascade indicating the steps inhibitabie by Cl iNH. Aii functions of factor Xiia and kaiiikrein are affected. The iower figure indicates that further digestion of factor Xiia by kaiiikrein and piasmin generates factor Xii fragment (Xiif), which is an initiator of the compiement cascade. Both factor Xiif and Cl are inhibited by Cl iNH.

We demonstrated that BK is an important mediator of EPR effect in cancer [36]. Figure 5 shows network of BK and other mediators involving in EPR effect. BK interacts with various proinflammatory factors involving vascular permeability. For instance, it is also known to activate endothelial cell-type nitric oxide synthase (eNOS), which is one of the primary enzymes to produce NO from L-arginine. We have reported that the BK-generating cascade is activated in tumor tissues [36]. More importantly, malignant ascetic and pleural fluids would be caused by activation of kallikrein-kinin system in carcinomatosis [37]. 

Then we h othesized that both lesions, tumorous and inflammatory, shared a common cascade of kinin generation. In fact, we succeeded in purifying two types of kinin from the ascitic fluid of a patient with gastric cancer by gel filtration and reversed phase high-performance liquid chromatography (Fig.3). 

An immediate reaction occurs within seconds to minutes, resulting in the rapid release of preformed mediators and newly generated mediators from the arachidonic acid cascade. Mediators of immediate hypersensitivity include histamine, leukotrienes, prostaglandin, tryptase, and kinins. These mediators cause vasodilation, increased vascular permeability, and production of nasal secretions. Histamine produces rhinorrhea, itching, sneezing, and nasal obstruction. 

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