Bradykinin and nitric oxide in infectious disease and cancer

Hiroshi Maeda, Takaaki Akaike, Jun Wu, Yoichiro Noguchi, Yoshifumi Sakata

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Vascular pathophysiology at the sites of bacterial infection and cancerous tissues share numerous common events similar to inflammatory tissue. Among them enhanced vascular permeability is the universal and hallmark event mediated by bradykinin. All 16 or more bacterial or fungal proteases we have examined activated one or more steps of the kinin generating Hageman-factor-kallikrein cascade. In the meantime, most of the microbial proteases rapidly inactivated various plasma inhibitors such as α1-protease inhibitor and α2-macroglobulin. In addition to the extracellular proteases, bacterial cell wall components (negatively charged LPS) of gram-negative bacteria and teichoic acid moieties of gram-positive bacteria activate the Hageman-factor-kallikrein system and exert hypotensive effects via kinin generation. Endotoxin (LPS) also induces nitric oxide synthase (NOS) which appears to exhibit a rather slow, but significant, effect in relaxing the vascular tone of the infected animal (thus hypotension). Furthermore, bacterial proteases can activate the matrix metalloproteinase (collagenase) resulting in exacerbation of tissue injury in the diseased animal. Many tumor cells or tissues excrete plasminogen activator, and hence activate plasminogen. The plasmin thus generated activates procollagenases, as well as the Hageman-factor-kallikrein system, resulting in pronounced extravasation. Fluid accumulation in pleural and ascitic carcinomatoses is largely due to the activated bradykinin-generating system. We can also demonstrate and control enhanced vascular permeability using kallikrein inhibitors, especially the polymer-conjugated soybean trypsin inhibitor which exhibits a prolonged plasma t( 1/4 ), kinin antagonists, NOS inhibitors, NO scavengers, inhibitors of prostaglandins and others. Bacterial proteases induce shock in mice which can be prevented by the soybean trypsin inhibitor by blocking the kallikrein-kinin cascade. Therapeutic use of kinin antagonists and a kallikrein inhibitor has been made for infectious diseases such as septicemia and in tumor pathology.

Original languageEnglish
Pages (from-to)222-230
Number of pages9
JournalImmunopharmacology
Volume33
Issue number1-3
DOIs
Publication statusPublished - 1996 Jun
Externally publishedYes

Keywords

  • Hageman factor
  • bacterial dissemination
  • bacterial infection
  • bradykinin
  • hypotension
  • kallikrein cascade
  • shock
  • tumor ascites
  • vascular permeability

ASJC Scopus subject areas

  • Pharmacology

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