[High molecular weight kininogen in inflammation and angiogenesis: a review of its properties and therapeutic applications].
The plasma kallikrein-kinin system (KKS) participates in the pathogenesis of inflammatory reactions involved in cellular injury, coagulation, fibrinolysis, kinin formation, complement activation, cytokine secretion and release of proteases. It has been shown that KKS activation in the systemic inflammatory response syndrome results in decrease of its component plasma proteins. Similar changes have been documented in diabetes, sepsis, children with vasculitis, allograft rejection, disseminated intravascular coagulation, patients with recurrent pregnancy losses, hereditary angioedema, adult respiratory distress syndrome and coronary artery disease. Direct involvement of the KKS in the pathogenesis of experimental acute arthritis and acute and chronic enterocolitis has been documented by previous studies from our laboratory using experimental animal models. It has been found that in HK deficient Lewis rats, experimental IBD was much less severe. We showed a genetic difference in kininogen structure between resistant Buffalo and susceptible Lewis rats, which results in accelerated cleavage of HK and it is responsible for the susceptibility to the inflammatory process in the Lewis rats. It has been demostrated that therapy with a specific plasma kallikrein inhibitor (P8720) modulated the experimental enterocolitis, arthritis and systemic inflammation. Furthermore, it has been shown that a bradykinin 2 receptor (B2R) antagonist attenuates the inflammatory changes in the same animal model. We have showed that a monoclonal antibody targeting HK decreases angiogenesis and arrests tumor growth in a syngeneic animal model. In summary, these results indicate that the plasma KKS plays a central role in the pathogenesis of chronic intestinal inflammation, arthritis and angiogenesis.
Isordia-Salas
Irma
I
The Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA. irmaisordia@yahoo.com.mx
Sainz
Irma M
IM
Pixley
Robin A
RA
Martínez-Murillo
Carlos
C
Colman
Robert W
RW
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D016918:Arthritis, Reactive / Q000503:physiopathology; D001896:Boron Compounds / Q000627:therapeutic use; D002448:Cell Adhesion / Q000502:physiology; D005342:Fibrinolysis / Q000502:physiology; D020022:Genetic Predisposition to Disease; D007249:Inflammation / Q000503:physiopathology; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000503:physiopathology; D016234:Kallikrein-Kinin System / Q000502:physiology*; D019679:Kininogen, High-Molecular-Weight / Q000096:biosynthesis / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009842:Oligopeptides / Q000627:therapeutic use; D010457:Peptidoglycan / Q000633:toxicity; D011135:Polysaccharides, Bacterial / Q000633:toxicity; D051381:Rats; D011915:Rats, Inbred BUF; D011917:Rats, Inbred Lew; D013329:Structure-Activity Relationship
D000911:Antibodies, Monoclonal; D001896:Boron Compounds; D019679:Kininogen, High-Molecular-Weight; D009842:Oligopeptides; D010457:Peptidoglycan; D011135:Polysaccharides, Bacterial; C099457:benzoyl-prolyl-phenylalanyl-boroarginine