Specific inhibition of plasma kallikrein modulates chronic granulomatous intestinal and systemic inflammation in genetically susceptible rats.

Abstract

The kallikrein-kinin (K-K) (contact) system is activated during acute and chronic relapsing phases of enterocolitis induced in genetically susceptible Lewis rats by intramural injection of peptidoglycan-polysaccharide (PG-APS). Using the selective plasma kallikrein inhibitor P8720, we investigate whether activation of the K-K system plays a primary role in chronic granulomatous intestinal and systemic inflammation in this model. Group I (negative control) received human serum albumin intramurally. Group II (treatment) received PG-APS intramurally and P8720 orally. Group III (positive control) received PG-APS intramurally and albumin orally. P8720 attenuated the consumption of the contact proteins, high molecular weight kininogen (P<0.03), and factor XI (P<0.04) in group II vs. group III. P8720 decreased chronic intestinal inflammation measured by blinded gross (P<0.01) and histologic (P<0.0005) scores as well as systemic complications (arthritis, splenomegaly, hepatomegaly, leukocytosis, and acute-phase reaction) (P<0.01) in group II as compared with group III. We conclude that relapsing chronic enterocolitis and systemic complications are in part due to plasma K-K system activation, and that inhibition of this pathway is a potential therapeutic approach to human inflammatory bowel disease and associated extraintestinal manifestations.

• Authors: A Stadnicki, R B Sartor, R Janardham, A Majluf-Cruz, C A Kettner, A A Adam, R W Colman
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 12 Issue 3 Pg. 325-33 (Mar 1998) ISSN: 0892-6638 [Print] United States
• PMID: 9506476 (Publication Type: Journal Article)

Chemical References

• Acute-Phase Proteins
• Boron Compounds
• Enzyme Inhibitors
• Kininogens
• Oligopeptides
• Peptidoglycan
• benzoyl-prolyl-phenylalanyl-boroarginine
• Factor XI
• Prekallikrein
• Kallikreins

Topics

• Acute-Phase Proteins (metabolism)
• Animals
• Arthritis (chemically induced, metabolism, physiopathology)
• Boron Compounds (blood, pharmacology, toxicity)
• Disease Models, Animal
• Disease Susceptibility
• Enzyme Inhibitors (pharmacology, toxicity)
• Factor XI (metabolism)
• Female
• Granulomatous Disease, Chronic (chemically induced, metabolism, pathology)
• Humans
• Inflammation
• Intestinal Diseases (chemically induced, metabolism, pathology)
• Kallikreins (antagonists & inhibitors)
• Kininogens (metabolism)
• Oligopeptides (blood, pharmacology, toxicity)
• Peptidoglycan (pharmacology)
• Prekallikrein (metabolism)
• Rats
• Rats, Inbred Lew