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Specific inhibition of plasma kallikrein modulates chronic granulomatous intestinal and systemic inflammation in genetically susceptible rats
Author(s) -
Stadnicki Antoni,
Sartor R. Balfour,
Janardham Ram,
MajlufCRUZ Abraham,
Kettner Charles A.,
Adam Albert A.,
Colman Robert W.
Publication year - 1998
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.12.3.325
Subject(s) - inflammation , systemic inflammation , kallikrein , granulomatous inflammation , immunology , biology , medicine , pathology , biochemistry , enzyme
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 peptidogly‐can‐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.—Stadnicki, A., Sartor, R. B., Janardham, R., Majluf‐Cruz, A., Kettner, C. A., Adam, A. A., Colman, R. W. Specific inhibition of plasma kallikrein modulates chronic granulomatous intestinal and systemic inflammation in genetically susceptible rats. FASEB J. 12, 325–333 (1998)