Selective kallikrein-kinin system activation in inbred rats differentially susceptible to granulomatous enterocolitis.
OBJECTIVE
Crohn's disease is characterized by unrestrained inflammation with a genetic component. Genetic susceptibility and activation of the kalli-krein-kinin (contact) system were investigated in experimental enterocolitis and extraintestinal inflammation induced by bacterial polymers.


METHODS
Kinetics of inflammation in inbred Lewis and Buffalo rats injected subserosally with peptidoglycan-polysaccharide polymers were correlated with in vivo and in vitro activation of the contact system.


RESULTS
Lewis rats had a biphasic course of enterocolitis. Acute inflammation peaked 1 day after injection, gradually decreasing until day 14 when intestinal inflammation spontaneously reactivated and persisted for 16 weeks, accompanied by arthritis, granulomatous hepatitis, anemia, and leukocytosis. Self-limited acute enterocolitis in Buffalo rats resolved by 24 days without extraintestinal involvement. Consumption of the precursor proteins prekalli-krein and high-molecular-weight kininogen indicated activation of the plasma contact system in Lewis rats and closely correlated with chronic intestinal inflammation. Contact system activation did not occur in Buffalo rats, even during acute inflammation. In vitro studies showed a decreased rate of kininogen cleavage in Buffalo plasma.


CONCLUSIONS
Selective in vivo and in vitro activation of the contact system in susceptible Lewis rats suggests that this pathway is one determinant of genetic susceptibility to granulomatous enterocolitis and systemic complications.
Sartor
R B
RB
Department of Medicine, University of North Carolina, Chapel Hill, USA.
DeLa Cadena
R A
RA
Green
K D
KD
Stadnicki
A
A
Davis
S W
SW
Schwab
J H
JH
Adam
A A
AA
Raymond
P
P
Colman
R W
RW
D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D001168:Arthritis / Q000503:physiopathology; D004198:Disease Susceptibility; D004760:Enterocolitis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D004789:Enzyme Activation; D005260:Female; D006099:Granuloma / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D016234:Kallikrein-Kinin System; D007610:Kallikreins / Q000378:metabolism; D007704:Kininogens / Q000097:blood / Q000378:metabolism; D007705:Kinins / Q000378:metabolism; D008107:Liver Diseases / Q000503:physiopathology; D010457:Peptidoglycan; D011108:Polymers; D011134:Polysaccharides; D011288:Prekallikrein / Q000378:metabolism; D051381:Rats; D011915:Rats, Inbred BUF; D011917:Rats, Inbred Lew
D000209:Acute-Phase Proteins; D007704:Kininogens; D007705:Kinins; D010457:Peptidoglycan; D011108:Polymers; D011134:Polysaccharides; C017894:alpha 1-inhibitor 3; D011288:Prekallikrein; D007610:Kallikreins