Activation of the kallikrein-kinin system after endotoxin administration to normal human volunteers

Abstract

The objective of this study was to determine the role of the kallikrein- kinin system in healthy humans after intravenous administration of either Escherichia coli endotoxin or saline. We studied a total of 18 healthy nonsmoking volunteers, 23 to 38 years old, in an open-label study at the Critical Care Medicine Department, Clinical Center, National Institutes of Health (Bethesda, MD) in which some of the patients served as their own controls. After baseline data collection, the subjects received intravenously either E coli endotoxin (n = 15, 4 ng/kg of body weight) or saline (n = 8, controls). Signs, symptoms, systemic blood pressure, factor XII, plasma prekallikrein (PK), factor XI (FXI), antithrombin III (AT-III), high molecular weight kininogen (HK), and alpha 2-macroglobulin-kallikrein complexes were measured at baseline and 1, 2, 3, 5, and 24 hours after injection of either saline or endotoxin. After infusion of endotoxin, we found the functional plasma levels of FXI decreased at 2 hours (P < .05) and at 5 hours (P < .05). Functional PK was significantly depressed by 2 hours (P < .05), at 5 hours (P < .05), and at 24 hours (P < .01), whereas the PK antigen was only low at 5 hours (P < .05). These changes were accompanied by a significant increase in circulating alpha 2-macroglobulin-kallikrein complexes at 3 hours (P < .05) and 5 hours (P < .01). No significant changes occurred in the plasma levels of factor XII or HK. We concluded that clinical response to intravenous endotoxin in healthy human volunteers is associated with activation of the kallikrein-kinin systems. Further investigation is needed with specific inhibitors of the kallikrein-kinin system to define its primary or secondary role in the endotoxin-mediated reactions.

Early depletion of contact system in patients with sepsis: a prospective matched control observational study

“…HK levels reflect activation of the contact system over a longer time than bradykinin levels and the lower plasma HK levels found in the present sepsis patient material are in accordance with several former studies (19,20,23,24,29,40,41). Presumably, prominent contact system activation must take place to affect the levels of the end substrate of the cascade, HK, since only clinical sepsis has been shown to cause detectable HK depletion, while milder experimental human models of sepsis do not seem to alter the levels (42,43). Many studies show a correlation between the degree of contact system activation and the severity of sepsis (19-23, 29, 30, 40, 41, 44).…”

“…Procalcitonin levels were higher in sepsis patients compared to controls (p < 0.001) and levels were lower at day 4 (6 [0.57-14] ng/ml) compared to at inclusion (45 [4.3-86] ng/ml, p < 0.002; n = 11). Median total plasma protein was lower in sepsis patients (43 [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53] lg/ml) compared to controls (54 [51-56] lg/ml, p < 0.001), but was similar in survivors and nonsurvivors as well as at day 4. In the sepsis patients, blood culture was positive for Escherichia coli in five patients, Streptococcus pneumoniae in four patients, enterococcus species in three patients, enterobacter species in one patient and Pseudomonas aeruginosa in one patient.…”

Procoagulant microparticles promote coagulation in a factor XI‐dependent manner in human endotoxemia

“…Prior investigations into the activation of coagulation in endotoxemia have provided evidence for both intrinsic and extrinsic pathway participation. DeLa Cadena and colleagues demonstrated activation of the contact pathway in a human model of endotoxemia by showing decreased FXI functional activity, decreased prekallikrein (PK) antigen and activity and increased levels of a2macroglobulin-kallikrein complexes after endotoxin administration [11]. Similar findings were seen with ex vivo endotoxin treatment of whole blood in a timeand dose-dependent manner [12].…”

Bradykinin and des-Arg9-bradykinin metabolic pathways and kinetics of activation of human plasma

“…First, it allows a more physiological understanding of the plasma metabolism of BK and des-Arg 9 -BK than that obtained by spiking serum with exogenous BK, even at a nanomolar concentration. Second, it could allow new insights into the role of in vivo activation of the contact system in different pathophysiological conditions where its involvement is suspected (14,27). To do that we activated the plasma with glass beads, a process that has been reported to be efficient in triggering the contact system (23).…”

“…The kinetic measurement of endogenous BK and of des-Arg 9 -BK during plasma activation will be particularly interesting in this latter case. Finally, the kinetic release of BK from endogenous HK and its metabolism to des-Arg 9 -BK could open a new area of research to reassess the role of endogenous kinins in different pathological states (14,27), where activation of the contact system of plasma has been documented.…”