Kinins and nitric oxide in patients with chronic chagas disease and systemic arterial hypertension.

BACKGROUND: Chronic Chagas disease (CCHD) associated with Systemic Arterial Hypertension (SAH) is frequently found in areas where the disease is endemic. The pathogenesis of patients with both pathologies (CCHD-SAH) is unsettled. Nitric Oxide (NO) and Kinins are important players in the myocardial inflammation process in experimental CCHD. No previous study has addressed this question in patients with CCHD, particularly in those with CCHD-SAH. Accordingly, this study was undertaken in an attempt to contribute to the understanding of the pathogenesis of patients with CCHD-SAH. METHODS: Thirty-seven patients with a positive serology for Chagas disease were enrolled; 15 had CCHD alone, 22 had CCHD-SAH (abnormal ECG/Doppler echocardiogram plus a systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg on admission), and 11 had SAH alone. Thirty healthy individuals matched by age and sex served as controls. Plasma High-molecular (Hkg) and low-molecular weight (LKg) kininogens, plasma kallikrein levels (Pkal and Tcal), Kininase II, and plasma NO were measured. RESULTS: HKg and LKg were lower in CCHD-SAH patients in comparison with other groups (P < .0001). Pkal and Tcal were higher in CCHD-SAH patients in comparison with the other groups (P< .0001). Kininase II levels were similar in SAH, CCHD, and CCHD-SAH patients, but lower in comparison with controls (P< .0001). NO levels were similar in CCHD and CCHD-SAH patients, but higher in comparison with SAH patients and controls (P > .0001). CONCLUSION: Such findings suggest increased Kinin and NO activity in patients with CCHD-SAH, thus contributing to the understanding of the pathogenesis of this condition.

[Kallikrein-Kinin System. Long History and Present. (To 90th Anniversary of Discovery of the System)].

The kallikrein-kinin system (KKS) is the key proteolytic system participating in control of a wide spectrum of physiological functions and the development of many pathological conditions. This explains great interest in structures, functions and molecular biology of separate components of the system, molecular mechanisms of their interaction and relationship with other regulatory systems. The information in this field for the last two decades clarifies the role of KKS in morphogenesis of cells, regulation of smooth muscular contractility of some organs, decrease of blood pressure, increase of vascular permeability, the development of inflammation, transformation of cells and the other functions of both physiological and pathological processes. Essential progress in understanding of functions KKS was made by the discovery and study of bradykinin receptors, cloning of kininogen and kallikrein encoding genes, revealing of domain structure of kininogen, prekallikrein and some kininases and decoding of mechanisms of contact phase of proteolytic system activation in blood plasma.

C1-inhibitor polymers activate the FXII-dependent kallikrein-kinin system: Implication for a role in hereditary angioedema.

BACKGROUND: The FXII-dependent kallikrein-kinin system (KKS) is tightly regulated by the serine protease inhibitor (serpin) C1-inhibitor (C1-inh). When regulation of the FXII-dependent KKS fails, which is the case in hereditary angioedema (HAE), patients consequently experience invalidating edema attacks. HAE is caused by mutations in the C1-inh encoding gene, and we recently demonstrated that some mutations give rise to the presence of polymerized C1-inh in the plasma of HAE patients. METHODS: C1-inh polymers corresponding to the size of polymers observed in vivo were produced using heat denaturation and gel filtration. The ability of these polymers to facilitate FXII activation was assessed in vitro in an FXII activation bandshift assay. After spiking of plasma with C1-inh polymers, kallikrein generation was analyzed in a global kallikrein generation method. Prekallikrein consumption in the entire Danish HAE cohort was analyzed using an ELISA method. RESULTS: C1-inh polymers mediated FXII activation, and a dose dependent kallikrein generation in plasma spiked with C1-inh polymers. An increased (pre)kallikrein consumption was observed in plasma samples from HAE patients presenting with C1-inh polymers in vivo. CONCLUSION: Polymerization of the C1-inh transforms the major inhibitor of the FXII-dependent KKS, into a potent activator of the very same system. GENERAL SIGNIFICANCE: The C1-inh polymers might play a role in the pathophysiology of HAE, but several diseases are characterized by the presence of serpin polymers. The role of serpin polymers has so far remained elusive, but our results indicate that such polymers can play a role as inflammatory mediators through the FXII-dependent KKS.

[Biological investigation of kinin-mediated angioedema]. / Exploration biologique des angiœdèmes à kinines.

Kinin-mediated angioedema results from accumulation of kinins, vasoactive and vasopermeant peptides, on the vascular endothelium. The disease is characterized by sudden episodes of swelling in the subcutaneous and submucosal tissues; the edema may occur spontaneously or it may be precipitated by triggering factors such as physical or emotional stress, or certain medicines. The characterization of kinin formation and catabolism systems helps improve knowledge of the aetiopathogenic mechanisms involved and provides the basis for classification of kinin-mediated angioedema conditions; thus, we may distinguish between angioedema with C1 inhibitor deficiency, whether inherited or acquired, and angioedema with normal C1 inhibitor activity, associated with increased kinin-forming activity or deficiency in kinin catabolism enzymes. In support of the clinical diagnosis, the physician may request laboratory investigation for a functional and molecular definition of the disease. Laboratory diagnosis is based on the characterization of: (1) kinin production control by C1 inhibitor investigation (function, antigen levels and circulating species); (2) kinin production (kininogenase activity, kininogen cleavage species); and (3) kinin catabolism enzymes (aminopeptidase P, carboxypeptidase N, angiotensin-I converting enzyme and dipeptidyl peptidase IV). An abnormal biological phenotype is supported by examination of susceptibility genes (SERPING1, F12 and XPNPEP2) and mutation segregation in the families.

[Cerebral blood flow and damage markers during ischemia/reperfusion of brain against a background of modulation of the kinin system's activity].

Cerebral hemodynamics' status under condition of experimental ischemia and following reperfusion of brain against a background of pharmacological modulation of kinins' formation, the kinin system's inhibition and depression of kinins' disruption was investigated by the method of hydrogenous clearance. The brain damage intensity during hypoperfusion of reperfusion period was measured by analyzing its damage markers. It was determined that the activation of kinins' formation by tripsin has a detrimental effect during ischemia/reperfusion of brain, producing an early development of hypoperfusion in reperfusion period, aggravating a brain damage. The depression of kinins' disruption by ACE-inhibitors leads to superfluous decreasing of local cerebral blood flow during hypoperfusion of reperfusion period. The inhibition of kinins' formation by contrykal improves the flow of reperfusion period, preventing the appearance of hypoperfusion and decreasing the brain damage intensity in comparison with a control group. On the whole an activation of the kinin system during ischemia/reperfusion of brain plays mostly pathogenetic role making worse the flow of reperfusion period and aggravating a brain damage.

Coagulation factor XIIa-kinin-mediated contribution to hypertension of chronic kidney disease.

BACKGROUND: Activated coagulation Factor XII (FXIIa) infusion increases peripheral resistance (TPR) and mean arterial pressure (MAP) of Brown Norway but not plasma kininogen deficient Brown Norway Katholiek (BNK) rats. FXIIa concentrations are elevated in hypertensive end-stage renal disease patients receiving conventional haemodialysis (CHD). Conversion to nocturnal haemodialysis (NHD) lowers peripheral resistance and MAP. OBJECTIVE: To determine whether the plasma coagulation FXIIa-kallikrein-kinin axis contributes to the hypertension of chronic kidney disease (CKD). METHODS: Plasma FXIIa and haemodynamic data were acquired in 11 CHD patients before and after 2 months of NHD. Cardiac and systemic haemodynamics of Brown Norway and BNK rats rendered hypertensive and uremic by 5/6 nephrectomy (NX) were determined before and after acute FXIIa inhibition. RESULTS: FXIIa was increased three-fold in CHD patients relative to control plasma (P < 0.05). After conversion to NHD, both ΔMAP and ΔTPR correlated with ΔFXIIa. In rats, plasma FXIIa was three-fold higher in both NX groups than respective SHAM controls (all P < 0.05), but MAP (147 ± 4 vs. 133 ± 2 mmHg; P < 0.05) and TPR (2.8 ± 0.2 vs. 2.3 ± 0.2 units; P < 0.05) were greater in Brown Norway NX (n = 16) than in BNK (n = 15) NX rats. FXIIa correlated with MAP only in Brown Norway NX, and plasma catecholamines were increased relative to SHAM only in Brown Norway NX (P < 0.05). In Brown Norway NX rats, FXIIa inhibitor infusion decreased MAP (-12 mmHg) and TPR (-0.5 Units) (both P < 0.05), and halved catecholamines (P < 0.05). No such changes occurred in BNK NX rats. CONCLUSION: FXIIa-kininogen mediated vasoconstriction contributes significantly to CKD hypertension in Brown Norway rats; this novel mechanism may be active in humans with CKD.

Characterization of the kallikrein-kinin system, metalloproteinases, and their tissue inhibitors in the in-stent restenosis after peripheral percutaneous angioplasty.

BACKGROUND: The kallikrein-kinin system (KKS) has several direct and indirect effects on cells and cellular mediators involved in the inflammatory process. Studies about inflammation on percutaneous transluminal angioplasty with stent (PTA/stent) to treat peripheral arterial disease (PAD) in humans are scarce. The matrix metalloproteinases (MMPs) are calcium-dependent zinc-containing endopeptidases expressed in various cells and tissues such as fibroblasts, inflammatory cells, and, smooth muscle cells. Changes in the extracellular matrix (ECM) take place in the pathogenesis of many cardiovascular pathologies. MMPs and their inhibitors (tissue inhibitors of metalloproteinases [TIMPs]) are crucial in ECM remodeling in both physiologic and pathologic conditions. The aim of this study was to evaluate the role of the KKS and the MMP metabolism, which are important mediators that may contribute to tissue repair, in the process of arterial restenosis due to intimal hyperplasia in the femoropopliteal segment with the aim of developing new interventions. METHODS: Thirty-nine consecutive patients were selected (regardless of ethnic group, age, or sex) for revascularization, who underwent PTA/stent of the femoropopliteal segment. Twenty-five patients with the same clinical characteristics who were scheduled for diagnostic angiography but not subjected to PTA/nitinol stent were also selected. The concentrations in blood of total and kininogen fractions were evaluated using immunoenzymatic methods. Plasma kallikrein was evaluated by the colorimetric method. Tissue kallikrein was evaluated by the spectrophotometric method. The activity of kininase II was measured by fluorometric analysis. Quantification of MMPs was performed by zymography, which is an electrophoresis technique, and TIMPs were measured by enzyme-linked immunosorbent assay. RESULTS: Among the 31 patients who completed the survey, there were 10 cases of angiographically defined restenosis of >50%, and 21 cases without restenosis. There was an increase in the concentrations of the substrates (high-molecular-weight kininogens and lower molecular weight kininogens) and enzymes (plasma and tissue kallikrein) in patients with restenosis, indicating activation of this inflammatory pathway in these patients. The activity of kininase II was not significantly different between the groups of patients studied. There were no statistical differences between restenosis and no restenosis patients for both MMPs and TIMPs dosage, but there is an upward trend of MMPs in time 6 months in patients with restenosis. CONCLUSIONS: With the aim of identifying factors contributing to restenosis after endovascular intervention, this study showed evidence of high activation of the KKS in the pathologic inflammatory process of PTA/stent restenosis. In the other hand, it could not show participation of metalloproteinase metabolism in PTA/stent restenosis.

[The role of endothelial dysfunction in the pathogenesis of non-inflammatory form of chronic abacterial prostatitis].

The evaluation of some indicators of blood proteolytic systems and their role in the development of endothelial dysfunction in noninflammatory form of chronic prostatitis abacterial (CAP III B) was performed. The association between the activity of blood proteolytic systems and endothelial damage in patients with CAP III B was examined. Indicators of blood kallikrein-kinin system and renin-angiotensin system (activity of kallikrein, alpha1-proteinase inhibitor, alpha2-macroglobulin, total argininesterase activity, activity of angiotensin converting enzyme, prekallikrein content) were evaluated in 32 patients with CAP III B before and after occlusive bronchial test. It was established that a violation of endothelium-dependent vasodilation is accompanied by an imbalance of pro- and antiproteolitic blood systems.

[Unilateral renal denervation and the renal kallikrein-bradykinin system in the rat]. / La dénervation rénale unilatérale et le système kallikréine-bradykinine rénal chez le rat.

AIM: The antihypertensive effect of renal denervation in hypertensive patients is partially explained by increased tubular natriuresis. To study the possible contribution of the kallikrein-kinin system (KKS) to this natriuretic effect in rats, we measured kallikrein activity (KA) and bradykinin concentrations (BK) in plasma and tissues. METHODS: To measure KA, we adapted and validated an enzymatic assay that cleaves para-nitroaniline (pNA) from the tripeptide H-D-Pro-Phe-Arg-pNA. The coefficients of variation (CV) within- and between-assays were less than 8% for plasma and tissue KA (plasma n=6 and 13; tissue n=4). Linear results for serially diluted samples confirmed the assay specificity. Tissue BK determinations were based on an established assay for plasma BK: tissue was homogenized and kinins extracted in ethanol, and BK was isolated by high-performance (HPLC) liquid chromatography and quantitated by radioimmunassay. Within- and between-assay CV for plasma BK were 18% (n=8 and n=35, respectively) and for BK in various tissues less than 16% (n=5-8). RESULTS: In male Wistar rats (n=3), plasma BK was 8.2 ± 6.6 fmol/mL (mean ± SD), and tissue BK (fmol/g) in 14 tested organs varied between brain (14 ± 3) and submaxillary gland (521 ± 315). Six days after left-sided unilateral renal denervation, left renal tissue BK (89 ± 9) was not different from right renal BK (75 ± 23). Similarly, KA was comparable in the two kidneys (left 18.0 ± 1.5, right 15.8 ± 1.4 µkat/g). CONCLUSION: Any possible effect of unilateral renal denervation on the kidney's KKS would have to be bilateral.

Change in blood kinin and plasma porcine pancreatic kallikrein concentrations after oral administration of kallikrein formulation in dog.

Oral formulation of tissue kallikrein consists primarily of porcine pancreatic kallikrein (PPK) and is used to improve peripheral circulation, menopausal symptoms, and impaired chorioretinal circulation. Although gastrointestinal absorption of tissue kallikrein after oral administration has been reported in nonclinical and clinical studies, the increase in the concentration of pharmacologically active kinins, which are produced from kininogens by tissue kallikrein, has not been investigated. In this study, kallikrein formulation was orally administered to dogs and an increase in PPK in plasma was confirmed, along with an increase in the blood kinin level. After oral administration of kallikrein formulation (10 U/kg or 20 U/kg PPK) to dogs, PPK concentration in plasma reached maximum 3 h after administration, and then decreased time-dependently. The maximum concentration was 6.01 ± 1.44 pg/ml in the 10 U/kg group and 10.88 ± 3.59 pg/ml in the 20 U/kg group (mean ± S.E.M, n = 5). After oral administration of kallikrein formulation (40 U/kg PPK) to dogs, the blood kinin concentration in the PPK-treated group was significantly increased 2 h after administration as compared to the purified water-treated group (before administration: 48.8 ± 2.1 ng/ml vs. 48.1 ± 1.9 ng/ml, 2 h after administration: 55.5 ± 1.6 ng/ml vs. 49.6 ± 1.4 ng/ml; mean ± S.E.M, n = 4, p < 0.05). In conclusion, PPK was considered to be absorbed after oral administration and to exert its pharmacological action via kinins produced by kininogen degradation in dogs.

[Kallikrein-kinin system parameters as markers of various adaptive capacities of the body in young male patients with mitral valve prolapse].

The activity of kinin system parameters was studied in 137 young male patients with mitral valve prolapse (MVP) in relation to the body's adaptive capacities. As compared with the controls, the patients with high (Group 1) and low (Group 2) adaptive capacities showed 57.08 and 79.14% increases in leukocyte elastase activity, respectively (p < 0.05). In Groups 1 and 2, the leukocyte elastase/alpha1-proteinase inhibitor ratio was 55.6% and by 2.16-fold higher, respectively, than in the controls (p < 0.05). Thus, the high the leukocyte elastase/alpha1-proteinase inhibitor ratio may serve as a biochemical marker of diminished adaptive capacities in young male patients with mitral valve prolapse and indicate a poor prognosis associated with degradation of a diversity of functionally significant proteins.

Cardioprotective effect of ornitho-kinin in an anesthetized, open-chest chicken model of acute coronary occlusion.

The generation of bradykinin (BK; Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) in blood and kallidin (Lys-BK) in tissues by the action of the kallikrein-kinin system has received little attention in non-mammalian vertebrates. In mammals, kallidin can be generated by the coronary endothelium and myocytes in response to ischemia, mediating cardioprotective events. The plasma of birds lacks two key components of the kallikrein-kinin system: the low molecular weight kininogen and a prekallikrein activator analogous to mammalian factor XII, but treatment with bovine plasma kallikrein generates ornitho-kinin [Thr6,Leu8]-BK. The possible cardioprotective effect of ornitho-kinin infusion was investigated in an anesthetized, open-chest chicken model of acute coronary occlusion. A branch of the left main coronary artery was reversibly ligated to produce ischemia followed by reperfusion, after which the degree of myocardial necrosis (infarct size as a percent of area at risk) was assessed by tetrazolium staining. The iv injection of a low dose of ornitho-kinin (4 microg/kg) reduced mean arterial pressure from 88 +/- 12 to 42 +/- 7 mmHg and increased heart rate from 335 +/- 38 to 402 +/- 45 bpm (N = 5). The size of the infarct was reduced by pretreatment with ornitho-kinin (500 microg/kg infused over a period of 5 min) from 35 +/- 3 to 10 +/- 2% of the area at risk. These results suggest that the physiological role of the kallikrein-kinin system is preserved in this animal model in spite of the absence of two key components, i.e., low molecular weight kininogen and factor XII.

Cardioprotective effect of ornitho-kinin in an anesthetized, open-chest chicken model of acute coronary occlusion

The generation of bradykinin (BK; Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) in blood and kallidin (Lys-BK) in tissues by the action of the kallikrein-kinin system has received little attention in non-mammalian vertebrates. In mammals, kallidin can be generated by the coronary endothelium and myocytes in response to ischemia, mediating cardioprotective events. The plasma of birds lacks two key components of the kallikrein-kinin system: the low molecular weight kininogen and a prekallikrein activator analogous to mammalian factor XII, but treatment with bovine plasma kallikrein generates ornitho-kinin [Thr6,Leu8]-BK. The possible cardioprotective effect of ornitho-kinin infusion was investigated in an anesthetized, open-chest chicken model of acute coronary occlusion. A branch of the left main coronary artery was reversibly ligated to produce ischemia followed by reperfusion, after which the degree of myocardial necrosis (infarct size as a percent of area at risk) was assessed by tetrazolium staining. The iv injection of a low dose of ornitho-kinin (4 µg/kg) reduced mean arterial pressure from 88 ± 12 to 42 ± 7 mmHg and increased heart rate from 335 ± 38 to 402 ± 45 bpm (N = 5). The size of the infarct was reduced by pretreatment with ornitho-kinin (500 µg/kg infused over a period of 5 min) from 35 ± 3 to 10 ± 2 percent of the area at risk. These results suggest that the physiological role of the kallikrein-kinin system is preserved in this animal model in spite of the absence of two key components, i.e., low molecular weight kininogen and factor XII.

Kallikrein-kinin system and fibrinolysis in hereditary angioedema due to factor XII gene mutation Thr309Lys.

In a subgroup of hereditary angioedema (HAE) patients with normal C1-esterase inhibitor levels, HAE is caused by a Thr309Lys mutation in the coagulation factor XII (F12) gene. The aim of this study was to examine elements of the kallikrein-kinin system ('contact system') and the downstream-linked coagulation, complement and fibrinolytic systems in the plasma of six patients with HAE caused by the Thr309Lys mutation and healthy probands. Blood samples were taken from participants during the symptom-free interval between attacks. Samples were analyzed for activity and concentrations of components of the kallikrein-kinin system and linked enzyme systems. The mean FXII clotting activity was 90% in patients with the FXII mutation, and the concentration of FXIIa was 4.1 ng/ml; this did not differ from healthy probands. Mean prekallikrein amidolytic activity and high-molecular-weight kininogen clotting activity were 130 and 144%, respectively, both higher than in healthy probands. The mean kallikrein-like activity of the HAE patients was 11.4 U/l and did not differ from healthy probands. There was no difference in FXII surface activation by silicon dioxide or in kallikrein-like activity with and without activation by dextran sulfate. Contrary to the results of a recently published study, no indication that the Thr309Lys mutation causes a 'gain-of-function' of FXIIa was observed in this investigation.

Plasma kallikrein mediates angiotensin II type 1 receptor-stimulated retinal vascular permeability.

Hypertension is a leading risk factor for the development and progression of diabetic retinopathy and contributes to a variety of other retinal diseases in the absence of diabetes mellitus. Inhibition of the renin-angiotensin system has been shown to provide beneficial effects against diabetic retinopathy, both in the absence and presence of hypertension, suggesting that angiotensin II (Ang II) and the Ang II type 1 receptor may contribute to retinal vascular dysfunction. We investigated the effects of the Ang II type 1 receptor antagonist candesartan on retinal vascular permeability (RVP) in normotensive rats with streptozotocin-induced diabetes mellitus and in rats with Ang II-induced hypertension. We showed that candesartan treatment decreased diabetes mellitus- and Ang II-stimulated RVP by 58% (P<0.05) and 79% (P<0.05), respectively, compared with untreated controls, suggesting that activation of the Ang II type 1 receptor contributes to blood-retinal barrier dysfunction. We found that plasma kallikrein levels are increased in the retina of rats with Ang II-stimulated hypertension and that intravitreal injection of either plasma kallikrein or bradykinin is sufficient to increase RVP. We showed that a novel small molecule inhibitor of plasma kallikrein, 1-benzyl-1H-pyrazole-4-carboxylic acid 4-carbamimidoyl-benzylamide, delivered systemically via a subcutaneous pump, decreased Ang II-stimulated RVP by 70% (P<0.05) and ameliorates Ang II-induced hypertension, measured from the carotid artery by telemetry, but did not reduce Ang II-induced retinal leukostasis. These findings demonstrate that activation of the Ang II type 1 receptor increases RVP and suggest that systemic plasma kallikrein inhibition may provide a new therapeutic approach for ameliorating blood-retinal barrier dysfunction induced by hypertension.

[The specific features of kallikrein-kinin system functioning in reproductive-aged women with hypertensive disease].

The performed clinical and biochemical study evaluated the specific features of kallikrein-kinin system (KKS) functioning in reproductive-aged women in health and in early hypertensive disease. The major molecular mechanism responsible for early hypertensive disease in young women was shown to be activation of the renin-angiotension-aldosterone system due to enhanced kininogenesis. These alterations in KKS performance were followed by the structural changes in vascular wall connective tissue, which was evident in endothelial dysfunction and which was a morphological basis for development of the major clinical signs of hypertensive disease.

The effect of electronegativity and angiotensin-converting enzyme inhibition on the kinin-forming capacity of polyacrylonitrile dialysis membranes.

The combination of negatively-charged membranes and angiotensin I-converting enzyme inhibitors (ACEi) evokes hypersensitivity reactions (HSR) during hemodialysis and bradykinin (BK)-related peptides have been hypothesized as being responsible for these complications. In this study, we tested the effects of neutralizing the membrane electronegativity (zeta potential) of polyacrylonitrile AN69 membranes by coating a polyethyleneimine layer (AN69-ST membranes) over the generation of kinins induced by blood contact with synthetic membranes. We used minidialyzers with AN69 or AN69-ST membranes in an ex vivo model of plasma and we showed that plasma dialysis with AN69 membranes led to significant BK and des-Arg(9)-BK release, which was potentiated by ACEi. This kinin formation was dramatically decreased by AN69-ST membranes, even in the presence of an ACEi, and kinin recovery in the dialysates was also significantly lower with these membranes. High molecular weight kininogen and factor XII detection by immunoblotting of the protein layer coating both membranes corroborated the results: binding of these proteins and contact system activation on AN69-ST membranes were reduced. This ex vivo experimental model applied to the plasma, dialysate and dialysis membrane could be used for the characterization of the kinin-forming capacity of any biomaterial potentially used in vivo in combination with drugs which modulate the pharmacological activity of kinins.

Kinin formation in the plasma and cerebral blood flow in under conditions of cerebral ischemia/reperfusion in rats during modulation of kinin system activity.

Suppression of kininogenesis is an adaptive phenomenon in cerebral ischemia/reperfusion in rats aimed at elimination of the no-reflow phenomenon. Hyperkininogenesis and suppression of kinin destruction are pathogenetically significant, because they augment the manifestations of no-reflow phenomenon during reperfusion following ischemia.

The dual role of the contact system in bacterial infectious disease.

Hemostasis is a sensitive and tightly regulated process, involving the vascular endothelium and blood cells as well as factors of the coagulation and fibrinolytic cascades. Over the last four decades evidence has accumulated that during infection, inflammatory mediators from the microbe and/or host are capable to modulate the equilibrium between the procoagulant and anticoagulant status of the host. Dependent on the mode of activation, these changes can cause either local or systemic inflammatory reactions that may be beneficial or deleterious to the human host. The present review aims to present the state of the art with respect to the role of the contact system (also known as the intrinsic pathway of coagulation or the kallikrein/kinin system) in innate immunity and systemic inflammatory reactions.