Plasma Kallikrein-Kinin System in Patients with Uncomplicated Sepsis and Septic Shock-Comparison with Cardiogenic Shock

Martínez-Brotóns, F; Oncins, J R; Mestres, J; Amargós, V; Reynaldo, C

doi:10.1055/s-0038-1645960

Cited by 41 publications

(23 citation statements)

References 14 publications

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“…Plasma kallikrein is also involved in induction of elastase release from neutrophils and conversion of prourokinase to urokinase to initiate fibrinolysis[34–37]. Plasma kallikrein hyperactivation parallels endothelial lesion, tissue injury, and sepsis, underscoring the correlation between plasma kallikrein alterations and inflammation [38–40]. …”

Section: Synthesis and Stucture Of The Kksmentioning

confidence: 99%

Human Plasma Kallikrein-Kinin System: Physiological and Biochemical Parameters

Bryant

Shariat‐Madar²

2009

CHAMC

118

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The plasma kallikrein-kinin system (KKS) plays a critical role in human physiology. The KKS encompasses coagulation factor XII (FXII), the complex of prekallikrein (PK) and high molecular weight kininogen (HK). The conversion of plasma to kallikrein by the activated FXII and in response to numerous different stimuli leads to the generation of bradykinin (BK) and activated HK (HKa, an antiangiogenic peptide). BK is a proinflammatory peptide, a pain mediator and potent vasodilator, leading to robust accumulation of fluid in the interstitium. Systemic production of BK, HKa with the interplay between BK bound-BK receptors and the soluble form of HKa are key to angiogenesis and hemodynamics. KKS has been implicated in the pathogenesis of inflammation, hypertension, endotoxemia, and coagulopathy. In all these cases increased BK levels is the hallmark. In some cases, the persistent production of BK due to the deficiency of the blood protein C1-inhibitor, which controls FXII, is detrimental to the survival of the patients with hereditary angioedema (HAE). In others, the inability of angiotensin converting enzyme (ACE) to degrade BK leads to elevated BK levels and edema in patients on ACE inhibitors. Thus, the mechanisms that interfere with BK liberation or degradation would lead to blood pressure dysfunction. In contrast, anti-kallikrein treatment could have adverse effects in hemodynamic changes induced by vasoconstrictor agents. Genetic models of kallikrein deficiency are needed to evaluate the quantitative role of kallikrein and to validate whether strategies designed to activate or inhibit kallikrein may be important for regulating whole-body BK sensitivity.

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Section: Synthesis and Stucture Of The Kksmentioning

confidence: 99%

Human Plasma Kallikrein-Kinin System: Physiological and Biochemical Parameters

Bryant

Shariat‐Madar²

2009

CHAMC

118

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“…Activation of the contact system of coagulation has been implicated in the pathophysiology of sepsis and septic shock, based on the reduced functional and/or antigenic levels of contact system proteins and inhibitors observed in patients, especially in those with hypotension (10,(32)(33)(34)(35)(36)(37) the assessment of the extent to which contact activation is responsible for the increased iC1-Inh levels found in patients is still a problem. The extent to which complement activation via the classical pathway may have contributed to the elevated levels of iCl-Inh is even more difficult to assess.…”

Section: Ci-cl-inh and Kallikrein-cl-inh Complexes In Patients Withmentioning

confidence: 99%

“…Plasma levels of functional Cl-Inh, measured as the capacity ofplasma to inactivate kallikrein, and ofCl-Inh antigen are increased in patients with uncomplicated sepsis (34,35), whereas reductions in functional Cl-Inh and normal or increased concentrations of ClInh antigen are found in patients with sepsis complicated by shock and/or adult respiratory distress syndrome, as well as in patients with typhoid fever (10,(32)(33)(34)(35)(36)(37). The discrepancy between plasma levels of functional and antigenic Cl-Inh in the latter conditions may indicate the presence ofcomplexed and/ or iCl-Inh.…”

Section: Introductionmentioning

confidence: 99%

“…Many investigators have studied the role of C1-Inh in the pathophysiology of sepsis (10,(32)(33)(34)(35)(36)(37). Plasma levels of functional Cl-Inh, measured as the capacity ofplasma to inactivate kallikrein, and ofCl-Inh antigen are increased in patients with uncomplicated sepsis (34,35), whereas reductions in functional Cl-Inh and normal or increased concentrations of ClInh antigen are found in patients with sepsis complicated by shock and/or adult respiratory distress syndrome, as well as in patients with typhoid fever (10,(32)(33)(34)(35)(36)(37).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Proteolytic inactivation of plasma C1- inhibitor in sepsis.

Nuijens¹,

Eerenberg-Belmer²,

Huijbregts³

et al. 1989

J. Clin. Invest.

138

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Activation of both the complement system and the contact system of intrinsic coagulation is implicated in the pathophysiology of sepsis. Because C1 inhibitor (Cl-Inh) (M, 110,000). Elevated iCl-Inh levels (_ 0.13 ,uM) were found in 81% of all patients, sometimes up to 1.6 MM. Levels of iCl-Inh on admission appeared to be of prognostic value: iCl-Inh was higher in 27 patients who died than in 21 patients who survived (P = 0.003). The mortality in 15 patients with iCl-Inh levels up to 0.2,uM was 27%, but in 12 patients with plasma iCl-Inh exceeding 0.44 gM, the mortality was 83%. The overall mortality in the patients with sepsis was 56%. We propose that the cleavage of Ci-Inh in patients with sepsis reflects processes that play a major role in the development of fatal complications during sepsis.

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“…Excessive activity of proteases in vivo is counteracted by protease inhibitors, such as ␣ 2 -macroglobulin. The role of ␣ 2 -macroglobulin has been emphasized by studies suggesting that the protease inhibitor plays a substantial role in the outcome of inflammatory conditions such as sepsis and systemic inflammatory response syndrome (SIRS) (1)(2)(3)(4). This proposition is further supported by results suggesting that disturbances in protease release and protease/␣ 2 -macroglobulin complex clearance are some of the critical factors determining the progression of inflammatory conditions (5)(6)(7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

The CAPACITY OF Α2-Macroglobulin TO INHIBIT AN EXOGENOUS PROTEASE IS SIGNIFICANTLY INCREASED IN CRITICALLY ILL AND SEPTIC PATIENTS

Schaefer

Brücker²,

Elbers³

et al. 2004

Shock

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The image of alpha2-macroglobulin is based on a paradigm evolved in the 1970s. During this decade alpha2-macroglobulin was shown to irreversibly entrap and thereby inhibit a maximum of two proteases. Additional binding of nonproteolytic proteins, i.e., inflammatory mediators and growth factors, is dependent on the conformational status of alpha2-macroglobulin. It was our aim to clarify whether the interaction of nonproteolytic proteins with alpha2-macroglobulin during inflammatory conditions might also modulate the capacity of alpha2-macroglobulin to inhibit proteases. To explore this possibility, bromelain, an exogenous protease, was titrated against plasma of critically ill or septic patients, whose pathophysiological conditions are defined by a massive release of inflammatory mediators. The stoichiometry of bromelain inhibition by alpha2-macroglobulin was quantified by caseolytic activity assays. The maximal alpha2-macroglobulin/bromelain inhibition ratios were significantly increased (1:6 and 1:8 in the two patient groups, P < 0.01) as compared with control groups (1:2 with purified alpha2-macroglobulin and 1:4 in healthy volunteers). The increase of alpha2-macroglobulin inhibition capacity in patients was paralleled by the appearance of a large signal on Western blots, suggesting the formation of additional complexes. Our results demonstrate alpha2-macroglobulin to have more flexibility than had been thought, and it may thereby contribute to a shift in a 30-year-old paradigm.

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Plasma Kallikrein-Kinin System in Patients with Uncomplicated Sepsis and Septic Shock-Comparison with Cardiogenic Shock

Cited by 41 publications

References 14 publications

Human Plasma Kallikrein-Kinin System: Physiological and Biochemical Parameters

Human Plasma Kallikrein-Kinin System: Physiological and Biochemical Parameters

Proteolytic inactivation of plasma C1- inhibitor in sepsis.

The CAPACITY OF Α2-Macroglobulin TO INHIBIT AN EXOGENOUS PROTEASE IS SIGNIFICANTLY INCREASED IN CRITICALLY ILL AND SEPTIC PATIENTS

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