Kininogen Depletion Research Articles

Kininogen supports inflammation and bacterial spreading during Streptococccus Pyogenes Sepsis.

BackgroundHigh-molecular-weight kininogen is a cofactor of the human contact system, an inflammatory response mechanism that is activated during sepsis. It has been shown that high-molecular-weight kininogen contributes to endotoxemia, but is not critical for local host defense during pneumonia by Gram-negative bacteria. However, some important pathogens, such as Streptococcus pyogenes, can cleave kininogen by contact system activation. Whether kininogen causally affects antibacterial host defense in S. pyogenes infection, remains unknown.MethodsKininogen concentration was determined in course plasma samples from septic patients. mRNA expression and degradation of kininogen was determined in liver or plasma of septic mice. Kininogen was depleted in mice by treatment with selective kininogen directed antisense oligonucleotides (ASOs) or a scrambled control ASO for 3 weeks prior to infection. 24 h after infection, infection parameters were determined.FindingsData from human and mice samples indicate that kininogen is a positive acute phase protein. Lower kininogen concentration in plasma correlate with a higher APACHE II score in septic patients. We show that ASO-mediated depletion of kininogen in mice indeed restrains streptococcal spreading, reduces levels of proinflammatory cytokines such as IL-1β and IFNγ, but increased intravascular tissue factor and fibrin deposition in kidneys of septic animals.InterpretationMechanistically, kininogen depletion results in reduced plasma kallikrein levels and, during sepsis, in increased intravascular tissue factor that may reinforce immunothrombosis, and thus reduce streptococcal spreading. These novel findings point to an anticoagulant and profibrinolytic role of kininogens during streptococcal sepsis.FundingFull details are provided in the Acknowledgements section.

Limited role of kininogen in the host response during gram-negative pneumonia-derived sepsis.

High-molecular-weight kininogen (HK), together with factor XI, factor XII and prekallikrein, is part of the contact system that has proinflammatory, prothrombotic, and vasoactive properties. We hypothesized that HK plays a role in the host response during pneumonia-derived sepsis. To this end mice were depleted of kininogen (KNG) to plasma HK levels of 28% of normal by repeated treatment with a specific antisense oligonucleotide (KNG ASO) for 3 wk before infection with the common human sepsis pathogen Klebsiella pneumoniae via the airways. Whereas plasma HK levels increased during infection in mice treated with a scrambled control ASO (Ctrl ASO), HK level in the KNG ASO-treated group remained reduced to 25-30% of that in the corresponding Ctrl ASO group both before and after infection. KNG depletion did not influence bacterial growth in lungs or dissemination to distant body sites. KNG depletion was associated with lower lung CXC chemokine and myeloperoxidase levels but did not impact neutrophil influx, lung pathology, activation of the vascular endothelium, activation of the coagulation system, or the extent of distant organ injury. These results were corroborated by studies in mice with a genetic deficiency of KNG, which were indistinguishable from wild-type mice during Klebsiella-induced sepsis. Both KNG depletion and KNG deficiency were associated with strongly reduced plasma prekallikrein levels, indicating the carrier function of HK for this zymogen. This study suggests that KNG does not significantly contribute to the host defense during gram-negative pneumonia-derived sepsis.

Endotoxin shock in dogs pretreated with cellulose sulphate, an agent causing partial plasma kininogen depletion

Journal Article Endotoxin shock in dogs pretreated with cellulose sulphate, an agent causing partial plasma kininogen depletion Get access A M Rothschild, A M Rothschild Department of Pharmacology, Faculty of Medicine, Ribeirão Prêto, Brazil Search for other works by this author on: Oxford Academic Google Scholar A Castania A Castania Department of Pharmacology, Faculty of Medicine, Ribeirão Prêto, Brazil Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 20, Issue 1, January 1968, Pages 77–78, https://doi.org/10.1111/j.2042-7158.1968.tb09628.x Published: 12 April 2011 Article history Received: 19 October 1967 Published: 12 April 2011

A possible alternative mechanism of kinin generation in vivo by cathepsin L

We investigated the ability of cathepsin L to induce a hypotensive effect after intravenous injection in rats and correlated this decrease in blood pressure with kinin generation. Simultaneously with blood pressure decrease, we detected plasma kininogen depletion in the treated rats. The effect observed in vivo was abolished by pre-incubation of cathepsin L with the cysteine peptidase-specific inhibitor E-64 (1 microM) or by previous administration of the bradykinin B2 receptor antagonist JE049 (4 mg/kg). A potentiation of the hypotensive effect caused by cathepsin L was observed by previous administration of the angiotensin I-converting enzyme inhibitor captopril (5 mg/kg). In vitro studies indicated that cathepsin L excised bradykinin from the synthetic fluorogenic peptide Abz-MTSVIRRPPGFSPFRAPRV-NH2, based on the Met375-Val393 sequence of rat kininogen (Abz = o-aminobenzoic acid). In conclusion, our data indicate that in vivo cathepsin L releases a kinin-related peptide, and in vitro experiments suggest that the kinin generated is bradykinin. Although it is well known that cysteine proteases are strongly inhibited by kininogen, cathepsin L could represent an alternative pathway for kinin production in pathological processes.

Plasma kallikrein-generating activity evoked by rat peritoneal-fluid mast cells following treatment with epinephrine, 8-bromo-cyclic 3′,5′-guanosine monophosphate or compound [formula omitted

Acting in a dose-dependent fashion, l-epinephrine caused rat peritoneal-fluid cells to rapidly deplete rat plasma kininogen in vitro; 8-bromo-cyclic 3′,5′-guanosine monophosphate (8-Br-cGMP) behaved similarly; N 6-2 1- O-dibutyril-cyclic 3′,5′-adenosine monophosphate (di Bu-cAMP) inhibited this effect of epinephrine or 8-Br-cGMP. After fractionation of peritoneal-fluid cells by differential centrifugation, this kininogen-depleting activity was observed only in mast cells; eosinophils, lymphocytes, and monocytes were inactive. Epinephrine-treated mast cells were ablt to hydrolyze the trypsin substrates N- p-toluenesulfonyl-arginine-methyl-ester (TAME) or N-benzoyl-arginine-ethyl-ester and to generate the capacity to hydrolyze these substrates in rat plasma; because this activity accompanied kininogen depletion, it was attributed to plasma kininogenase (plasma kallikrein). Diisopropyl-fluorophosphate (DFP) inhibited the mast cell esterase activity toward TAME but did not prevent activated cells from depleting plasma kininogen. Thus, mast cell-bound argininase ester esterase may not have been necessary for the activation of plasma kininogenase. Mast cell heparin, exposed following epinephrine or 8-Br-cGMP treatment, may have been the activator of plasma kallikrein. Unlike DFP, Trasylol [polyvalent bovine proteinase inhibitor (BPTI)] inhibited both mast cell esterase and kininogen-depleting activity. This inhibitor may have acted on mast cells both as a heparin antagonist and and a non-specific esterase inhibitor. Compound 48 80 , at concentrations causing 40 per cent release of mast cell histamine, failed to cause mast cells to exhibit the ability to active plasma kallikrein. At high concentrations it activated the kininogen depleting action of mast cells, but to a lesser degree than did epinephrine or 8-Br-cGMP. These compounds did not release histamine; it may be concluded, therefore, that the ability to activate plasma kininogenase was present in non-histamine releasing mast cells.

Venoconstrictor activity of some precursor fractions of stable plasma protein solution.

Stable plasma protein solution (SPPS) is a 5% solution of human plasma albumin and some globulins. Rapid infusion of some batches of SPPS and analogous solutions prepared by similar processes induce paradoxical hypotensive reactions. In the current experiments, a number of precursor fractions of a single batch of SPPS were examined for kininogen content and for venoconstrictor activity on the isolated central vein of the rabbit ear. Unheated SPPS contained both venoconstrictor activity and kininogen. Among the various precursor fractions examined, Cohn fraction II + III (a precursor of fraction III-0) contained the greatest venoconstrictor activity. There was no evidence of kininogen depletion during the stages of fractionation examined but some generation of venoconstrictor material. Column chromatography suggested a molecular weight of approximately 1,500 for the major active material in unheated SPPS. It appears possible that the 14-amino acid hypotensive peptide present in fraction III-0 may also be present in SPPS, where it may contribute to the hypotensive effects of this solution.

Haemorrhagic and inflammatory properties of collagenase fromC. histolyticum

Collagenase from Clostridium histolyticum induced haemorrhages when applied to the surface of dog lung; it exerted a similar effect on mouse lung when injected intrathoracically. Injected into rat paws, bacterial collagenase induced haemorrhage and oedema. Effects of collagenase were prevented by several procedures that inhibit collagenolytic activity (heating at various temperatures and incubation with metal-complexing agents such as EDTA, penicillamine and dithiothreitol). Protein protease inhibitors, dexamethasone and standard acidic anti-inflammatory drugs had only a slight or no effect on collagenase-induced haemorrhages; dexamethasone and acidic anti-inflammatory drugs blocked collagenase-induced oedema. Inhibition of endogenous kinin-releasing mechanisms by administration of hexadimethrine, a recognized inhibitor of the activation of clotting Factor XII, and depletion of kininogen by administration of carrageenin blocked collagenase-induced oedema. Collagenase did not increase permeability of rat skin vessels, nor did it release potential inflammatory mediators, such as bradykinin or prostaglandins, from plasma or platelets. Bacterial collagenase-induced haemorrhage presumably resulted from enzymatic destruction of membranous structures; at least a portion of the inflammatory response may be due to activation of a kinin-like system.

Plasma kininogen during the oestrous cycle, early pregnancy and pseudopregnancy in the rat.

1. Changes in the plasma kinin precursor, kininogen, occur following treatment with oestrogens and progestogens. This work was undertaken to attempt to relate plasma kininogen values to hormonal changes in various reproductive states. 2. During the oestrous cycle kininogen concentrations follow a nychthemeral rhythm, kininogen depletion occurring during the increase in general activity of the rat. 3. Superimposed on the nychthemeral changes in kininogen concentration are changes which may be related to the hormonal events of the oestrous cycle. 4. During early pregnancy and pseudopregnancy the kininogen level rises; this increase may be due to changes in the circulating levels of oestrogens and progestogens. 5. It is suggested that the changes in kininogen concentration may result from utilization of kinin which could be of functional significance.

Adrenergic and cholinergic control of the activation of the kalli-krein-kinin system in the rat blood.

Sympathomimetic amines activate the kallikrein system of rat blood, causing up to 50% lowering of kininogen, transient kinin release and transient benzoyl arginine ethyl ester (BAEE) hydrolase activity. The action of catecholamines mimics and could be a model for the study of kallikrein activation and kinin release observed following nerve stimulation (Hilton & Lewis [1], Gautvik, Kriz, Lund-Learsen and Waaler [2], Inoki, Toyoda & Yamamoto [3], Turker & Turker [4], Inoki, Hayashi, Kudo, Matsumoto & Yamamoto [5]). Catecholamine activation of the kininogen-consuming process has the following characteristics: a) reproducible in vitro in rat whole oxaleted blood (6); b) not obtained in cell-free plasma nor in plasma containing either platelets, eosinophils, lymphocytes or erythrocytes (7); c) effectiveness: epinephrine > nor-epinephrine; isoprenaline ineffective, does not block the action of epinephrine (6); d) inhibited by either alpha or beta-adrenergic antagonists, the former being more potent (6); e) inhibited by acetylsalicylic acid (Aspirin), bovine kallikrein inhibitor (Trasylol) or soy bean trypsin inhibitor (SBTI) (6,7). f) reproducible in rat plasma treated with rat peritoneal fluid cell (PFC) suspensions exposed to epinephrine for 2 min.; not obtained with untreated PFC; after activation by epinephrine, PFC can be centrifuged and washed without loss of their acquired activity (8); g) not obtained when PFC free of mast cells are added to plasma in the presence of epinephrine (8); h) inhibited by dibutyril cyclic-AMP, 5 × 10−5M (9); i) possibly associated with mast cell vacuolization and intracellular granule retraction, a phenomenon observed in epinephrine or nor-epinephrine-treated rat mesentery mast cells (10) which is inhibited by Aspirin (8), at the same concentrations which block kininogen depletion; j) epinephrine activation of kallikrein in the presence of PFC is not accompanied by the release of histamine from such cells. Increased amounts of histamine are however observed in the tissues of epinephrine-treated rats (11, 12); they are to be attributed to enhanced, short-term synthesis of histamine induced by epinephrine, (Rosengren & Svensson) (13); k) kininogen depletion and mast cell vacuolization apparently identical to those produced by catecholamines, are shown in rats treated with carbamylcholine, a cholinergic agonist. The effect on kininogen can also be shown in vitro, in oxalated blood incubated for 5 min. with carbamylcholine. This excludes reflexly released catecholamines as mediators of kallikrein activation in carbamylcholine treated rats.

Kinins – Evidence for the Involvement in Lymphostatic Encephalopathy in Rats

Five days after blockade of the cervical lymph vessels rats suffer from lymphostatic encephalopathy with impaired central nervous function and cerebral edema. The vascular permeability in the brain for i.v. injected Evans blue is increased. The enhancement of the permeability is suppressed after depletion of kininogen with hog pancreatic kallikrein and cellulose sulphate or by increase of the kinin destroying enzymes (carboxypeptidase B). Trasylol® and SBTI have no effect. Kinins are shown to play a role in a situation with lymphogenic edema.

The divergent effects of endotoxin fractions on human plasma and leukocytes

Bacterial endotoxin is a lipid-polysaccharide-protein complex with many biological effects. We have fractioned crude endotoxin by centrifugation, acid hydrolysis and column chromatography into preparations of various molecular weights containing primarily polysaccharide or polysaccharide with known amounts of lipid. These fractions were tested in vitro for stimulation of kininogen depletion in heparinized human plasma and for stimulation of lysozyme leak from isolated human polymorphonuclear granulocytes. All fractions regardless of molecular size were capable of stimulating kininogen depletion in plasma, with the fraction highest in polysaccharide being the most potent. In contrast, only the large molecular size fractions were capable of interacting with granulocytes to produce a lysozyme leak, and the polysaccharide fraction was completely ineffective. These data are consistent with the hypothesis that endotoxin has a polysaccharide antigen which reacts with antibody and complement in plasma to stimulate kinin-forming enzymes. However, chemically unaltered endotoxin of large molecular size is necessary for interaction with granulocytes and complement to stimulate phagocytic activity by the cells. Correlating these data with those previously obtained, we conclude that the endotoxin-granulocyte interaction is likely to be more important in producing toxicity and kinin formation in vivo than the endotoxin-plasma interaction.

Some pharmacodynamic properties of carrageenin in the rat.

1. Carrageenin oedema is suppressed by pre-treating the rats with cellulose sulphate, a kininogen depleting agent. This inhibition is closely related to the dose of cellulose sulphate and to the time course of kininogen depletion.2. Oedema induced by egg white or by dextran, in which the mediators are histamine and 5-hydroxytryptamine, is quite unaffected by cellulose sulphate treatment.3. Carrageenin injected intravenously lowers the arterial blood pressure of rats. This hypotensive effect is unaffected by histamine antagonists and is abolished by protease inhibitors and thus seems to be due to kinin release from plasma substrates.4. Like cellulose sulphate, carrageenin enhances the esterolytic activity of the blood from treated rats when incubated with benzoyl-arginine ethyl ester.5. The ability of carrageenin to activate the kinin-forming system could account for both its inflammatory and hypotensive effects.

Depletion of kininogen I by bromelain and its significance in the prevention of rat pulmonary edema

Depletion of kininogen I by bromelain and its significance in the prevention of rat pulmonary edema

Hageman factor activation and kinin formation in human plasma induced by cellulose sulfate solutions.

SummaryCellulose sulfate was previously reported as an anticoagulant and as a substance that will induce kinin formation in normal human plasma in vitro. The present data confirm these findings but in addition indicate that at lesser concentrations it is a procoagulant as well. Further, cellulose sulfate will induce permeability-enhancing activity in normal human plasma. Cellulose sulfate does not induce the formation of kinins, or permeability-enhancing activity, nor does it enhance clotting when added to human plasma deficient in Hageman factor. Further the induction of permeability-enhancing activity in normal human plasma is blocked by the addition of rabbit anti-Hageman serum prior to the addition of cellulose sulfate. These data therefore indicate that cellulose sulfate, like ellagic acid, activates Hageman factor in normal human plasma in vitro. On the basis of this datum, it is suggested that the mechanism of kinin formation and kininogen depletion in dogs given cellulose sulfate (4) is the same a...

Kinin formation and kininogen depletion in rats after intravenous injection of ellagic acid.

Kinin formation and kininogen depletion in rats after intravenous injection of ellagic acid.