Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The "systemic inflammatory response" is a multifaceted defensive reaction of the body to surgical trauma and cardiopulmonary bypass (CPB), characterized by systemic activation of fibrinolysis, coagulation, complement, immune cells, platelets, and oxidative pathways, all overlaid onto localized trauma to the grafted vessel or vascular beds susceptible to ischemia/reperfusion. There is going to be no single magic bullet to diminish such a broad host defense response to surgery. The best chance lies with combinatorial--or promiscuous--pharmacotherapy. Combinations of anti-fibrinolytics, anti-coagulants targeted higher up the coagulation cascade, anti-thrombin receptor therapy, improved coated circuits, anti-complement, anti-leukocyte, and antioxidant therapies may blunt sufficient arms of the systemic inflammatory response to be clinically effective. The alternative is a promiscuous drug like aprotinin, which targets plasmin in the fibrinolytic pathway, kallikrein in the coagulation pathway, thrombin receptors on platelets and endothelium, and leukocytes at the extravasation step. Because of the overriding safety concerns relating to the use of anti-fibrinolytics in cardiothoracic surgery, any future combinatorial or promiscuous pharmacotherapy involving anti-fibrinolytics will require solid underpinning with a known mechanism of action and clinical safety data powered to detect well-defined adverse events (stroke, myocardial injury, renal failure requiring dialysis), preferably in isolation and not as a composite endpoint.
 ...
PMID:Pharmacologic strategies for combating the inflammatory response. 1829 23

All the components of the kallikrein-kinin system are located in the cardiac muscle and its deficiency may lead to cardiac dysfunction. In recent years, numerous observations obtained from clinical and experimental models of diabetes, hypertension, cardiac failure, ischemia, myocardial infarction, and left ventricular hypertrophy have suggested that the reduced activity of the local kallikrein-kinin system may be instrumental for the induction of cardiovascular-related diseases. The cardioprotective property of the angiotensin-converting enzyme inhibitors is primarily mediated via a kinin-releasing pathway, which may cause regression of the left ventricular hypertrophy in hypertensive situations. The ability of kallikrein gene delivery to produce a wide spectrum of beneficial effects makes it a promising candidate in treating hypertension and cardiovascular and renal diseases. In addition, stable kinin agonists may also be available in the future as therapeutic agents for cardiovascular and renal disorders. However, there are also possibilities of adverse effects that may be caused by these compounds.
 ...
PMID:Cardiovascular activities of the bradykinin system. 1845 46

Mesenchymal stem cells (MSCs) migrate to sites of tissue injury and serve as an ideal vehicle for cellular gene transfer. As tissue kallikrein has pleiotropic effects in protection against oxidative organ damage, we investigated the potential of kallikrein-modified MSCs (TK-MSCs) in healing injured kidney after acute ischemia/reperfusion (I/R). TK-MSCs secreted recombinant human kallikrein with elevated vascular endothelial growth factor levels in culture medium, and were more resistant to oxidative stress-induced apoptosis than control MSCs. Expression of human kallikrein was identified in rat glomeruli after I/R injury and systemic TK-MSC injection. Engrafted TK-MSCs exhibited advanced protection against renal injury by reducing blood urea nitrogen, serum creatinine levels, and tubular injury. Six hours after I/R, TK-MSC implantation significantly reduced renal cell apoptosis in association with decreased inducible nitric oxide synthase expression and nitric oxide levels. Forty-eight hours after I/R, TK-MSCs inhibited interstitial neutrophil and monocyte/macrophage infiltration and decreased myeloperoxidase activity, superoxide formation, p38 mitogen-activated protein kinase phosphorylation, and expression of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and intercellular adhesion molecule-1. In addition, tissue kallikrein and kinin significantly inhibited H2O2-induced apoptosis and increased Akt phosphorylation and cell viability in cultured proximal tubular cells. These results indicate that implantation of kallikrein-modified MSCs in the kidney provides advanced benefits in protection against ischemia-induced kidney injury by suppression of apoptosis and inflammation.
 ...
PMID:Kallikrein-modified mesenchymal stem cell implantation provides enhanced protection against acute ischemic kidney injury by inhibiting apoptosis and inflammation. 1855 97

Adenovirus-mediated kallikrein delivery has been shown to promote blood vessel growth in the limb under both ischemic and normoperfused conditions. Here we investigated whether a continuous supply of kallikrein and kinin peptide can induce neovascularization in a rat model of hindlimb ischemia. Rats underwent femoral artery ligation and localized injection of tissue kallikrein, bradykinin or B1 receptor agonist, followed by infusion of proteins by osmotic minipump. Regional blood flow was monitored weekly by laser Doppler perfusion imaging. Three weeks after surgery, rats receiving kallikrein and kinins showed a significant increase in the perfusion ratio of ischemic vs. normoperfused limb compared to control rats. Similarly, a microsphere assay showed that kallikrein and kinins significantly increased regional blood flow without altering blood pressure. Moreover, kallikrein and kinins significantly augmented capillary and arteriole densities, as quantified by immunostaining with CD-31 and smooth muscle alpha-actin. Both tissue kallikrein and bradykinin increased hemoglobin content in Matrigel implants in mice, providing further evidence of the angiogenic properties. Kinins, when delivered subcutaneously via Matrigel in rats, also increased regional perfusion. This is the first demonstration that local application of tissue kallikrein protein or kinin peptide has therapeutic value in the treatment of ischemic disease by promoting neovascularization.
 ...
PMID:Tissue kallikrein and kinin infusion promotes neovascularization in limb ischemia. 1862 94

Broadly speaking, C1 inhibitor plays important roles in the regulation of vascular permeability and in the suppression of inflammation. Vascular permeability control is exerted largely through inhibition of two of the proteases involved in the generation of bradykinin, factor XIIa and plasma kallikrein (the plasma kallikrein-kinin system). Anti-inflammatory functions, however, are exerted via several activities including inhibition of complement system proteases (C1r, C1s, MASP2) and the plasma kallikrein-kinin system proteases, in addition to interactions with a number of different proteins, cells and infectious agents. These more recently described, as yet incompletely characterized, activities serve several potential functions, including concentration of C1 inhibitor at sites of inflammation, inhibition of alternative complement pathway activation, inhibition of the biologic activities of gram negative endotoxin, enhancement of bacterial phagocytosis and killing, and suppression of the influx of leukocytes into a site of inflammation. C1 inhibitor has been shown to be therapeutically useful in a variety of animal models of inflammatory diseases, including gram negative bacterial sepsis and endotoxin shock, suppression of hyperacute transplant rejection, and treatment of a variety of ischemia-reperfusion injuries (heart, intestine, skeletal muscle, liver, brain). In humans, early data appear particularly promising in myocardial reperfusion injury. The mechanism (or mechanisms) of the effect of C1 inhibitor in these conditions is (are) not completely clear, but involve inhibition of complement and contact system activation, in addition to variable contributions from other C1 inhibitor activities that do not involve protease inhibition.
 ...
PMID:Biological activities of C1 inhibitor. 1867 18

Tissue kallikrein exerts various biological functions through kinin formation with subsequent kinin B2 receptor activation. Recent studies showed that tissue kallikrein directly activates kinin B2 receptor in cultured cells expressing human kinin B2 receptor. In the present study, we investigated the role of tissue kallikrein in protection against cardiac injury through direct kinin B2 receptor activation using kininogen-deficient Brown Norway Katholiek rats after acute myocardial infarction. Tissue kallikrein was injected locally into the myocardium of Brown Norway Katholiek rats after coronary artery ligation with and without coinjection of icatibant (a kinin B2 receptor antagonist) and N(omega)-nitro-L-arginine methylester (an NO synthase inhibitor). One day after myocardial infarction, tissue kallikrein treatment significantly improved cardiac contractility and reduced myocardial infarct size and left ventricle end diastolic pressure in Brown Norway Katholiek rats. Kallikrein attenuated ischemia-induced apoptosis and monocyte/macrophage accumulation in the ischemic myocardium in conjunction with increased NO levels and reduced myeloperoxidase activity. Icatibant and N(omega)-nitro-L-arginine methylester abolished kallikrein's effects, indicating a kinin B2 receptor NO-mediated event. Moreover, inactive kallikrein had no beneficial effects in cardiac function, myocardial infarction, apoptosis, or inflammatory cell infiltration after myocardial infarction. In primary cardiomyocytes derived from Brown Norway Katholiek rats under serum-free conditions, active, but not inactive, kallikrein reduced hypoxia/reoxygenation-induced apoptosis and caspase-3 activity, and the effects were mediated by kinin B2 receptor/nitric oxide formation. This is the first study to demonstrate that tissue kallikrein directly activates kinin B2 receptor in the absence of kininogen to reduce infarct size, apoptosis, and inflammation and improve cardiac performance of infarcted hearts.
 ...
PMID:Tissue kallikrein elicits cardioprotection by direct kinin b2 receptor activation independent of kinin formation. 1876

Reduced migratory function of circulating angiogenic progenitor cells (CPCs) has been associated with impaired neovascularization in patients with cardiovascular disease (CVD). Previous findings underline the role of the kallikrein-kinin system in angiogenesis. We now demonstrate the involvement of the kinin B2 receptor (B(2)R) in the recruitment of CPCs to sites of ischemia and in their proangiogenic action. In healthy subjects, B(2)R was abundantly present on CD133(+) and CD34(+) CPCs as well as cultured endothelial progenitor cells (EPCs) derived from blood mononuclear cells (MNCs), whereas kinin B1 receptor expression was barely detectable. In transwell migration assays, bradykinin (BK) exerts a potent chemoattractant activity on CD133(+) and CD34(+) CPCs and EPCs via a B(2)R/phosphoinositide 3-kinase/eNOS-mediated mechanism. Migration toward BK was able to attract an MNC subpopulation enriched in CPCs with in vitro proangiogenic activity, as assessed by Matrigel assay. CPCs from cardiovascular disease patients showed low B(2)R levels and decreased migratory capacity toward BK. When injected systemically into wild-type mice with unilateral limb ischemia, bone marrow MNCs from syngenic B(2)R-deficient mice resulted in reduced homing of sca-1(+) and cKit(+)flk1(+) progenitors to ischemic muscles, impaired reparative neovascularization, and delayed perfusion recovery as compared with wild-type MNCs. Similarly, blockade of the B(2)R by systemic administration of icatibant prevented the beneficial effect of bone marrow MNC transplantation. BK-induced migration represents a novel mechanism mediating homing of circulating angiogenic progenitors. Reduction of BK sensitivity in progenitor cells from cardiovascular disease patients might contribute to impaired neovascularization after ischemic complications.
 ...
PMID:Role of kinin B2 receptor signaling in the recruitment of circulating progenitor cells with neovascularization potential. 1902 19

The kidney kallikrein-kinin system plays important roles in inflammation, coagulation, angiogenesis, and regulation of vessel tone and permeability. In this issue of the JCI, Liu et al. provide data that suggest a protective role for kallikrein in animal models of anti-glomerular basement membrane(GBM) antibody-induced nephritis, an experimental model of Goodpasture disease (see the related article beginning on page 911). Furthermore, human systemic lupus erythematosus and lupus nephritis were shown to be associated with kallikrein 1 (KLK1) and the KLK3 promoter. The authors suggest that kallikrein genes are involved in the development of SLE and lupus nephritis and may exert a renoprotective role. It is possible, however, that the kallikrein-kinin system may play dual roles: protecting the kidney against ischemia and interstitial fibrosis while also mediating vasodilation, inflammation, and activation of the innate immune response.
 ...
PMID:Kallikreins and lupus nephritis. 1930 30

From the first description of the "systemic inflammatory response" in the early 1990s, it has been recognized that this is a multifaceted response of the body to the combined insult of cardiothoracic surgery with bypass, involving causation by "activation of complement, coagulation, fibrinolytic, and kallikrein cascades, activation of neutrophils with degranulation and protease enzyme release, oxygen radical production, and the synthesis of various cytokines from mononuclear cells." Yet the intervening 15 years have seen a narrowing of research into individual systems and interventions naively targeted at single pathways without achieving clinically meaningful benefits. The time has come to redefine the systemic inflammatory response so that research can be more productively focused on objectively measuring and interdicting this multisystem disorder. A key concept of this new understanding is that translation into a hard adverse event occurs when the systemic imbalance is combined with a localized trigger. Triggers might be inadvertently provided by transient episodes of ischemia/malperfusion to vulnerable organs or handling trauma to major vessels. Future research should be directed at suppressing systemic activation with combinations of drugs and improved circuit coating, whereas changes in clinical practice and continuous monitoring of perfusion parameters can help eliminate localized triggering events.
 ...
PMID:Redefining the systemic inflammatory response. 1961 54

Blood-brain barrier disruption and brain edema are detrimental in ischemic stroke. The kallikrein-kinin system appears to play an important role in the regulation of vascular permeability and is invoked in edema formation. The effects of kinins are mediated by bradykinin receptors B1R and B2R. However, little is known about the exact roles of bradykinin receptors in the early stage of cerebral ischemia. In this study, we demonstrated that ischemia upregulated the level of B1R and B2R at 24h after reperfusion by immunofluorescence assays, mainly expressed in astrocytes and neurons, respectively, in the ischemic penumbra. Moreover, B2R inhibition more effectively reduced neurological severity scores, blood-brain barrier permeability and cytokines release than B1R inhibition did. Additionally, B2R inhibition also significantly suppressed B1R protein level. Therefore, blockade of B2R may be a more effective strategy for the treatment of ischemic brain injury than B1R inhibition within 24h after reperfusion.
 ...
PMID:Blockade of bradykinin B2 receptor more effectively reduces postischemic blood-brain barrier disruption and cytokines release than B1 receptor inhibition. 1964 18


<< Previous 1 2 3 4 5 6 7 8 9 Next >>