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)

Activated protein C (APC), a plasma serine protease, is best known for its ability to inhibit blood clot formation. APC acts as an anticoagulant by degrading coagulation cofactors Va and VIIIa, thereby attenuating the coagulation cascade. Over the past 15 years, impressive research advances have provided novel insights into the diverse biological activities of this molecule. APC is now viewed not only as an anticoagulant but also as a signaling molecule that provides a pivotal link between the pathways of coagulation, inflammation, apoptosis, and vascular permeability. The protective effect of APC supplementation in patients with severe sepsis likely reflects the ability of APC to modulate multiple pathways implicated in sepsis pathophysiology. This review attempts to summarize key studies that support the therapeutic potential of APC in conditions beyond sepsis such as stroke, ischemia-reperfusion injury, lung injury, asthma, pancreatitis, wound healing, and angiogenesis. A comprehensive PUBMED literature review up to May 2006 was conducted.
 ...
PMID:Activated protein C in sepsis and beyond: update 2006. 1712 35

Sepsis-induced purpura fulminans is a rare but life-threatening disorder, characterized by hemorrhagic infarction of the skin caused by disseminated intravascular coagulation and dermal vascular thrombosis. The pathogenesis is linked to enhanced expression of the natural procoagulants and depletion of the natural anticoagulant proteins particularly protein C. Meningococcal sepsis is the most common cause, followed by pneumococcal sepsis in adults. The syndrome is associated with more than 50% mortality secondary to multiple organ dysfunction syndrome and is accompanied by long-term morbidity. Necrotic lesions usually progress to distal ischemia, and skin grafting and extremities or limb amputation are often required. Early antibiotic administration and intensive care management according to the recommendations of severe sepsis and shock is crucial for patients' survival. Adjuvant therapies against inflammatory and coagulation cascades and augmenting fibrinolysis are still controversial and need further assessment. Among them activated protein C and supplementation therapy have given promising results.
 ...
PMID:Purpura fulminans in sepsis. 1717 Jun 24

Hyperbaric oxygen has been found to be beneficial in treating heatstroke animals. We attempted to further assess the possible mechanism of therapeutic protection offered by hyperbaric oxygen in experimental heatstroke. Anesthetized rats, immediately after the onset of heatstroke, were randomized into the following groups and given: a) hyperbaric oxygen (100% O(2) at 253 kPa for 1 h); or b) normal air. They were exposed to 43 degrees C temperature to induce heatstroke. When the untreated rats underwent heat stress, their survival time values were found to be 20-24 min. Resuscitation with hyperbaric oxygen increased the survival time to new values of 152-176 min. All untreated heatstroke rats displayed cerebrovascular dysfunction (evidenced by hypotension, intracranial hypertension, and cerebral hypoperfusion, hypoxia, and ischemia), hypercoagulable state (evidenced by increased levels of activated partial thromboplastin time, prothrombin time, and D-dimer, but decreased values of platelet count and protein C in plasma), and tissue ischemia/injury (evidenced by increased levels of creatinine, serum urea nitrogen, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase in plasma, and dihydrobenzoic acid, lipid peroxidation, and oxidized-form glutathione/reduced-form of glutathione ratio in hypothalamus). The cerebrovascular dysfunctions, hypercoagulable state, tissue ischemia/injury, and brain oxidative stress that occurred during heatstroke were all suppressed by hyperbaric oxygen therapy. The current results indicate that hyperbaric oxygen therapy may resuscitate rats that had a heatstroke by decreasing multiple organ dysfunction and brain oxidative stress.
 ...
PMID:Hyperbaric oxygen improves survival in heatstroke rats by reducing multiorgan dysfunction and brain oxidative stress. 1750 57

Periventricular leukomalacia (PVL), the dominant form of brain injury in premature infants, is characterized by white matter injury (WMI) and is associated with cerebral palsy. The pathogenesis of PVL is complex and likely involves ischemia/reperfusion, free radical formation, excitotoxicity, impaired regulation of cerebral blood flow, a procoagulant state, and inflammatory mechanisms associated with maternal and/or fetal infection. Using an established animal model of human PVL, we investigated whether activated protein C (APC), an anti-coagulant factor with anti-inflammatory, anti-apoptotic, anti-oxidant, and cytoprotective activities, could reduce endotoxin-induced WMI in the developing rat brain. Intraperitoneal injections of lipopolysaccharide (LPS) (0.5 mg/kg body weight) were given at embryonic days 18 (E18) and 19 (E19) to pregnant Sprague-Dawley rats; control rats were injected with sterile saline. A single intravenous injection of recombinant human (rh) APC (0.2 mg /kg body weight) was given to pregnant rats following the second LPS dose on embryonic day 19 (E19). Reduced cell death in white matter and hypomyelination were shown on TUNEL and myelin basic protein (MBP) staining, respectively, on late postnatal days (P7) in APC-treated groups. There were significantly fewer TUNEL+nuclei in the periventricular WM in the APC+LPS group than in the untreated LPS group. Compared to the APC+LPS and control group, MBP expression was weak in the LPS group on P7, indicating endotoxin-induced hypomyelination in the developing rat brain. APC attenuated the LPS-induced protein expression of inflammatory cytokines, tumor necrosis factor-alpha, and interleukin-6, as evaluated by ELISA in neonatal rat brains. A single intraperitoneal injection of rhAPC (0.2 mg/kg body weight) to neonatal rats on P1 also had similar protective and anti-inflammatory effects against maternally administered LPS. Collectively, these data support the hypothesis that APC may provide protection against an endotoxin-evoked inflammatory response and WMI in the developing rat brain. Moreover, our results suggest that the possible use of APC in treatment of preterm infants and pregnant women with maternal or placental infection may minimize the risk of PVL and cerebral palsy.
 ...
PMID:Activated protein C reduces endotoxin-induced white matter injury in the developing rat brain. 1764 74

We present a case of mesenteric ischemia in a 32-year-old woman. The rarity of this potentially fatal condition in this age group, the diagnostic and therapeutic challenges associated with such a condition, and secondary causes that must always be investigated are highlighted. In this case, activated protein C resistance resulted in thrombosis of the superior mesenteric artery and subsequent bowel ischemia.
 ...
PMID:Mesenteric artery occlusion secondary to activated protein C resistance: a life-threatening combination. 1821 86

Portal vein thrombosis secondary to protein C deficiency is a rare finding. Diagnosing a portal vein thrombosis itself is difficult due to nonspecific symptoms such as nausea, vomiting, anorexia, and weight loss. Proving that a protein C deficiency is the cause of a portal vein thrombosis is even more difficult as an extensive and thorough workup is required to rule out malignancies, myeloproliferative disorders, and hypercoaguable states which can all lead to thromboses. Patients require anticoagulation to prevent two dangerous complications of portal vein thrombosis; portal hypertension leading to esophageal varices with massive hemetemesis and extension of thrombus from the portal vein into the mesenteric veins leading to intestinal ischemia and death. In this case report, we present a patient with the complaint of painless jaundice who was found to have an incidental finding of portal vein thrombosis secondary to protein C deficiency. The different etiologies of portal vein thrombosis, along with diagnosis and treatment options will be discussed and highlighted.
 ...
PMID:A rare incidental finding in a case of painless jaundice. 3071 33

Perinatal hypoxia-ischemia remains the single most important cause of brain injury in the newborn, leading to death or lifelong sequelae. White matter injuries in newborn infants have long-term effects on physical, visual, motor, sensory, cognitive and social development in human infants. There is no known cure for neonatal hypoxic ischemic encephalopathy (NHIE). Activated protein C has potent anticoagulant activity due to its ability to inactivate factor Va and VIIIa. APC is the first effective biological therapy approved for the treatment of severe sepsis. Although APC is well defined as a physiological anticoagulant, emerging data suggest that it also has cytoprotective, anti-inflammatory and antiapoptotic properties. APC has been shown to provide neuroprotection in ischemic brain and spinal cord injury. Here, we propose that APC, which modulates many of these processes, may represent a promising therapeutic agent for NHIE. Seven days old Wistar Albino rat pups have been used in the study (n=42). Experimental groups in the study were: sham-operated group, APC treated group, and vehicle treated group. In hypoxia-ischemia groups, the left common carotid artery was ligated permanently on the seventh postnatal day. Two hours after the procedure, hypoxia (92% nitrogen and 8% oxygen) was applied for 2.5 h. APC were injected (intraperitoneally; i.p.) as a single dose immediately after the hypoxia period. Brain nitrite levels, neuronal cell death, and apoptosis were evaluated in both hemispheres 72 h after the hypoxic-ischemic insult. Histopathological evaluation demonstrated that APC significantly diminished the number of "apoptotic cells" in the hippocampal CA1, CA2, CA3 and gyrus dentatus regions in both hemispheres. APC treatment significantly reduced "apoptotic cell death" in both hemispheres, when compared with vehicle treated group. APC significantly preserved the number of neurons CA1, CA3 regions of the hippocampus, when compared with vehicle treated group. Our results showed that hypoxic-ischemic injury caused a significant increase in NO production. The APC-treated animals were reduced brain nitrite levels in carotid ligated hemispheres. To our knowledge, this is the first study that demonstrates a protective effect of the APC against hypoxia-ischemia in the developing brain.
 ...
PMID:Effects of activated protein C on neonatal hypoxic ischemic brain injury. 1842 Jan 81

Ischaemia-reperfusion injury of the lung is a major cause of morbidity and mortality, particularly following lung transplantation, the mainstay treatment for patients with end-stage pulmonary disease. Effective measures to prevent this complication are lacking. Thrombomodulin (TM) is an endothelial cell receptor and cofactor for thrombin-mediated generation of the anticoagulant and anti-inflammatory activated protein C (APC). The N-terminal lectin-like domain (LLD) of TM has no direct effects on coagulation, but has distinct anti-inflammatory properties, interfering with leukocyte adhesion, complement activation and cytokine generation, all of which are hallmarks of ischaemia-reperfusion injury. Using a murine model of lung ischaemia-reperfusion injury (90 min ischaemia, 4 h reperfusion), the present study shows that mice lacking the LLD of TM respond with increased extravasation of neutrophils and macrophages into the lung parenchyma and bronchoalveolar fluid (BALF), with augmented BALF levels of cytokines interleukin (IL)-1beta and granulocyte-monocytic colony-stimulating factor (GM-CSF). Pre-treatment of wild-type mice with recombinant LLD, as compared with controls, significantly suppresses protein leakage and accumulation of leukocytes in the BALF. These novel findings support further evaluation of recombinant lectin-like domain of thrombomodulin to protect the lung against tissue-damaging pro-inflammatory responses following ischaemia-reperfusion.
 ...
PMID:The lectin-like domain of thrombomodulin protects against ischaemia-reperfusion lung injury. 1850 17

Free flap necrosis continues to be a significant problem in microvascular surgery. Despite improved microsurgical techniques and equipment, flap loss remains the major operative complication. Although ischemia-induced reperfusion injury remains a significant etiologic factor in flap loss, there is continued interest in endothelial mechanisms that regulate microvascular injury and thrombosis. In recent years, activated protein C (APC) has emerged as a promising therapy in counteracting microcirculatory injury. APC is an anticoagulant that is also involved in signaling pathways that modulate inflammation, apoptosis, and vascular permeability. This article presents the mechanism of action of APC and the benefits of this therapeutic agent, including a possible role in the prevention of free flap ischemia-reperfusion injury.
 ...
PMID:Activated protein C: an emerging therapeutic agent in the prevention of ischemia-reperfusion injury. 1859 23

Activated protein C (APC) is a serine protease with anticoagulant and direct cytoprotective activities. Early postischemic APC application activates the cellular protein C pathway in brain endothelium and neurons, which is neuroprotective. Whether late APC administration after a transient ischemic attack is neuroprotective and whether APC influences brain repair is not known. Here, we determined safety and efficacy of late APC and tissue-plasminogen activator (tPA) administrations in a mouse model of transient brain ischemia. tPA given at 6 h after onset of ischemia killed all mice within 2 d, whereas APC given at 6 or 24 h after ischemia onset improved significantly functional outcome and reduced spread of the ischemic lesion. At 7 d postischemia, APC multiple dosing (0.8 mg/kg, i.p.) at 6-72 or 72-144 h enhanced comparably cerebral perfusion in the ischemic border by approximately 40% as shown by in vivo lectin-FITC angiography, blocked blood-brain barrier leakage of serum proteins, and increased the number of endothelial replicating cells by 4.5- to 4.7-fold. APC multidosing at 6-72 h or 72-144 h increased proliferation of neuronal progenitor cells in the subventricular zone (SVZ) by 40-50% and migration of newly formed neuroblasts from the SVZ toward the ischemic border by approximately twofold. The effects of APC on neovascularization and neurogenesis were mediated by protease-activated receptor 1 and were independent of the reduction by APC of infarction volume. Our data show that delayed APC administration is neuroprotective and mediates brain repair (i.e., neovascularization and neurogenesis), suggesting a significant extension of the therapeutic window for APC intervention in postischemic brain.
 ...
PMID:Activated protein C promotes neovascularization and neurogenesis in postischemic brain via protease-activated receptor 1. 1903 71


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>