Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020672 (hypothermia)
 17,327 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute and fulminant liver failure induced by viral hepatitis, alcohol or other hepatotoxic drugs, are associated with tumor necrosis factor (TNF) production. In a mouse model of lethal hepatitis induced by TNF, apoptosis and necrosis of hepatocytes, but also lethality, hypothermia and influx of leukocytes into the liver, are prevented by a broad-spectrum matrix metalloproteinase (MMP) inhibitor, BB-94. Mice deficient in MMP-2, MMP-3 or MMP-9 had lower levels of apoptosis and necrosis of hepatocytes, and better survival. We found induction of MMP-9 activity and fibronectin degradation. Our findings suggest that several MMPs play a critical role in acute, fulminant hepatitis by degrading the extracellular matrix and allowing massive leukocyte influx in the liver. BB-94 also prevented lethality in TNF/interferon-gamma therapy in tumor-bearing mice. A broad-spectrum MMP inhibitor may be potentially useful for the treatment of patients with acute and perhaps chronic liver failure, and in cancer therapies using inflammatory cytokines.
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PMID:Inhibition of matrix metalloproteinases blocks lethal hepatitis and apoptosis induced by tumor necrosis factor and allows safe antitumor therapy. 1168 84

Hepatic ischemia-reperfusion injury is an important cause of graft dysfunction after liver transplantation. Liver sinusoidal endothelial cells (LSECs) are particularly sensitive to ischemia-reperfusion injury and undergo apoptosis. This study investigates the protective role of PGE(1) on apoptosis of LSEC during hypoxia-reoxygenation in vitro. Hypothermia-hypoxia followed by reoxygenation triggered LSEC apoptosis, and prostaglandin PGE(1) protected LSEC from apoptosis in a dose-dependent manner. The release of matrix metalloproteinases (MMPs) and nitric oxide (NO) by LSECs were increased after hypoxia reoxygenation. Both the MMP inhibitor BB3103 and the NO inhibitor LNAM effectively decreased LSEC apoptosis, suggesting a separate role of MMPs and NO in hypoxia-reoxygenation-induced LSEC apoptosis. PGE(1) down-regulated NO production by inhibiting the expression of inducible NO synthase in LSEC. PGE(1) also inhibited MMP-2 release from LSEC during hypoxia reoxygenation. These results indicate that the protection of LSECs from apoptosis by PGE(1) in hepatic ischemia-reperfusion injury is mediated by inhibiting inducible NO synthase and MMP release.
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PMID:Prostaglandin E(1) protects human liver sinusoidal endothelial cell from apoptosis induced by hypoxia reoxygenation. 1207 35

Recent evidence suggests that matrix metalloproteinases (MMPs) contribute to acute edema and lesion formation following ischemic and traumatic brain injuries (TBI). Experimental and clinical studies have also reported the beneficial effects of posttraumatic hypothermia on histopathological and behavioral outcome. The purpose of this study was to determine whether therapeutic hypothermia would affect the activity of MMPs after TBI. Male Sprague-Dawley rats were traumatized by moderate parasagittal fluid-percussion (F-P) brain injury. Seven groups (n=5/group) of animals were investigated: sham-operated, TBI with normothermia (37 degrees C), and TBI with hypothermia (33 degrees C). Normothermia animals were killed at 4, 24, 72 h and 5 days, and hypothermia animals at 24 or 72 h. Brain temperature was reduced to target temperature 30 mins after trauma and maintained for 4 h. Ipsilateral and contralateral cortical, hippocampal, and thalamic regions were analyzed by gelatin and in situ zymography. In traumatized normothermic animals, TBI significantly (P<0.005) increased MMP-9 levels in ipsilateral (right) cortical and hippocampal regions, compared with contralateral or sham animals, beginning at 4 h and persisting to 5 days. At 1, 3, and 5 days after TBI, significant increases in MMP-2 levels were observed. In contrast to these findings observed with normothermia, posttraumatic hypothermia significantly reduced MMP-9 levels. Hypothermic treatment, however, did not affect the delayed activation of MMP-2. Clarifying the mechanisms underlying the beneficial effects of posttraumatic hypothermia is an active area of research. Posttraumatic hypothermia may attenuate the deleterious consequences of brain trauma by reducing MMP activation acutely.
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PMID:Influence of therapeutic hypothermia on matrix metalloproteinase activity after traumatic brain injury in rats. 1595 64

Reperfusion injury is a complication of recanalization therapies after focal cerebral ischemia. The disruption of the blood-brain barrier (BBB) caused by up-regulated metalloproteinases (MMPs) can lead to edema and hemorrhage. Middle cerebral artery occlusion (MCAO=90 min) and reperfusion (R=24 h vs. 5 days) was induced in male Wistar rats. Rats were randomized in four groups: (1) control (C), (2) twice daily minocycline (30 mg/kg bodyweight) every day (M), (3) hypothermia (33 degrees C) for 4 h starting 60 min after occlusion (H), (4) combination of groups 2 and 3 (MH). Serial MRI was performed regarding infarct evolution and BBB disruption, MMP-2 and MMP-9 were assessed by zymography of serum and ischemic brain tissue, and a functional neuroscore was done at 24 h and 5 days. M and H reduced both infarct sizes, volume and signal intensity of BBB breakdown and improved neuroscore at all points in time to the same extent. This was most likely due to inhibition of MMP-2 and MMP-9. The presence of MMP-9 at 24 h or MMP-2 at 5 days in brain tissue correlated with BBB breakdown whereas serum MMP-2- and -9 showed no relationship with BBB breakdown. The combination MH had a small but not significantly additional effect over the single treatments. Minocycline seems to be as neuroprotective as hypothermia in the acute and subacute phase after cerebral ischemia. One essential mechanism is the inhibition of MMPs. The combination therapy is only slightly superior. The net effect of MMPs inhibition up to 5 days after focal cerebral ischemia is still beneficial.
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PMID:Minocycline and hypothermia for reperfusion injury after focal cerebral ischemia in the rat: effects on BBB breakdown and MMP expression in the acute and subacute phase. 1803 17

Fatalities due to an extreme ambient temperature might present with poor or nonspecific pathologies; thus, the diagnosis of the cause of death in such cases is one of the most difficult tasks in forensic pathology. The present study investigated the molecular pathology of alveolar damage involving pulmonary edema with special regard to hyperthermia (heatstroke) and hypothermia (cold exposure) in forensic autopsy cases (total, n=122; within 48 h postmortem). Intrapulmonary mRNA and immunohistochemical expressions of matrix metalloproteinases (MMPs), intercellular adhesion molecule-1 (ICAM-1), claudin-5 (CLDN-5) and aquaporins (AQPs) were examined. Relative mRNA quantification using Taqman real-time PCR assay demonstrated higher expressions of all markers except for AQP-5 in fatal hyperthermia, and higher expression of MMP-9 in fatal hypothermia. Acute cardiac death, mechanical asphyxiation, fire fatality and intoxication did not present any characteristic findings. In immunostaining, only MMPs showed evident differences among the causes of death: MMP-9 was intensely positive in most cases of hyperthermia and hypothermia, but MMP-2 expression was evident only in hyperthermia. These findings suggest alveolar damage involving pulmonary edema, characteristic of fatal hyperthermia and hypothermia. Systematic analysis of gene expressions using real-time PCR might be a useful procedure in forensic death investigation.
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PMID:Molecular pathology of pulmonary edema in forensic autopsy cases with special regard to fatal hyperthermia and hypothermia. 2359 50

Ischemic stroke destroys blood-brain barrier (BBB) integrity. There are currently no effective treatments available in the clinical setting. Post-ischemia treatment with phenothiazine drugs [combined chlorpromazine and promethazine (C+P)] has been shown to be neuroprotective in stroke. The present study determined the effect of C+P in BBB integrity. Sprague-Dawley rats were divided into the following groups ( n=8 each): (1) stroke, (2) stroke treated by C+P with temperature control, and (3) stroke treated by C+P without temperature control. Infarct volume and neurological deficits were measured to assess the neuroprotective effect of C+P. BBB permeability was determined by brain edema and Evans blue leakage. Expression of BBB integral molecules, including proteins of aquaporin-4 and -9 (AQP-4, AQP-9), matrix metalloproteinase-2 and -9 (MMP-2, MMP-9), zonula occludens-1 (ZO-1), claudin-1/5, occludin, and laminin were determined by Western blot. Stroke caused brain infarction and neurological deficits, as well as BBB damage, which were all attenuated by C+P through drug-induced hypothermia. When the reduced temperature was controlled to physiological levels, C+P still conferred neuroprotection, suggesting a therapeutic effect independent of hypothermia. Furthermore, C+P significantly attenuated the increase in AQP-4, AQP-9, MMP-2, and MMP-9 levels after stroke, and reversed the decrease in tight junction protein (ZO-1, claudin-1/5, occludin) and basal laminar protein (laminin) levels. This study clearly indicates a beneficial effect of C+P on BBB integrity after stroke, which may be independent of drug-induced hypothermia. These findings further prove the clinical target and cell-signal communication of C+P treatment, which may direct us closer toward the development of an efficacious neuroprotective therapy.
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PMID:Therapeutic Target and Cell-signal Communication of Chlorpromazine and Promethazine in Attenuating Blood-Brain Barrier Disruption after Ischemic Stroke. 3056 51