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Mice Deficient in Interleukin-1 Converting Enzyme Are Resistant to Neonatal Hypoxic-Ischemic Brain Damage

Interleukin-1 (IL-1) converting enzyme (ICE) is a cysteine protease that cleaves inactive pro-IL-1β to active IL-1β. The pro-inflammatory cytokine IL-1β is implicated as a mediator of hypoxic-ischemic (HI) brain injury, both in experimental models and in humans. ICE is a member of a family of ICE-li...

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Published in:Journal of cerebral blood flow and metabolism 1999-10, Vol.19 (10), p.1099-1108
Main Authors: Liu, Xiao-Hong, Kwon, Deborah, Schielke, Gerald P., Yang, Guo-Yuan, Silverstein, Faye S., Barks, John D. E.
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description Interleukin-1 (IL-1) converting enzyme (ICE) is a cysteine protease that cleaves inactive pro-IL-1β to active IL-1β. The pro-inflammatory cytokine IL-1β is implicated as a mediator of hypoxic-ischemic (HI) brain injury, both in experimental models and in humans. ICE is a member of a family of ICE-like proteases (caspases) that mediate apoptotic cell death in diverse tissues. The authors hypothesized that in neonatal mice with a homozygous deletion of ICE (ICE-KO) the severity of brain injury elicited by a focal cerebral HI insult would be reduced, relativefto wild-type mice. Paired litters of 9- to 10-day-old ICE-KO and wild-type mice underwent right carotid ligation, followed by 70 or 120 minutes of exposure to 10% O2, In this neonatal model of transient focal cerebral ischemia followed by reperfusion, the duration of hypoxia exposure determines the duration of cerebral ischemia and the severity of tissue damage. Outcome was evaluated 5 or 21 days after lesioning; severity of injury was quantified by morphometric estimation of bilateral cortical; striatal, and dorsal hippocampal volumes. In animals that underwent the moderate HI insult (70-minute hypoxia), damage was attenuated in ICE-KO mice, when evaluated at 5 or 21 days post-lesioning. In contrast, in mice that underwent the more severe HI insult (120-minute hypoxia), injury severity was the same in both groups. Reductions in intra-HI CBF, measured by laser Doppler flowmetry, and intra- and post-HI temperatures did not differ between groups. These results show that ICE activity contributes to the progression of neonatal HI brain injury in this model. Whether these deleterious effects are mediated by proinflammatory actions of IL-lβ and/or by pro-apoptotic mechanisms is an important question for future studies.
doi_str_mv 10.1097/00004647-199910000-00006
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E.</creatorcontrib><title>Mice Deficient in Interleukin-1 Converting Enzyme Are Resistant to Neonatal Hypoxic-Ischemic Brain Damage</title><title>Journal of cerebral blood flow and metabolism</title><addtitle>J Cereb Blood Flow Metab</addtitle><description>Interleukin-1 (IL-1) converting enzyme (ICE) is a cysteine protease that cleaves inactive pro-IL-1β to active IL-1β. The pro-inflammatory cytokine IL-1β is implicated as a mediator of hypoxic-ischemic (HI) brain injury, both in experimental models and in humans. ICE is a member of a family of ICE-like proteases (caspases) that mediate apoptotic cell death in diverse tissues. The authors hypothesized that in neonatal mice with a homozygous deletion of ICE (ICE-KO) the severity of brain injury elicited by a focal cerebral HI insult would be reduced, relativefto wild-type mice. 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E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mice Deficient in Interleukin-1 Converting Enzyme Are Resistant to Neonatal Hypoxic-Ischemic Brain Damage</atitle><jtitle>Journal of cerebral blood flow and metabolism</jtitle><addtitle>J Cereb Blood Flow Metab</addtitle><date>1999-10-01</date><risdate>1999</risdate><volume>19</volume><issue>10</issue><spage>1099</spage><epage>1108</epage><pages>1099-1108</pages><issn>0271-678X</issn><eissn>1559-7016</eissn><coden>JCBMDN</coden><abstract>Interleukin-1 (IL-1) converting enzyme (ICE) is a cysteine protease that cleaves inactive pro-IL-1β to active IL-1β. The pro-inflammatory cytokine IL-1β is implicated as a mediator of hypoxic-ischemic (HI) brain injury, both in experimental models and in humans. ICE is a member of a family of ICE-like proteases (caspases) that mediate apoptotic cell death in diverse tissues. The authors hypothesized that in neonatal mice with a homozygous deletion of ICE (ICE-KO) the severity of brain injury elicited by a focal cerebral HI insult would be reduced, relativefto wild-type mice. Paired litters of 9- to 10-day-old ICE-KO and wild-type mice underwent right carotid ligation, followed by 70 or 120 minutes of exposure to 10% O2, In this neonatal model of transient focal cerebral ischemia followed by reperfusion, the duration of hypoxia exposure determines the duration of cerebral ischemia and the severity of tissue damage. Outcome was evaluated 5 or 21 days after lesioning; severity of injury was quantified by morphometric estimation of bilateral cortical; striatal, and dorsal hippocampal volumes. In animals that underwent the moderate HI insult (70-minute hypoxia), damage was attenuated in ICE-KO mice, when evaluated at 5 or 21 days post-lesioning. In contrast, in mice that underwent the more severe HI insult (120-minute hypoxia), injury severity was the same in both groups. Reductions in intra-HI CBF, measured by laser Doppler flowmetry, and intra- and post-HI temperatures did not differ between groups. These results show that ICE activity contributes to the progression of neonatal HI brain injury in this model. Whether these deleterious effects are mediated by proinflammatory actions of IL-lβ and/or by pro-apoptotic mechanisms is an important question for future studies.</abstract><cop>London, England</cop><pub>SAGE Publications</pub><pmid>10532634</pmid><doi>10.1097/00004647-199910000-00006</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record>
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ispartof Journal of cerebral blood flow and metabolism, 1999-10, Vol.19 (10), p.1099-1108
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subjects Animals
Animals, Newborn
Biological and medical sciences
Body Temperature
Brain - blood supply
Brain - enzymology
Brain Ischemia - genetics
Brain Ischemia - metabolism
Carotid Arteries
Caspase 1 - genetics
Caspases - metabolism
Cerebral Cortex - blood supply
Cerebral Cortex - metabolism
Cerebrovascular Circulation
Corpus Striatum - blood supply
Corpus Striatum - metabolism
Disease Models, Animal
Hippocampus - blood supply
Hippocampus - metabolism
Hypoxia, Brain - genetics
Hypoxia, Brain - metabolism
Ligation
Medical sciences
Mice
Mice, Inbred C57BL
Mice, Knockout
Neurology
Vascular diseases and vascular malformations of the nervous system
title Mice Deficient in Interleukin-1 Converting Enzyme Are Resistant to Neonatal Hypoxic-Ischemic Brain Damage
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