Multiple effects of hypothermia on inflammatory response following ischemia-reperfusion injury in experimental ischemic neuropathy.
Hypothermia is neuroprotective in peripheral nerve ischemia, but the mechanism(s) of neuroprotection are not well known. A major mechanism of ischemia-reperfusion (IR) injury is the inflammatory response. We therefore dissected the effects of hypothermia on inflammatory mediators in peripheral nerve ischemia of rats. Following functional and pathological evaluations for the effect of hypothermia on IR injury, we undertook immunohistochemical studies of inflammatory cells, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), and nuclear factor kappa B (NF-kappaB) in nerve subjected to IR under defined hypothermic conditions with varying time delays (0, 1, 3, and 4 h) and depth of hypothermia (28 degrees C, 32 degrees C, and 35 degrees C). Functionally and pathologically, significant hypothermic neuroprotection was confirmed in the intraischemically treated groups but not in the postischemically treated groups. In endoneurial microvessels, intraischemic hypothermia inhibited ICAM-1 upregulation but not TNF-alpha, NF-kappaB, and IL-6 expressions. We demonstrated significantly reduced granulocyte and mononuclear phagocyte infiltration into nerve with intraischemic hypothermia but not with postischemic hypothermia. Cytokine (TNF-alpha and IL-6) positive cells were significantly decreased in both epineurium and endoneurium with intraischemic hypothermia. Excess NF-kappaB expression was seen in both Schwann cell and axon under normothermia (35 degrees C) but was inhibitable with deep hypothermia (28 degrees C). We conclude that intraischemic hypothermia significantly attenuates the inflammatory response by its effect on multiple key mediators including cytokines, ICAM-1, and NF-kappaB.
Kawamura
Nobutoshi
N
Mayo Clinic, Department of Neurology, 811 Guggenheim Building, 200 First Street SW, Rochester, MN 55905, USA.
Schmeichel
Ann M
AM
Wang
Yanping
Y
Schmelzer
James D
JD
Low
Phillip A
PA
D000200:Action Potentials / Q000502:physiology / Q000528:radiation effects; D000818:Animals; D001522:Behavior, Animal; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D007839:Functional Laterality; D007036:Hypothermia, Induced / Q000379:methods*; D007150:Immunohistochemistry / Q000379:methods; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000628:therapy*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D010523:Peripheral Nervous System Diseases / Q000150:complications* / Q000378:metabolism; D010586:Phagocytes / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000150:complications* / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015850:Interleukin-6; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1