OKABAYASHI Kiyoshi Yamaguchi University, School of Medicine, Associate Professor, 医学部, 助教授 (50127627)
KASAOKA Shunji Yamaguchi University, University Hospital, Assistant Professor, 医学部附属病院, 講師 (90243667)
ISHIKAWA Toshizo Yamaguchi University, School of Medicine, Professor, 医学部, 教授 (90034991)
FUJISAWA Hirosuke Yamaguchi University, School of Medicine, Assistant Professor, 医学部, 講師 (50238565)
TSURUTA Ryosuke Yamaguchi University, School of Medicine, Research Associate, 医学部附属病院, 助手 (30263768)
秋村 龍夫 山口大学, 医学部附属病院, 講師 (30202542)
|Budget Amount *help
¥28,470,000 (Direct Cost: ¥21,900,000、Indirect Cost: ¥6,570,000)
Fiscal Year 2004: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2003: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2002: ¥20,540,000 (Direct Cost: ¥15,800,000、Indirect Cost: ¥4,740,000)
The prognoses of severe acute brain insults (encephalopathy in cardio-pulmonary arrest victims, stroke, head injury, etc) are very poor, so that the elucidation of pathophysiology and the treatment strategies in these brain insults are extremely important and urgent. We have switched our idea that immuno-endocrinological pathways might participate on the pathophysiology besides the conventional mechanisms, such as Ca^<2+> ・ glutamate theory, free radicals theory and so on. In the present project, we have done fundamental researches and clinical studies, based on neuro-immuno-endocrinological and also conventional approaches.
1.Post resuscitation encephalopathy patients (cardio-pulmonary resuscitation).
1)Neurologically poor outcome (Glasgow outcome scale ; severe disabled, vegetative state, death)
(1)Xe-CT cerebral blood flow : <30ml/100g/min, poor reactivity to acetazolamide. (2)Internal jugular venous blood oxygen saturation (SjvO_2) : high (>80%). (3)T1-weighted im
age of magnetic resonance imaging : presence of hyper-intense lesions in the basal ganglia. (4)Neuron specific enolase : elevated in both cerebro spinal fluid (CSF) and in serum. (5)Interleukin (IL)-6, IL-8 : remarkably elevated in CSF.
2.Subarachnoid hemorrhage (SAH, post-operative) patients.
1)Catecholamine serge (high concentrations of norepinephrine and epinephrine in blood) occurred in SAH patients and caused cardiomyopathy.
2)Free radical (8-OH-2 deoxyguanosine ; 8-OHdG) : elevated gradually for 14 days in succession in CSF, but no difference with or without cerebral vaso-spasm.
3)NOx (NO_2^-+NO_3^-) : constantly elevated for 14 days in CSF, and weakly correlated to 8-OHdG.
4)Inflammatory cytokines (IL-8, IL-6, tumor necrosis factor □ ; TNF□, high mobility group box 1 ; HMGB1) : remarkably elevated in CSF.
5)Anti-inflammatory cytokines (IL4, IL-8) : moderately elevated in CSF.
3.Traumatic brain injury patients.
1)Inflammatory cytokines (IL-6) : remarkably elevated in CSF.
Basic researches have been performed by a primary culture microglia of new-born rats, human volunteer monocyte and a forebrain ischemia model of rats.
1.Primary culture microglia of new-born rats.
The microglia remarkably rose in NOx and inflammatory cytokines (TNF□, IL-1□, IL-6) by endotoxin irritation.
1)Estrogen (17□ estradiol)
Estrogen could restrain the release of TNF□, IL-1□ and IL-6 to approximately half of each level at least for 24hrs, respectively.
2)Immuno-suppressants (methylpredmisolone, cyclosporine, tacrolimus) and an anti-inflammatory drug (indiometacin). All of these drugs essentially restrained NOx and inflammatory cytokines, but it became clear that each drug had different properties.
2.Human cultural monocyte.
The monocytes remarkably rose in NOx, inflammatory (TNF□, IL-1□, IL-6, IL-12p70) and anti-inflammatory (IL-10) cytokines by endotoxin irritation. Hypothermic (33.0□) condition rose the levels of TNF□, IL-1□, IL-6, and IL-12p70 from those under normothermic (37.0□) condition, but did not affect NOx production.
3.Forebrain ischemic models were established by bilateral common carotid arteries occlusion and/or blood withdrawal in rats. But the immuno-suppressants and anti-inflammatory drugs have not been examined in the brain ischemic models.
In conclusion, prognostic neurologic outcome of severe acute brain insults in human could be evaluate by cerebral blood flow, SjvO2, severity of cardiomyopathy caused by catecholamine surge, and CSF levels of NSE, IL-6 and IL-8. We clearly demonstrated that immuno-endocrinological events are involved in the pathophysiology of severe acute brain insults in human. Immunity of the damaged brain is unbelievably changed, which are demonstrated by the elevation of TNF□, IL-1□, IL-6, HMGB1 and 8-OHdG in CSF of the patients. Most of the cytokines and the free radicals assumed to be produced by the inflammatory cells such as microglia and monocyte.
These results might be useful to make strategies to protect/resuscitate the damaged brain in human. Less