Experimental Fluid Percussion Brain Injury Induces Temporally and Regionally Specific Expression of Heat Shock Protein Genes

다국어 초록 (Multilingual Abstract)

Although the induction of various members of hsp (heat shock protein) gene family has been linked to the resistanceto apoptosis by a range of diverse stress stimuli, detail information has not been available yet as to the temporal andspatial expression patterns of various hsp genes after traumatic brain injury. In the present study, using a lateral fluidpercussion (FP) injury as a model of traumatic brain injury, expression profiles of stress induced hsp genes were comparativelyevaluated in the adult rat brain by in situ hybridization (ISH). We found that the temporal and regional expressionpatterns between the hsp70 superfamily members, hsp110 and hsp70, and the small hsp member, hsp25 are distinct.While the hsp110 and hsp70 expression was observed as early as 1 hr after injury and maximally induced at 3 hrafter injury, the hsp25 expression appeared 6 hr after injury and the expression sustained until 6 days after the injury.Moreover, the expression of hsp110 and hsp70 was localized primarily in the impact site, that of the small hsp25 wasobserved throughout the ipsilateral cortical area in the distant regions remote from the impact site as well as in theimpact site following injury. These results suggest that the sequential and combinatorial manipulation of various hspgenes can be exploited in reducing acute and delayed post-traumatic apoptosis and associated neurological dysfunction.

국문 초록 (Abstract)

유압출 뇌손상에 의한 heat shock protein 유전자들의발현 양상김영화, 김달수1, 박선화, 김태식, 선 웅, 김 현, 김창미*고려대학교 의과대학 해부학교실, 1가톨릭 대학교 의정부성모병원 신경외과학교실HSP유전자군은 다양한 스트레스 자극에 의해 발현이 유도되는 것으로 알려져 있음에도 불구하고 외상성 뇌 손상 후 hsp유전자들의 발현양상에 대한 명확한 보고가 없다. 이 연구에서는 외상성 뇌손상 모델로써 유압출 뇌손상 동물모델을 사용하였으며, 외상성 뇌손상 스트레스에 의해 유도되는 hsp 유전자들의 발현양상은 in situ hybridization 방법을 사용하여 비교 분석하였다. 그 결과 hsp70 superfamily member인 hsp110, hsp70과 작은 hsp member인 hsp25의 발현 양상은 많은 차이를 보였다.Hsp110과 hsp70은 뇌손상 후 1시간 내에 발현하기 시작하여 손상 후 3시간에 최고의 발현을 보였으며, hsp25는 손상 후6시간에 발현하기 시작하여 손상 후 6일까지 지속되었다. Hsp110과 hsp70은 손상부위에서 높은 발현을 보인 반면, hsp25는손상 부위 뿐만 아니라 손상부위와 멀리 떨어진 같은 쪽 대뇌피질 전 영역에 걸쳐 발현하였다. 이러한 결과는 다양한 hsp유전자들을 조합하여 순차적으로 조작함으로써 급성 혹은 지연된 외상성 뇌 손상 후 세포사 및 신경학적 기능이상을 완화시킬 수 있을 가능성을 시사한다.

참고문헌 (Reference)

1 "Traumatic axonal injury after closedhead injury in the neonatal pig" 19 (19): 843-853, 2002(b)

2 "The preconditionedhippocampus accelerates HSP70 heat shock gene expressionfollowing transient ischemia in the gerbil" 155 : 7-10, 1993

3 "The distribution andlocalization of hsp110 in brain" 869 : 49-55, 2000

4 "Restoration of cerebrovascular responsivenessto hyperventilation by the oxygen radical scavengerN-acetylcysteine following experimental traumatic brain injury" 75 : 774-779, 1991

5 "Regional patterns of blood-brain barrierbreakdown following central and lateral fluid percussion injury inrodents" 415-430, 1993

6 "Overexpression ofHSP25 reduces the level of TNF-α-induced oxidative DNA damage biomarker, 8-hydroxy-2′-deoxyguanosine, in L929 cells" 174 : 27-34, 1998

7 "Overexpression of the rat inducible 70 k-Da heat stress proteinin a transgenic mouse incresease the resistance of the heart toischemic injury" 95 : 1446-1456, 1995

8 "Neuropathological sequelae of traumatic brain injury relationship to neurochemical and biomechanical mechanisms" 74 : 315-342, 1996

9 "Mild traumatic brain injuryinduces apoptotic cell death in the cortex that is preceded bydecreases in cellular Bcl-2 Immunoreactivity" 110 : 605-616, 2002(a)

10 "Massive increase inextracellular potassium and the indiscriminate release of glutamatefollowing concussive brain injury" 889-911, 1990

11 "Mammalian Hsp70 and Hsp110 proteins bind to RNA motifsinvolved in mRNA stability" 274 (274): 17318-17324, 1999

12 "Induction of heat shock gene at the siteof tissue injury in the rat brain" 2 : 1559-1564, 1989

13 "Induction of Apg-a following transient forebrainischemia in the rat brain" 247 : 796-801, 1998

14 "Immunohistochemiacal research on brain stem injury: expression of heat shock protein 70 in rat brainafter traumatic brain stem injury" 14 (14): 135-137, 1998

15 "Human hsp27, Drosophila hsp27 and human alphaB-crystallin expression-mediatedincrease in glutathione is essential for protective activity ofthese proteins against TNF alpha-induced cells death" 15 : 2695-2706, 1996

16 "Hsp110 protects heat-denatured proteins and confers cellular thermoresistance" 272 (272): 31636-31640, 1997

17 "Heat shock proteins as markers of neural injury" 6 : 93-100, 1989

18 "Heat shock proteinhsp70 protects cells from thermal stress even after deletion of itsATP-binding domain" 2036-2040, 1992

19 "Heat shock protein 70 antagonizes apoptosis-including factor" 3 : 839-843, 2001

20 "Experimental brain injury induces regionally distinct apoptosis during the acute and delayed post traumatic period" 18 (18): 5663-5672, 1998

21 "Diffuse prolonged depression of cerebral oxidative metabolismfollowing concussive brain injury in the rat" 1-10, 1991

22 "Differential expression of c-fos, Hsp70 and Hsp27 after photothrombic injury in the rat brain" 45 : 239-246, 1997

23 "Development ofregional cerebral edema after lateral fluid-percussion brain injuryin the rat" 51 263-264, 1990

24 "Cerebralactivation and distribution of inducible hsp110 and hsp70 mRNAsfollowing focal ischemia in rat" 167 : 135-144, 2001

25 "Cellular responses to experimentalbrain injury" 5 (5): 437-442, 1995

26 "Altered gene expression in cerebral ischemia" 2121-24 2127, 1993

27 "Activation of CPP32-like caspase contributes to neuronalapoptosis and neurological dysfunction after traumatic brain injury" 17 (17): 7415-7424, 1997