| 研究生: |
李英勝 Lee, Ying-Sheng |
|---|---|
| 論文名稱: |
骨髓幹細胞在高壓氧治療中風時扮演之角色 The role of bone marrow stem cells in hyperbaric oxygen treated stroke |
| 指導教授: |
蔡坤哲
Tsai, Kuen-Jer |
| 學位類別: |
碩士 Master |
| 系所名稱: |
醫學院 - 臨床醫學研究所 Institute of Clinical Medicine |
| 論文出版年: | 2013 |
| 畢業學年度: | 101 |
| 語文別: | 英文 |
| 論文頁數: | 48 |
| 中文關鍵詞: | 骨髓幹細胞 、高壓氧治療 、中風 |
| 外文關鍵詞: | bone marrow stem cells, hyperbaric oxygen treatment, stroke |
| 相關次數: | 點閱:93 下載:0 |
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研究報告指出高壓氧對於腦中風病人有保護的作用,而高壓氧亦會促進骨髓幹細胞的增生並移動到缺氧而損傷的組織。 本實驗目的在探討使用高壓氧治療腦中風後骨髓幹細胞被召集到腦組織的情況,以及神經細胞新生、膠質細胞增生、血管上皮細胞新生和調節發炎反應的狀況。
大鼠以中大腦動脈阻塞模擬中風產生,之後分別進行為期三週十五次的高壓氧治療,以及兩天兩次的高壓氧治療。並使用修改的神經學損傷嚴重程度評分表(mNSS)來做為行為學上的評量以評估預後情形,以及利用不同種類的免疫組織染色法(CD34-DAPI, BrdU-NeuN, BrdU-GFAP, BrdU-RECA-1, and DAPI-MPO)來觀察腦組織切片,探討高壓氧是否會影響骨髓幹細胞的移行以及是否會影響神經細胞新生、膠質細胞增生、血管上皮細胞新生、神經滋養物質的產生和調節發炎反應的情形。實驗結果發現,在大鼠以中大腦阻塞引發的暫時性腦中風為模型下, 高壓氧治療可以調節腦中風後所引起的傷害。在以三週高壓氧為治療週期的組別中可觀察較低的神經損傷嚴重程度分數(第二十一天 分數為6.2);而只有兩天高壓氧治療的組別損傷嚴重程度分數較高(第二十一天,分數為9.75)。 這意味著三週的高壓氧治療療程比只有兩天高壓氧治療有著較好的神經學上的改善。而較長時間的高壓氧治療也會使得較多的骨髓幹細胞聚集到損傷的腦組織,因此治療時間長短是重要因素。此外,高壓氧治療會有較多程度的神經細胞新生、膠質細胞增生、血管上皮細胞新生及神經滋養物質的產生,並減少中性球聚集到損傷的腦組織進而調節發炎的反應。
結論是高壓氧在腦中風的治療會促進神經保護修補。此外,治療時間若由兩天延長到三週更可以增加治療的效果。
關鍵字:骨髓幹細胞、高壓氧治療、中風
Several studies have provided evidence about neuroprotection by hyperbaric oxygen (HBO) therapy in stroke cases. HBO also promotes bone marrow stem cells (BMSCs) proliferation and mobilization. The study investigates the influence of HBO therapy on migration of BMSCs, neurogenesis, gliosis, angiogenesis and inflammation after transient ischemic stroke.
Rats that sustained one hour of transient middle cerebral artery occlusion (MCAO) were treated with HBO 15 times within 3 weeks or HBO two times within two days. The results were examined using a behavior test (modified neurological severity score, mNSS) and immunohistochemistry staining on CD34-DAPI, BrdU-NeuN, BrdU-GFAP, BrdU-RECA-1, and DAPI-MPO were used to evaluate the effects of HBO therapy on migration of bone marrow stem cells, neurogenesis and gliosis, angiogenesis and inflammation as well as expression of neurotrophic factors were also evaluated.
HBO significantly attenuated ischemic injury of transient MCAO. There was lower mNSS score in the three weeks HBO group (6.2 in day 21), comparing with two days HBO group (9.75 in day 21). It explained that three weeks of HBO treatment had a significantly better neurological outcome than two days HBO course, suggesting the dose-dependent effect of HBO therapy. Mobilization of BMSCs to ischemic area was more improved in long course HBO treatments but not by short course treatments, suggesting that the duration of therapy is crucial for promoting the homing of BMSCs to ischemic brain by HBO therapies. HBO also can stimulate expression of trophic factors and improve neurogenesis , gliosis and angiogenesis. HBO can also decreased the effect of neutrophil aggregation then attenuated inflammation.These effects may help neuronal repair after ischemic stroke and increasing the course of HBO therapy from 2 days to 3 weeks might enhance therapeutic effects on ischemic stroke.
Key word: Bone marrow stem cells; hyperbaric oxygen treatment; stroke
Back T, Hoehn M, Mies G, Busch E, Schmitz B, Kohno K, Hossmann KA (Penumbral tissue alkalosis in focal cerebral ischemia: relationship to energy metabolism, blood flow, and steady potential. Ann Neurol 47:485-492.2000).
Baraniak PR, McDevitt TC (Stem cell paracrine actions and tissue regeneration. Regen Med 5:121-143.2010).
Belayev L, Alonso OF, Busto R, Zhao W, Ginsberg MD (Middle cerebral artery occlusion in the rat by intraluminal suture. Neurological and pathological evaluation of an improved model. Stroke 27:1616-1622.1996).
Benedek A, Moricz K, Juranyi Z, Gigler G, Levay G, Harsing LG, Jr., Matyus P, Szenasi G, Albert M (Use of TTC staining for the evaluation of tissue injury in the early phases of reperfusion after focal cerebral ischemia in rats. Brain Res 1116:159-165.2006).
Benedetti S, Lamorgese A, Piersantelli M, Pagliarani S, Benvenuti F, Canestrari F (Oxidative stress and antioxidant status in patients undergoing prolonged exposure to hyperbaric oxygen. Clin Biochem 37:312-317.2004).
Bogoslovsky T, Spatz M, Chaudhry A, Maric D, Luby M, Frank J, Warach S (Stromal-derived factor-1[alpha] correlates with circulating endothelial progenitor cells and with acute lesion volume in stroke patients. Stroke 42:618-625.2011).
Boltze J, Kowalski I, Geiger K, Reich D, Gunther A, Buhrle C, Egger D, Kamprad
M, Emmrich F (Experimental treatment of stroke in spontaneously hypertensive rats by CD34+ and. Ger Med Sci 3:Doc09.2005).
Buffo A, Rolando C, Ceruti S (Astrocytes in the damaged brain: molecular and cellular insights into their reactive response and healing potential. Biochem Pharmacol 79:77-89.2010).
Chang CF, Niu KC, Hoffer BJ, Wang Y, Borlongan CV (Hyperbaric oxygen therapy for treatment of postischemic stroke in adult rats. Exp Neurol 166:298-306.2000).
Chopp M, Li Y (Treatment of neural injury with marrow stromal cells. Lancet Neurol 1:92-100.2002).
Drummond GR, Cai H, Davis ME, Ramasamy S, Harrison DG (Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression by hydrogen peroxide. Circ Res 86:347-354.2000).
Ginsberg MD (Adventures in the pathophysiology of brain ischemia: penumbra, gene expression, neuroprotection: the 2002 Thomas Willis Lecture. Stroke 34:214-223.2003).
Goldstein LJ, Gallagher KA, Bauer SM, Bauer RJ, Baireddy V, Liu ZJ, Buerk DG, Thom SR, Velazquez OC (Endothelial progenitor cell release into circulation is triggered by hyperoxia-induced increases in bone marrow nitric oxide. Stem Cells 24:2309-2318.2006).
Guo S, Kim WJ, Lok J, Lee SR, Besancon E, Luo BH, Stins MF, Wang X, Dedhar S, Lo EH (Neuroprotection via matrix-trophic coupling between cerebralendothelial cells and neurons. Proc Natl Acad Sci U S A 105:7582-7587.2008).
Guo S, Zhou Y, Xing C, Lok J, Som AT, Ning M, Ji X, Lo EH (The vasculome of the mouse brain. PLoS One 7:e52665.2012).
Hossmann KA (Viability thresholds and the penumbra of focal ischemia. Ann Neurol 36:557-565.1994).
JACOBSON I, LAWSON DD (THE EFFECT OF HYPERBARIC OXYGEN ON EXPERIMENTAL CEREBRAL INFARCTION IN THE DOG. WITH PRELIMINARY CORRELATIONS OF CEREBRAL BLOOD FLOW AT 2 ATMOSPHERES OF OXYGEN. J Neurosurg 20:849-859.1963).
JACOBSON JH, MORSCH JH, RENDELL-BAKER L (CLINICAL EXPERIENCE AND IMPLICATIONS OF HYPERBARIC OXYGENATION. THE HISTORICAL PERSPECTIVE OF HYPERBARIC THERAPY. Ann N Y Acad Sci 117:651-670.1965).
Jones SR, Carpin KM, Woodward SM, Khiabani KT, Stephenson LL, Wang WZ, Zamboni WA (Hyperbaric oxygen inhibits ischemia-reperfusion-induced neutrophil CD18 polarization by a nitric oxide mechanism. Plast Reconstr Surg 126:403-411.2010).
Kawabori M, Kuroda S, Ito M, Shichinohe H, Houkin K, Kuge Y, Tamaki N (Timing and cell dose determine therapeutic effects of bone marrow stromal cell transplantation in rat model of cerebral infarct. Neuropathology.2012).
Khan M, Meduru S, Gogna R, Madan E, Citro L, Kuppusamy ML, Sayyid M, Mostafa M, Hamlin RL, Kuppusamy P (Oxygen cycling in conjunction with stemcell transplantation induces NOS3 expression leading to attenuation of fibrosis and improved cardiac function. Cardiovasc Res 93:89-99.2012).
Kim H, Li Q, Hempstead BL, Madri JA (Paracrine and autocrine functions of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in brain-derived endothelial cells. J Biol Chem 279:33538-33546.2004).
Kranke P, Bennett M, Roeckl-Wiedmann I, Debus S (Hyperbaric oxygen therapy for chronic wounds. Cochrane Database Syst Rev:CD004123.2004).
Kriz J (Inflammation in ischemic brain injury: timing is important. Crit Rev Neurobiol 18:145-157.2006).
Kriz J, Lalancette-Hebert M (Inflammation, plasticity and real-time imaging after cerebral ischemia. Acta Neuropathol 117:497-509.2009).
Kubes P, Granger DN (Nitric oxide modulates microvascular permeability. Am J Physiol 262:H611-H615.1992).
Kubes P, Suzuki M, Granger DN (Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A 88:4651-4655.1991).
Lapidot T, Dar A, Kollet O (How do stem cells find their way home? Blood 106:1901-1910.2005).
Li Y, Chen J, Zhang CL, Wang L, Lu D, Katakowski M, Gao Q, Shen LH, Zhang J, Lu M, Chopp M (Gliosis and brain remodeling after treatment of stroke in rats with marrow stromal cells. Glia 49:407-417.2005).
Lin KC, Niu KC, Tsai KJ, Kuo JR, Wang LC, Chio CC, Chang CP (Attenuatinginflammation but stimulating both angiogenesis and neurogenesis using hyperbaric oxygen in rats with traumatic brain injury. J Trauma Acute Care Surg 72:650-659.2012).
Liu JX, Pinnock SB, Herbert J (Novel control by the CA3 region of the hippocampus on neurogenesis in the dentate gyrus of the adult rat. PLoS One 6:e17562.2011).
Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR (Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science 290:1779-1782.2000).
Miljkovic-Lolic M, Silbergleit R, Fiskum G, Rosenthal RE (Neuroprotective effects of hyperbaric oxygen treatment in experimental focal cerebral ischemia are associated with reduced brain leukocyte myeloperoxidase activity. Brain Res 971:90-94.2003).
Milovanova TN, Bhopale VM, Sorokina EM, Moore JS, Hunt TK, Hauer-Jensen M, Velazquez OC, Thom SR (Hyperbaric oxygen stimulates vasculogenic stem cell growth and differentiation in vivo. J Appl Physiol 106:711-728.2009).
Mink RB, Dutka AJ (Hyperbaric oxygen after global cerebral ischemia in rabbits reduces brain vascular permeability and blood flow. Stroke 26:2307-2312.1995).
Osanai T, Kuroda S, Sugiyama T, Kawabori M, Ito M, Shichinohe H, Kuge Y, Houkin K, Tamaki N, Iwasaki Y (Therapeutic effects of intra-arterial delivery of bone marrow stromal cells in traumatic brain injury of rats--in vivo cell tracking study by near-infrared fluorescence imaging. Neurosurgery 70:435-444.2012).
Papayannopoulou T, Scadden DT (Stem-cell ecology and stem cells in motion. Blood 111:3923-3930.2008).
Popp A, Jaenisch N, Witte OW, Frahm C (Identification of ischemic regions in a rat model of stroke. PLoS One 4:e4764.2009).
Radomski MW, Palmer RM, Moncada S (Comparative pharmacology of endothelium-derived relaxing factor, nitric oxide and prostacyclin in platelets. Br J Pharmacol 92:181-187.1987).
Roth V, Herron MS, Bueno RA, Jr., Chambers CB, Neumeister MW (Stimulating angiogenesis by hyperbaric oxygen in an isolated tissue construct. Undersea Hyperb Med 38:509-514.2011).
Rupadevi M, Parasuraman S, Raveendran R (Protocol for middle cerebral artery occlusion by an intraluminal suture method. J Pharmacol Pharmacother 2:36-39.2011).
Schabitz WR, Schade H, Heiland S, Kollmar R, Bardutzky J, Henninger N, Muller H, Carl U, Toyokuni S, Sommer C, Schwab S (Neuroprotection by hyperbaric oxygenation after experimental focal cerebral ischemia monitored by MRI. Stroke 35:1175-1179.2004).
Shen LH, Li Y, Chen J, Zacharek A, Gao Q, Kapke A, Lu M, Raginski K, Vanguri P, Smith A, Chopp M (Therapeutic benefit of bone marrow stromal cells administered 1 month after stroke. J Cereb Blood Flow Metab 27:6-13.2007).
Shen LH, Li Y, Chen J, Zhang J, Vanguri P, Borneman J, Chopp M (Intracarotid transplantation of bone marrow stromal cells increases axon-myelin remodelingafter stroke. Neuroscience 137:393-399.2006).
Sofroniew MV, Vinters HV (Astrocytes: biology and pathology. Acta Neuropathol 119:7-35.2010).
Sugiyama T, Kohara H, Noda M, Nagasawa T (Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 25:977-988.2006).
Thom SR, Bhopale VM, Velazquez OC, Goldstein LJ, Thom LH, Buerk DG (Stem cell mobilization by hyperbaric oxygen. Am J Physiol Heart Circ Physiol 290:H1378-H1386.2006).
Thom SR, Milovanova TN, Yang M, Bhopale VM, Sorokina EM, Uzun G, Malay DS, Troiano MA, Hardy KR, Lambert DS, Logue CJ, Margolis DJ (Vasculogenic stem cell mobilization and wound recruitment in diabetic patients: increased cell number and intracellular regulatory protein content associated with hyperbaric oxygen therapy. Wound Repair Regen 19:149-161.2011).
Tsai KJ, Tsai YC, Shen CK (G-CSF rescues the memory impairment of animal models of Alzheimer's disease. J Exp Med 204:1273-1280.2007).
Veltkamp R, Siebing DA, Sun L, Heiland S, Bieber K, Marti HH, Nagel S, Schwab S, Schwaninger M (Hyperbaric oxygen reduces blood-brain barrier damage and edema after transient focal cerebral ischemia. Stroke 36:1679-1683.2005).
Wacker BK, Park TS, Gidday JM (Hypoxic preconditioning-induced cerebral ischemic tolerance: role of microvascular sphingosine kinase 2. Stroke 40:3342-3348.2009).
Wacker BK, Perfater JL, Gidday JM (Hypoxic preconditioning induces stroke tolerance in mice via a cascading HIF, sphingosine kinase, and CCL2 signaling pathway. J Neurochem.2012).
Wang Y, Deng Y, Zhou GQ (SDF-1alpha/CXCR4-mediated migration of systemically transplanted bone marrow stromal cells towards ischemic brain lesion in a rat model. Brain Res 1195:104-112.2008).
Wen J, Zhang JQ, Huang W, Wang Y (SDF-1alpha and CXCR4 as therapeutic targets in cardiovascular disease. Am J Cardiovasc Dis 2:20-28.2012).
Xiao X, Liu Y, Qi C, Qiu F, Chen X, Zhang J, Yang P (Neuroprotection and enhanced neurogenesis by tetramethylpyrazine in adult rat brain after focal ischemia. Neurol Res 32:547-555.2010).
Yang ZJ, Xie Y, Bosco GM, Chen C, Camporesi EM (Hyperbaric oxygenation alleviates MCAO-induced brain injury and reduces hydroxyl radical formation and glutamate release. Eur J Appl Physiol 108:513-522.2010).
Yin W, Badr AE, Mychaskiw G, Zhang JH (Down regulation of COX-2 is involved in hyperbaric oxygen treatment in a rat transient focal cerebral ischemia model. Brain Res 926:165-171.2002).
Zhang RL, Zhang ZG, Zhang L, Chopp M (Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia. Neuroscience 105:33-41.2001).
Zhao W, Belayev L, Ginsberg MD (Transient middle cerebral artery occlusion by intraluminal suture: II. Neurological deficits, and pixel-based correlation of
33
histopathology with local blood flow and glucose utilization. J Cereb Blood Flow Metab 17:1281-1290.1997).
校內:2018-02-06公開