臺灣博碩士論文加值系統

Part I
研究目的: 頭部外傷將引發受損細胞或死亡細胞釋放各種調節因子並吸引微小膠細胞活化。活化狀態下的微小膠細胞將會改變其形態，並移行至受損區域釋放甲型腫瘤壞死因子及其他反應物質。本篇文章將探討，於液注撞擊所引發的頭部外傷過程中，給予傳統複方中藥MLC601是否可以藉由改善微小膠細胞的活化作用，達到降低損傷並促進運動功能的恢復。本篇文章使用MLC的原因在於
它對於腦中風治療有有顯著療效，並已經用以臨床實驗評估。
研究方法及資料：將動物隨機分成三組: 假手術組、頭部外傷給予安慰劑組及頭部外傷給予MLC601治療組。MLC給藥方式採用頭部外傷後一小時(早期)給予腹腔注射一劑MLC601(每公斤體重四毫克)，之後每一天注射一劑，連續三天。頭部外傷前及術後第四天(晚期)給予，連續評估其神經及運動功能缺陷。頭外部傷後第四天，使用免疫螢光染色及顯微鏡觀測神經元凋亡及微小膠細胞表達甲型腫瘤壞死因子於損傷區域表達之情形。免疫組織化學染色法用以觀察受損區域微小膠細胞之細胞數及型態。
研究結果：實驗顯示，於頭部外傷後會導致腦損傷、神經元凋亡、神經及運動功能缺陷、微小膠細胞聚集、微小膠細胞型態改變及過度表達甲型腫瘤壞死因子。以上這些現象，會因為早期MLC601的治療而得到較為明顯的改善。
結論與建議：傳統複方中藥MLC601可藉由調節微小膠細胞之變形及表達甲型腫瘤壞死因子達到大鼠頭部外傷之治療功效。
Part II
研究目的：探討於高山症發生前，先給予高壓氧前處理誘導熱休克蛋白質70產生，藉以保護及對抗高山症誘發之急性肺損傷及肺水腫機制。
研究方法及資料：將動物隨機分成四組，第一組:非高壓氧前處理及非高海拔壓力之控制組；第二組:非高壓氧前處理及誘發高海拔壓力組；第三組:高壓氧前處理及誘發高海拔壓力組；第四組:高壓氧前處理並給予熱休克蛋白質70抗體及誘發高海拔壓力組。高壓氧前處理是採取將動物至於2.0絕對大氣壓並供應100%氧氣濃度之高壓氧艙中一小時，連續五天。高海拔壓力誘導方式是將動物放置於0.47大氣壓(約6000公尺海拔高度，9.7%氧氣濃度)之低壓艙連續三小時。源自兔子的抗老鼠之熱休克蛋白質70多株抗體則於高海拔暴露前一小時以靜脈注射方式提供。當動物經過3小時高海拔壓力刺激後回復至常壓狀態時，即以過量麻醉劑進行安樂死並將動物器官移除進行組織及分子表現分析。 。
研究結果：非高壓氧前處理並誘發高海拔壓力組與控制組比較，有明顯的肺泡水腫、嗜中性白血球浸潤及肺泡出血之表現。此外，肺組織中第一型及第五型水通道蛋白及其訊息核糖核酸之表現量與控制組比較，則呈現低度表現。然而，事先給予高壓氧前處理再誘導高海拔壓力時，則可有效改善肺水腫及恢復第一型、第五型水通道蛋白質及其訊息核糖核酸在肺組織中表現量。反之，如果在高壓氧前處理後給予熱休克蛋白質70抗體，降低了肺組織中熱休克蛋白質70表現量，則將逆轉高壓氧前處理對於高海拔壓力的保護作用。
結論與建議：高壓氧前處理將可以透過熱休克蛋白質70的表現達到預防高海拔誘導的肺水腫。

Part I
Objective: Traumatic brain injury (TBI) causes increased release of several mediators from injured and dead cells and elicits microglial activation. Activated microglia change morphology, migrate to injury sites, and release tumor necrosis factor-alpha (TNF-α) and others. In this study we used a controlled fluid percussion injury model of TBI in the rat to determine whether immediate treatment with MLC601, a traditional Chinese medicine, would affect microglial activation and improve recovery. MLC was chosen for this study because it is beneficial in treating stroke patients and it has been approved for clinical trials.
Methods and Materials: A controlled fluid percussion injury model of TBI in the rat was used to determine early treatment (1 h post-injury) or late treatment (4 days postinjury) with MLC 601, would affect microglial activation and improve
recovery. Rats were randomly divided into three groups: Sham operation group, TBI with vehicle group, TBI with MLC601 treatment group. Rats with induced TBI were treated with a single intraperitoneal injection of MLC 601 (4 mg/kg) 1h after injury, and then with one injection per day for 2 days. Acute neurological and motor deficits were assessed in all rats the day before and 4 days after injury. An immunofluorescence microscopy method was used to count the numbers of the cells colocalized with neuron- and apoptosis-specific markers, and the cells colocalized with microglia- and TNF-α-specific markers, in the contused brain regions 4 days post-injury. An immunohistochemistry methods was used to evaluate both the number and the morphological transformation of microglia in the injured areas.
Results: It was found that early treatment with MLC 601 had better effects in reducing TBI-induced cerebral contusion than did the late therapy with MLC 601. Cerebral contusion caused by TBI was associated with neurological motor deficits, brain apoptosis, and activated microglia (e.g., microgliosis, amoeboid
microglia, and microglial overexpression of TNF-α), which all were significantly attenuated by MLC 601 therapy.
Conclusion and Suggestion: These results suggest that early MLC601 therapy may improve outcomes of TBI in rats by attenuating microgliosis, morphological transformation of microglia, and microglial overexpression of TNF-α.
Part II
Objective：HBO2P (hyperbaric oxygen preconditioning) induces the overexpression of HSP70 (heat-shock protein 70) and attenuates brain edema in rats during simulated high-altitude exposure. However, it is not known whether the increased lung injury scores and the decreased levels of both aquaporin (AQP1) and AQP5 proteins and messenger RNA (mRNA) expression in the lung caused by HAE can be affected by HSP70-mediated HBO2P in rats. In the present study, we hypothesized that HBO2P would protect against HAE-induced acute lung injury and edema via promoting HSP70 in lungs prior to the onset of HAE.
Methods and Materials： Rats were randomly divided into four groups: the non-HBO2P+ non-HAE group, the non-HBO2P+HAE group, the HBO2P+HAE group, and the HBO2P+HSP-70 antibodies (Abs)+HAE group. The HBO2P groups were given 100% O2 at 2.0 absolute atmospheres for 1 hour per day for 5 consecutive days. The HAE groups were exposed to simulated HAE (9.7% O2 at 0.47 absolute atmospheres of 6,000 m) in a hypobaric chamber for 3 days, polyclonal rabbit anti-mouse HSP-70-neutralizing Abs were intravenously injected 24 hours before the HAE experiments. Immediately after returning to normal atmosphere, the rats were overdosed with a general anesthetic, and then their bungs were excised en bloc for both histologic and molecular evaluation and analysis.
Results： In non-HBO2P+HAE group, the animals displayed higher scores of alveolar edema, neutrophil infiltration, and hemorrhage compared with those of non-HBO2P+non-HAE controls. In contrast, the levels of both aquaporin (AQP) 1 and AQP 5 proteins and mRNA expression in the lung in the non-HBO2P+HAE group were significantly lower than those of non-HBO2P controls. The increased lung injury scores and the decreased levels of both AQP1 and AQP5 proteins and mRNA expression in the lung caused by HAE was significantly reduced by HBO2P+HAE. Furthermore, HSP70 Abs, in addition to reducing lung HSP70 proteins, significantly attenuated the beneficial effects of HBO2P in HAE.
Conclusion and Suggestion： Our results suggest that high-altitude lung edema can be prevented by HSP-70-mediated HBO2P in rats.

PART I 1
第一章 緒論 1
第二章 文獻探討 3
第三章 研究設計 8
第四章 研究結果 11
第五章 討論與建議 13
第六章 結論 14
參考文獻 15
圖目錄 21
Fig.1 腦損傷後細胞死亡的病態生理機轉 ……………… 21
Fig.2 MLC601的9種植物成份與5種動物成份 ……………… 22
Fig.3 腦損傷後投予MLC601於早期晚期對腦傷體積效果 ……………… 23
Fig.4 腦損傷後投予MLC601於早期晚期對腦切片結果 ……………… 24
Fig.5 腦損傷後投予MLC601對於腦細胞凋亡的效應 ……………… 25
Fig.6 腦損傷後投予MLC601對於神經運動功能的影響 ……………… 26
Fig.7 腦損傷後投予MLC601對於微小膠細胞變形的療效 ……………… 27
Fig.8 腦損傷後投予MLC601對於微小膠細胞之甲型腫瘤壞死因子表達的治療成效
………………
28

PART II 29
第一章 緒論 29
第二章 文獻探討 30
第三章 研究設計 33
第四章 研究結果 37
第五章 討論與建議 39
參考文獻 42
圖表目錄 48
Table 1 基因序列引物 ………………………. 48
Fig.1 實驗設計結構圖示 ………………………. 49
Fig.2 肺臟組織中的休克熱蛋白70表現 ………………………. 50
Fig.3 各實驗組肺臟組織切片於顯微鏡下的表現
……………………….
51
Fig.4 各實驗組肺臟組織重量間的差異表現 ………………………. 52
Fig.5 各實驗組肺臟組織內第一型與第五型水通道蛋白的免疫學分析比較
……………………….
53
Fig.6 各實驗組肺組織中第一型及第五型水通道蛋白及其訊息核糖核酸的RT-PCR分析比較

……………………….

54

part 1
1.Allan, S. M. and N. J. Rothwell (2001). "Cytokines and acute neurodegeneration." Nat Rev Neurosci 2(10): 734-744.
2.Arvin, B., L. F. Neville, F. C. Barone and G. Z. Feuerstein (1996). "The role of inflammation and cytokines in brain injury." Neurosci Biobehav Rev 20(3): 445-452.
3.Black, J. E., K. R. Isaacs, B. J. Anderson, A. A. Alcantara and W. T. Greenough (1990). "Learning causes synaptogenesis, whereas motor activity causes angiogenesis, in cerebellar cortex of adult rats." Proc Natl Acad Sci U S A 87(14): 5568-5572.
4.Chen, C., N. Venketasubramanian, R. N. Gan, C. Lambert, D. Picard, B. P. Chan, E. Chan, M. G. Bousser and S. Xuemin (2009). "Danqi Piantang Jiaonang (DJ), a traditional Chinese medicine, in poststroke recovery." Stroke 40(3): 859-863.
5.Cheong, C. U., C. P. Chang, C. M. Chao, B. C. Cheng, C. Z. Yang and C. C. Chio (2013). "Etanercept attenuates traumatic brain injury in rats by reducing brain TNF- alpha contents and by stimulating newly formed neurogenesis." Mediators Inflamm 2013: 620837.
6.Chio, C. C., C. H. Chang, C. C. Wang, C. U. Cheong, C. M. Chao, B. C. Cheng, C. Z. Yang and C. P. Chang (2013). "Etanercept attenuates traumatic brain injury in rats by reducing early microglial expression of tumor necrosis factor-alpha." BMC Neurosci 14: 33.
7.Ding, Y., J. Li, Q. Lai, J. A. Rafols, X. Luan, J. Clark and F. G. Diaz (2004). "Motor balance and coordination training enhances functional outcome in rat with transient middle cerebral artery occlusion." Neuroscience 123(3): 667-674.
8.Ding, Y., B. Yao, Y. Zhou, H. Park, J. P. McAllister, 2nd and F. G. Diaz (2002). "Prereperfusion flushing of ischemic territory: a therapeutic study in which histological and behavioral assessments were used to measure ischemia-reperfusion injury in rats with stroke." J Neurosurg 96(2): 310-319.
9.Ding, Y., Y. Zhou, Q. Lai, J. Li, H. Park and F. G. Diaz (2002). "Impaired motor activity and motor learning function in rat with middle cerebral artery occlusion." Behav Brain Res 132(1): 29-36.
10.Feuerstein, G. Z., T. Liu and F. C. Barone (1994). "Cytokines, inflammation, and brain injury: role of tumor necrosis factor-alpha." Cerebrovasc Brain Metab Rev 6(4): 341-360.
11.Fujimoto, S. T., L. Longhi, K. E. Saatman, V. Conte, N. Stocchetti and T. K. McIntosh (2004). "Motor and cognitive function evaluation following experimental traumatic brain injury." Neurosci Biobehav Rev 28(4): 365-378.
12.Ghirnikar, R. S., Y. L. Lee and L. F. Eng (1998). "Inflammation in traumatic brain injury: role of cytokines and chemokines." Neurochem Res 23(3): 329-340.
13.Griffiths, M. R., P. Gasque and J. W. Neal (2010). "The regulation of the CNS innate immune response is vital for the restoration of tissue homeostasis (repair) after acute brain injury: a brief review." Int J Inflam 2010: 151097.
14.Hanisch, U. K. (2002). "Microglia as a source and target of cytokines." Glia 40(2): 140-155.
15.Hernandez-Ontiveros, D. G., N. Tajiri, S. Acosta, B. Giunta, J. Tan and C. V. Borlongan (2013). "Microglia activation as a biomarker for traumatic brain injury." Front Neurol 4: 30.
16.Heurteaux, C., C. Gandin, M. Borsotto, C. Widmann, F. Brau, M. Lhuillier, B. Onteniente and M. Lazdunski (2010). "Neuroprotective and neuroproliferative activities of NeuroAid (MLC601, MLC901), a Chinese medicine, in vitro and in vivo." Neuropharmacology 58(7): 987-1001.
17.Iosif, R. E., H. Ahlenius, C. T. Ekdahl, V. Darsalia, P. Thored, S. Jovinge, Z. Kokaia and O. Lindvall (2008). "Suppression of stroke-induced progenitor proliferation in adult subventricular zone by tumor necrosis factor receptor 1." J Cereb Blood Flow Metab 28(9): 1574-1587.
18.Isaacs, K. R., B. J. Anderson, A. A. Alcantara, J. E. Black and W. T. Greenough (1992). "Exercise and the brain: angiogenesis in the adult rat cerebellum after vigorous physical activity and motor skill learning." J Cereb Blood Flow Metab 12(1): 110-119.
19.Kadhim, H. J., J. Duchateau and G. Sebire (2008). "Cytokines and brain injury: invited review." J Intensive Care Med 23(4): 236-249.
20.Kleim, J. A., E. Lussnig, E. R. Schwarz, T. A. Comery and W. T. Greenough (1996). "Synaptogenesis and Fos expression in the motor cortex of the adult rat after motor skill learning." J Neurosci 16(14): 4529-4535.
21.Kreutzberg, G. W. (1996). "Microglia: a sensor for pathological events in the CNS." Trends Neurosci 19(8): 312-318.
22.Lim, Y. A., L. A. Murray, M. K. Lai and C. Chen (2013). "NeuroAiD(R) (MLC601) and amyloid precursor protein processing." Cerebrovasc Dis 35 Suppl 1: 30-37.
23.Loane, D. J. and K. R. Byrnes (2010). "Role of microglia in neurotrauma." Neurotherapeutics 7(4): 366-377.
24.Lucas, S. M., N. J. Rothwell and R. M. Gibson (2006). "The role of inflammation in CNS injury and disease." Br J Pharmacol 147 Suppl 1: S232-240.
25.Maas, A. I., G. Murray, H. Henney, 3rd, N. Kassem, V. Legrand, M. Mangelus, J. P. Muizelaar, N. Stocchetti and N. Knoller (2006). "Efficacy and safety of dexanabinol in severe traumatic brain injury: results of a phase III randomised, placebo-controlled, clinical trial." Lancet Neurol 5(1): 38-45.
26.McAdams, R. M. and S. E. Juul (2012). "The role of cytokines and inflammatory cells in perinatal brain injury." Neurol Res Int 2012: 561494.
27.McCoy, M. K. and M. G. Tansey (2008). "TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease." J Neuroinflammation 5: 45.
28.McKeating, E. G. and P. J. Andrews (1998). "Cytokines and adhesion molecules in acute brain injury." Br J Anaesth 80(1): 77-84.
29.Moha Ou Maati, H., M. Borsotto, F. Chatelain, C. Widmann, M. Lazdunski and C. Heurteaux (2012). "Activation of ATP-sensitive potassium channels as an element of the neuroprotective effects of the Traditional Chinese Medicine MLC901 against oxygen glucose deprivation." Neuropharmacology 63(4): 692-700.
30.Page, S. J. (2013). "Selective TNF inhibition for chronic stroke and traumatic brain injury: an observational study involving 629 consecutive patients treated with perispinal etanercept." CNS Drugs 27(5): 395-397.
31.Plata-Salaman, C. R. (1991). "Immunoregulators in the nervous system." Neurosci Biobehav Rev 15(2): 185-215.
32.Plata-Salaman, C. R. (1998). "Cytokine-induced anorexia. Behavioral, cellular, and molecular mechanisms." Ann N Y Acad Sci 856: 160-170.
33.Quintard, H., M. Borsotto, J. Veyssiere, C. Gandin, F. Labbal, C. Widmann, M. Lazdunski and C. Heurteaux (2011). "MLC901, a traditional Chinese medicine protects the brain against global ischemia." Neuropharmacology 61(4): 622-631.
34.Rothwell, N. J. (1997). "Cytokines and acute neurodegeneration." Mol Psychiatry 2(2): 120-121.
35.Rothwell, N. J. and G. N. Luheshi (2000). "Interleukin 1 in the brain: biology, pathology and therapeutic target." Trends Neurosci 23(12): 618-625.
36.Rothwell, N. J. and J. K. Relton (1993). "Involvement of cytokines in acute neurodegeneration in the CNS." Neurosci Biobehav Rev 17(2): 217-227.
37.Schallert, T., S. M. Fleming, J. L. Leasure, J. L. Tillerson and S. T. Bland (2000). "CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury." Neuropharmacology 39(5): 777-787.
38.Shiozaki, T., T. Hayakata, O. Tasaki, H. Hosotubo, K. Fuijita, T. Mouri, G. Tajima, K. Kajino, H. Nakae, H. Tanaka, T. Shimazu and H. Sugimoto (2005). "Cerebrospinal fluid concentrations of anti-inflammatory mediators in early-phase severe traumatic brain injury." Shock 23(5): 406-410.
39.Silverstein, F. S., J. D. Barks, P. Hagan, X. H. Liu, J. Ivacko and J. Szaflarski (1997). "Cytokines and perinatal brain injury." Neurochem Int 30(4-5): 375-383.
40.Siniscalchi, A., L. Gallelli, G. Malferrari, D. Pirritano, R. Serra, E. Santangelo and G. De Sarro (2014). "Cerebral stroke injury: the role of cytokines and brain inflammation." J Basic Clin Physiol Pharmacol 25(2): 131-137.
41.Tobinick, E. (2013). "Author''s reply to Page: "Selective TNF inhibition for chronic stroke and traumatic brain injury: an observational study involving 629 consecutive patients treated with perispinal etanercept"." CNS Drugs 27(5): 399-402.
42.Walker, K. R. and G. Tesco (2013). "Molecular mechanisms of cognitive dysfunction following traumatic brain injury." Front Aging Neurosci 5: 29.
43.Wang, Y., S. Z. Lin, A. L. Chiou, L. R. Williams and B. J. Hoffer (1997). "Glial cell line-derived neurotrophic factor protects against ischemia-induced injury in the cerebral cortex." J Neurosci 17(11): 4341-4348.
44.Woodcock, T. and M. C. Morganti-Kossmann (2013). "The role of markers of inflammation in traumatic brain injury." Front Neurol 4: 18.

part 2
1.Das, D. K., N. Maulik and Moraru, II (1995). "Gene expression in acute myocardial stress. Induction by hypoxia, ischemia, reperfusion, hyperthermia and oxidative stress." J Mol Cell Cardiol 27(1): 181-193.
2.Klug, C. A., K. Tasaki, N. Tjandra, C. Ho and J. Schaefer (1997). "Closed form of liganded glutamine-binding protein by rotational-echo double-resonance NMR." Biochemistry 36(31): 9405-9408.
3.Su, X., Y. Song, J. Jiang and C. Bai (2004). "The role of aquaporin-1 (AQP1) expression in a murine model of lipopolysaccharide-induced acute lung injury." Respir Physiol Neurobiol 142(1): 1-11.
4. Bai, X. W., B. Sun, F. Wang, S. H. Pan, D. B. Xue, H. Zhu and H. C. Jiang (2009). "[The effect of hyperbaric oxygen on acute pancreatitis through downregulating hypoxia-inducible factor.]." Zhonghua Wai Ke Za Zhi 47(19): 1459-1463.
5.Bartsch, P. (1997). "High altitude pulmonary edema." Respiration 64(6): 435-443.
6.Bruemmer-Smith, S., F. Stuber and S. Schroeder (2001). "Protective functions of intracellular heat-shock protein (HSP) 70-expression in patients with severe sepsis." Intensive Care Med 27(12): 1835-1841.
7.Cao, H., K. Ju, L. Zhong and T. Meng (2013). "Efficacy of hyperbaric oxygen treatment for depression in the convalescent stage following cerebral hemorrhage." Exp Ther Med 5(6): 1609-1612.
8.Celik, O., H. H. Bay, A. Arslanhan, B. Oroglu, S. U. Bozkurt, U. S. Sehirli and M. I. Ziyal (2014). "Effect of hyperbaric oxygen therapy on cerebral vasospasm: a vascular morphometric study in an experimental subarachnoid hemorrhage model." Int J Neurosci 124(8): 593-600.
9.Dahl, N. A. and W. M. Balfour (1964). "Prolonged Anoxic Survival Due to Anoxia Pre-Exposure: Brain Atp, Lactate, and Pyruvate." Am J Physiol 207: 452-456.
10.Das, D. K., N. Maulik and Moraru, II (1995). "Gene expression in acute myocardial stress. Induction by hypoxia, ischemia, reperfusion, hyperthermia and oxidative stress." J Mol Cell Cardiol 27(1): 181-193.
11.Dehnert, C., M. M. Berger, H. Mairbaurl and P. Bartsch (2007). "High altitude pulmonary edema: a pressure-induced leak." Respir Physiol Neurobiol 158(2-3): 266-273.
12.Dong, G. X. and Y. P. Feng (2002). "[Effects of NBP on ATPase and anti-oxidant enzymes activities and lipid peroxidation in transient focal cerebral ischemic rats]." Zhongguo Yi Xue Ke Xue Yuan Xue Bao 24(1): 93-97.
13.Gu, G. J., Y. P. Li, Z. Y. Peng, J. J. Xu, Z. M. Kang, W. G. Xu, H. Y. Tao, R. P. Ostrowski, J. H. Zhang and X. J. Sun (2008). "Mechanism of ischemic tolerance induced by hyperbaric oxygen preconditioning involves upregulation of hypoxia-inducible factor-1alpha and erythropoietin in rats." J Appl Physiol (1985) 104(4): 1185-1191.
14.Hanaoka, M., M. Tanaka, R. L. Ge, Y. Droma, A. Ito, T. Miyahara, T. Koizumi, K. Fujimoto, T. Fujii, T. Kobayashi and K. Kubo (2000). "Hypoxia-induced pulmonary blood redistribution in subjects with a history of high-altitude pulmonary edema." Circulation 101(12): 1418-1422.
15.Hu, S. L., R. Hu, F. Li, Z. Liu, Y. Z. Xia, G. Y. Cui and H. Feng (2008). "Hyperbaric oxygen preconditioning protects against traumatic brain injury at high altitude." Acta Neurochir Suppl 105: 191-196.
16.Hultgren, H. N. (1997). "High altitude pulmonary edema: hemodynamic aspects." Int J Sports Med 18(1): 20-25.
17.Hultgren, H. N., R. Wilson and J. C. Kosek (1997). "Lung pathology in high-altitude pulmonary edema." Wilderness Environ Med 8(4): 218-220.
18.Jang, A. S., J. U. Lee, I. S. Choi, K. O. Park, J. H. Lee, S. W. Park and C. S. Park (2004). "Expression of nitric oxide synthase, aquaporin 1 and aquaporin 5 in rat after bleomycin inhalation." Intensive Care Med 30(3): 489-495.
19.Kasic, J. F., M. Yaron, R. A. Nicholas, J. A. Lickteig and R. Roach (1991). "Treatment of acute mountain sickness: hyperbaric versus oxygen therapy." Ann Emerg Med 20(10): 1109-1112.
20.Kitagawa, K., M. Matsumoto, T. Oda, M. Niinobe, R. Hata, N. Handa, R. Fukunaga, Y. Isaka, K. Kimura, H. Maeda and et al. (1990). "Free radical generation during brief period of cerebral ischemia may trigger delayed neuronal death." Neuroscience 35(3): 551-558.
21.Lekic, T., A. Manaenko, W. Rolland, R. P. Ostrowski, K. Virbel, J. Tang and J. H. Zhang (2011). "Beneficial effect of hyperbaric oxygenation after neonatal germinal matrix hemorrhage." Acta Neurochir Suppl 111: 253-257.
22.Li, Z., C. Gao, Y. Wang, F. Liu, L. Ma, C. Deng, K. C. Niu, M. T. Lin and C. Wang (2011). "Reducing pulmonary injury by hyperbaric oxygen preconditioning during simulated high altitude exposure in rats." J Trauma 71(3): 673-679.
23.Lin, H. J., C. T. Wang, K. C. Niu, C. Gao, Z. Li, M. T. Lin and C. P. Chang (2011). "Hypobaric hypoxia preconditioning attenuates acute lung injury during high-altitude exposure in rats via up-regulating heat-shock protein 70." Clin Sci (Lond) 121(5): 223-231.
24.Nawashiro, H., K. Tasaki, C. A. Ruetzler and J. M. Hallenbeck (1997). "TNF-alpha pretreatment induces protective effects against focal cerebral ischemia in mice." J Cereb Blood Flow Metab 17(5): 483-490.
25.Nie, H., L. Xiong, N. Lao, S. Chen, N. Xu and Z. Zhu (2006). "Hyperbaric oxygen preconditioning induces tolerance against spinal cord ischemia by upregulation of antioxidant enzymes in rabbits." J Cereb Blood Flow Metab 26(5): 666-674.
26.Ostrowski, R. P. and J. H. Zhang (2011). "Hyperbaric oxygen for cerebral vasospasm and brain injury following subarachnoid hemorrhage." Transl Stroke Res 2(3): 316-327.
27.Paralikar, S. J. (2012). "High altitude pulmonary edema-clinical features, pathophysiology, prevention and treatment." Indian J Occup Environ Med 16(2): 59-62.
28.Peng, Z. R., A. L. Yang and Q. D. Yang (2014). "The effect of hyperbaric oxygen on intracephalic angiogenesis in rats with intracerebral hemorrhage." J Neurol Sci 342(1-2): 114-123.
29.Salhanick, S. D., B. Belikoff, D. Orlow, D. Holt, W. Reenstra and J. A. Buras (2006). "Hyperbaric oxygen reduces acetaminophen toxicity and increases HIF-1alpha expression." Acad Emerg Med 13(7): 707-714.
30.Scherz-Shouval, R. and Z. Elazar (2007). "ROS, mitochondria and the regulation of autophagy." Trends Cell Biol 17(9): 422-427.
31.Scherz-Shouval, R., E. Shvets, E. Fass, H. Shorer, L. Gil and Z. Elazar (2007). "Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4." EMBO J 26(7): 1749-1760.
32.Schoene, R. B. (1997). "High-altitude pulmonary edema: more lessons from the master." Wilderness Environ Med 8(4): 202-203.
33.Sterling, D. L., J. D. Thornton, A. Swafford, S. F. Gottlieb, S. P. Bishop, A. W. Stanley and J. M. Downey (1993). "Hyperbaric oxygen limits infarct size in ischemic rabbit myocardium in vivo." Circulation 88(4 Pt 1): 1931-1936.
34.Su, X., Y. Song, J. Jiang and C. Bai (2004). "The role of aquaporin-1 (AQP1) expression in a murine model of lipopolysaccharide-induced acute lung injury." Respir Physiol Neurobiol 142(1): 1-11.
35.Tasaki, K., C. A. Ruetzler, T. Ohtsuki, D. Martin, H. Nawashiro and J. M. Hallenbeck (1997). "Lipopolysaccharide pre-treatment induces resistance against subsequent focal cerebral ischemic damage in spontaneously hypertensive rats." Brain Res 748(1-2): 267-270.
36.Towne, J. E., K. S. Harrod, C. M. Krane and A. G. Menon (2000). "Decreased expression of aquaporin (AQP)1 and AQP5 in mouse lung after acute viral infection." Am J Respir Cell Mol Biol 22(1): 34-44.
37.Wang, G. H., X. G. Zhang, Z. L. Jiang, X. Li, L. L. Peng, Y. C. Li and Y. Wang (2010). "Neuroprotective effects of hyperbaric oxygen treatment on traumatic brain injury in the rat." J Neurotrauma 27(9): 1733-1743.
38.Wang, L., W. Li, Z. Kang, Y. Liu, X. Deng, H. Tao, W. Xu, R. Li, X. Sun and J. H. Zhang (2009). "Hyperbaric oxygen preconditioning attenuates early apoptosis after spinal cord ischemia in rats." J Neurotrauma 26(1): 55-66.
39.Wang, Q. H., Y. J. Yang, C. F. Chen, Y. Yao and M. Li (2009). "[Protective effects of delayed multiple course hyperbaric oxygen treatment against hypoxic-ischemic brain damage in neonatal rats]." Zhongguo Dang Dai Er Ke Za Zhi 11(6): 464-470.
40.Wang, X. L., Y. J. Yang, M. Xie, X. H. Yu and Q. H. Wang (2009). "[Hyperbaric oxygen promotes the migration and differentiation of endogenous neural stem cells in neonatal rats with hypoxic-ischemic brain damage]." Zhongguo Dang Dai Er Ke Za Zhi 11(9): 749-752.
41.Wilson, M. H., S. Newman and C. H. Imray (2009). "The cerebral effects of ascent to high altitudes." Lancet Neurol 8(2): 175-191.
42.Yanamoto, H., N. Hashimoto, I. Nagata and H. Kikuchi (1998). "Infarct tolerance against temporary focal ischemia following spreading depression in rat brain." Brain Res 784(1-2): 239-249.
43.Yang, Y., L. Ma, W. Guan, Y. Wang, Y. Du, Q. Ga and R. L. Ge (2014). "Differential plasma proteome analysis in patients with high-altitude pulmonary edema at the acute and recovery phases." Exp Ther Med 7(5): 1160-1166.
44.Zhou, W., M. Marinescu and R. Veltkamp (2014). "Only Very Early Oxygen Therapy Attenuates Posthemorrhagic Edema Formation and Blood-Brain Barrier Disruption in Murine Intracerebral Hemorrhage." Neurocrit Care in press.