隨著現代工作型態的改變與生活壓力的增加，國人熬夜、輪班工作、疲勞駕駛的狀況趨之嚴重；在台灣，輪班工作者已佔所有勞動工作者中的35.5%。雖然睡眠剝奪可能會引起記憶衰退、認知下降，並增加罹患慢性疾病的風險，但目前探討睡眠剝奪對多重器官傷害影響的研究非常少，睡眠剝奪如何影響器官的傷害，進而造成健康的危害仍待深入探討。本研究目標為：1、建立小鼠睡眠剝奪模式及其所造成器官的傷害；2、探討睡眠剝奪在器官傷害中可能的作用機轉。在建立器官傷害模式中，將小鼠隨機分組，利用改良式多平台法，分別給予小鼠0、24、48、72小時之睡眠剝奪，於睡眠剝奪後予以犧牲，採集血液與多重臟器進行組織及生化分析；針對器官的傷害可能參與的氧化性壓力及發炎反應的作用，測量在氧化性壓力中較具指標性的脂質過氧化的含量；另外，分析並評估血清與各臟器中是否有發炎反應的產生，測量發炎的指標：一氧化氮含量、IL-1β、IL-6、TNF-α等重要的細胞激素表現量。實驗結果顯示，睡眠剝奪後的小鼠的心臟以及肝臟的生化指標有異常，隨著睡眠剝奪時間的增加，各器官之傷害指標有惡化的趨勢。而血清、肝臟、心臟、肺臟、脾臟皆有發生細胞激素表現量的異常上升或下降，一氧化氮含量在這些臟器內也有改變。總結而論，睡眠剝奪會導致小鼠體內的多重器官傷害產生，而造成器官傷害的原因，可能與其誘導的發炎免疫相關反應有關連。

Sleep has important functions for every organ in the body and sleep deprivation leads to disorders that cause irrepairable damage. Although sleep deprivation can induce cognitive impairment and increase the risk of chronic illnesses, the effect of sleep deprivation on organ damage is still unclear. The aims of this study were to establish a model of sleep deprivation and to investigate organ damages induced in the model. In this study, mice were submitted to 0, 24, 48 and 72 h sleep deprivation induced by a modified multiple platform method. Blood and organ samples were collected. Organ damages were evaluated by biochemical analysis and histological examination. Malondialdehyde, nitrite, and pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 levels were measured. Sleep deprivation induced heart and liver damages in a deprived time dependent manner. Cytokine and nitrite expression were changed in serum, liver, heart, lung and spleen. In conclusion, sleep deprivation might induce multiple organ damage with altered cytokines and oxidative stress.

Afari N, Buchwald D. Chronic fatigue syndrome: a review. The American Journal of Psychiatry. 160:221-236, 2003.
Alscher RG, Donahue JL, Cramer CL. Hypoxia-inducible factor 1: master regulator of O2 homeostasis. Reactive oxygen species antioxidants: Relationships in green cells. Physiologia Plantarum. 100:224-233, 1997.
Anderson JL. ST segment elevation acute myocardial infarction and complications of myocardial infarction. In: Goldman L, Schafer AI, eds. Cecil Medicine. 24th ed. Philadelphia, Pa: Saunders Elsevier; 2011:chap 73.
Bala A, Chetia P, Dolai N, Khandelwal B, Haldar PK. Cat's whiskers flavonoid attenuated oxidative DNA damage and acute inflammation: its importance in lymphocytes of patients with rheumatoid arthritis. Inflammopharmacology. 22:55-61, 2014.
Bajraktarov S, Novotni A, Manusheva N, Nikovska DG, Miceva-Velickovska E, Zdraveska N, et al. Main effects of sleep disorders related to shift work-opportunities for preventive programs. The EPMA Journal. 2:365-370, 2011.
Baldwin Jr, AS. The NF-κB and I kappaB proteins: new discoveries and insights. Annual Review of Immunology. 14:649-683, 1996.
Banks S, Dinges DF. Behavioral and physiological consequences of sleep restriction. Journal of Clinical Sleep Medicine. 3:519-528, 2007.
Beers TM. Flexible schedules and shift work: Replacing the ‘9 to 5’ workday? Monthly Labor Review. p.33-40, 2000.
Benjamin GA. Shit work: Improve the quality of life for employees who aren't on the 9-to-5 routine. The Personael Journal. 63:72-76, 1984.
Bogdan C, Röllinghoff M, Diefenbach A. The role of nitric oxide in innate immunity. Immunological Reviews. 173:17-26, 2000.
Boisard P, Cartron D, Gollac M, Valeyer A. Time and work: Duration of work. Dublin, Ireland: European foundation for the improvement of living and workinf conditions. 2003.
Borbély AA, Neuhaus HU. Sleep deprivation: Effect on sleep and EEG in the rats. Journal of comparative physiology. 133:71-87, 1979.
Bureau of Labor Statistics. Workplace Injuries and Illnesses—2009. Washgton, DC: US Department of Labor. 2009.
Carrico CJ. The elusive pathophysiology of the multiple organ failure syndrome. Annals of Surgery. 218:109-110, 1993.
Carskadon MA , Dement WC. Normal human sleep: an overview. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. St. Louis, MO: Elsevier Saunders. p:16-26, 2011
Centers for Disease Control and Prevention. Short sleep duration among workers—United States, 2010. Morbidity and Mortality Weekly Report. 61:281-285, 2012.
Chang CJ, Wang SY, Liu HW. The effect of shift system on sleep quality, psychological disturbance, and family function of workers in Taiwan. The Kaohsiung Journal of Medical Science. 9:410-417, 1993.
Chen JR, Wang TJ, Huang HY, Chen LJ, Huang YS, Wang YJ, Tseng GF. Fatigue reversibly reduced cortical and hippocampal dendritic spines concurrent with compromise of motor endurance and spatial memory. Neuroscience. 161:1104-1113, 2009.
Cheng Y, Guo YL, Yeh WY. A national survey of psychosocial job stressors and their implications for health among working people in Taiwan. International Archives of Occupational and Environmental Health. 74:495-504, 2001.
Chai HJ, Xu SM. Damage effects of sleep deprivation on myocardium and its antioxygen index in rats. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 24:71-76, 2008.
Charifi C, Paut-Pagano L, Debilly G, Cespuglio R, Jouvet M, Valatx JL. Effect of noradrenergic denervation of the amygdala upon recovery after sleep deprivation in the rat. Neuroscience Letters. 287:41-44, 2000.
Chiou WF, Chou CJ, Ko HC, Chen CF. Effects of six anti-inflammatory Chinese herbs on LPS/IFNγ: induced nitric oxide production in RAW 264.7 macrophages. The Journal of Chinese Medicine. 11:87-94, 2000.
Ciulla MM, De Marco F, Montelatici E, Lazzari L, Perrucci GL, Magrini F. Assessing cytokines' talking patterns following experimethal myocardial damage by applying Shannon's information theory. Journal of Theoretical Biology. 343:25-31, 2014.
Cohen HB, Dement WC. Sleep: changes in threshold to electroconvulsive shock in rats after deprivation of "paradoxical" phase. Science. 158:756-759, 1964.
Connor J, Whitlock G, Norton R, Jackson R. The role of driver sleepiness in car crashes: a systematic review of epidemiological studies. Accident Analysis & Prevention. 33:31-41, 2001.
Copinschi G. Metabolic and endocrine effects of sleep deprivation. Essential Psychopharmacology. 6:341-347, 2005.
Curtin JF, Donovan M, Cotter TG. Regulation and measurement of oxidative stress in apoptosis. Journal of Immunological Methods. 265:49-72, 2002.
Dahl RE, Harvey AG. Sleep in children and adolescents with behavioral and emotional disorders. Sleep Medicine Clinics. 2:501-511, 2007.
Dal Secco D, Moreira AP, Freitas A, Silva JS, Rossi MA, Ferreira SH, Cunha FQ. Nitric oxide inhibits neutrophil migration by a mechanism dependent on ICAM-1: role of soluble guanylate cyclase. Nitric Oxide. 15:77-86, 2006.
Dinges DF, Douglas SD, Hamarman S, Zaugg L, Kapon S. Sleep deprivation and human immune function. Advances in Neuroimmunology. 5:97-110, 1995.
Dos Reis Santos I, Danaga AR, de Carvalho Aguiar I, Oliveira EF, Dias IS, Urbano JJ, et al. Cardiovascular risk and mortality in end-stage renal disease patients undergoing dialysis: sleep study, pulmonary function, respiratory mechanics, upper airway collapsibility, autonomic nervous activity, depression, anxiety, stress and quality of life: a prospective, double blind, randomized controlled clinical trial. BMC Nephrology. 14:215, 2013.
Estabrooke IV, McCarthy MT, Ko E, Chou TC, Chemelli RM, Yanagisawa M, et al. Fos Expression in Orexin Neurons Varies with Behavioral State. The Journal of Neuroscience. 21:1656-1662, 2001.
European Transport Safety Council's Driver Fatigue Working Party. The role of driver fatigue in commercial road transport crashes, 90-76024-09-X European Transport Safety Council ETSC. 2001.
Everson CA. Clinical assessment of blood leukocytes, serum cytokines, and serum immunoglobulins as responses to sleep deprivation in laboratory rats. American Journal of Physiology - Regulatory, Integrative and Comparative Physiology. 289:1054-1063, 2005.
Everson CA, Laatsch CD, Hogg N. Antioxidant defense responses to sleep loss and sleep recovery. American Journal of Physiology - Regulatory, Integrative and Comparative Physiology. 288:374-383, 2005.
Everson CA. Sustained sleep deprivation impairs host defense. American Journal of Physiology. 265:1148-1154, 1993.
Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature. 408:239-247, 2000.
Foyer CH, Lelandais M, Kunert KJ. Photooxidative stress in plants. Physiologia Plantarum. 92:696-717, 1994.
Gangwisch JE, Feskanich D, Malaspina D, Shen S, Forman JP. Sleep duration and risk for hypertension in women: results from the nurses' health study. American Journal of Hypertension. 26:903-911, 2013.
Green LC, Ruiz de Luzuriaga K, Wagner DA, Rand W, Isffan N, Young VR, Tannenbaum SR. Nitrate biosynthesis in man. Proceedings of the National Academy of Sciences of USA. 78:7764-7768, 1981.
Gregory AM, Sadeh A. Sleep, emotional and behavioral difficulties in children and adolescents. Sleep Medicine Reviews. 16:129-136, 2012.
Härmä M. Workhours in relation to work stress, recovery and health. Scandinavian Journal of Work, Environment and Health. 32:502-514, 2006.
Haus EL, Smolensky MH. Shift work and cancer risk: potential mechanistic roles of circadian disruption, light at night, and sleep deprivation. Sleep Medicine Reviews. 17:273-284, 2013.
Hawkins RC, Tan HL. Comparison of the diagnostic utility of CK, CK-MB (activity and mass), troponin T and troponin I in patients with suspected acute myocardial infarction. Singapore Medical Journal. 40:680-684, 1999.
Huang LZ, Wei L, Zhao HF, Huang BK, Rahman K, Qin LP. The effect of Eleutheroside E on behavioral alterations in murine sleep deprivation stress model. European Journal of Pharmacology. 658:150-155, 2011.
Huck NO, McBride SA, Kendall AP, Grugle NL, Killgore WD. The effects of modafinil, caffeine and dextroamphetamine on judgments of simple versus complex emotional expressions following sleep deprivation. International Journal of Neuroscience. 118:487-502, 2008.
Hui L, Hua F, Diandong H, Hong Y. Effects of sleep and sleep deprivation on immunoglobulins and complement in humans. Brain, Behavior, and Immunity. 21:308-310, 2007.
Ignarro LJ, Murad F. Nitric oxide: biochemistry, molecular biology, and therapeutic implications. Pharmacology. 34:1-516, 1995.
Ilan Y, Martinowitz G, Abramsky O, Glazer G, Lavie P. Prolonged sleep-deprivation induced disturbed liver functions serum lipid levels, and hyperphosphatemia. European Journal of Clinical Investigation. 22:740-743, 1992.
Känel RV. Psychosocial stress and cardiovascular risk: current opinion. Swiss Medical Weekly. 20:142-155, 2012.
Klein B, Brailly H. Cytokine-binding proteins: stimulating antagonists. Immunology Today. 16:216-220, 1995.
Kripke DF, Garfi nkel L, Wingard DL, Klauber MR, Marler MR. Mortality associated with sleep duration and insomnia. Archives of General Psychiatry. 59:131-136, 2002.
Kumar R, Clermont G, Vodovotz Y, Chow CC. The dynamics of acute inflammation. Journal of Theoretical Biology. 230:145-155, 2004.
Lin YH, Chen CY, Hong WH, Lin YC. Perceived job stress and health complaints at a bank call center: comparison between inbound and outbound services. Industrial Health. 481:349-356, 2010.
Lima AM, de Bruin VM, Rios ER, de Bruin PF. Differential effects of paradoxical sleep deprivation on memory and oxidative stress. Naunyn-Schmiedeberg's Archives of Pharmacology. 387:399-406, 2014.
Luckhaupt SE, Tak SWZ, Calvert GM. The prevalence of short sleep duration by industry and occupation in the National Health Interview Survey. Sleep. 33:149-159, 2010.
Majde JA, Krueger JM. Links between the innate immune system and sleep. Journal of Allergy and Clinical Immunology. 116:1188-1198, 2005.
Martindale JL, Holbrook NJ. Cellular response to oxidative stress: signaling for suicide and survival. Journal of Cellular Physiology. 192:1-15, 2002.
Martino TA, Oudit GY, Herzenberg AM, Tata N, Koletar MM, Kabir GM, Belsham DD, Backx PH, Ralph MR, Sole MJ. Circadian rhythm disorganization produces profound cardiovascular and renal disease in hamsters. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 294:1675-1683, 2008.
Martins GA, Cardoso MA, Aliberti JC, Silva JS. Nitric oxide-induced apoptotic cell death in the acute phase of Trypanosoma cruzi infection in mice. Immunology Letters. 63:113-120, 1998.
Mikurube H, Kaneko M, Murata C, Komaki Y, Ishikawa N, Higashiyama R et al. Daniel Association of change in the type of job with prevalence of components of the metabolic syndrome-special reference to job stress. Nihon Koshu Eisei Zasshi. 52:987-993, 2005.
Miyashita T, Yamaguchi T, Motoyama K, Unno K, Nakano Y, Shimoi K. Social stress increases biopyrrins, oxidative metabolites of bilirubin, in mouse urine. Biochemical and Biophysical Research Communications. 349:775-780, 2006.
Mönnikes H, Tebbe JJ, Hildebrandt M, Arck P, Osmanoglou E, Rose M, Klapp B, Wiedenmann B, Heymann-Mönnikes I. Role of stress in functional gastrointestinal disorders. Evidence for stress-induced alterations in gastrointestinal motility and sensitivity. Digestive Diseases. 19:201-211, 2001.
Motoyama T, Okamoto K, Kukita I, Hamaguchi M, Kinoshita Y, Ogawa H. Possible role of increased oxidant stress in multiple organ failure after systemic inflammatory response syndrome. Critical Care Medicine. 31:1048-1052, 2003.
Mullington JM, Haack M, Toth M, Serrador JM, Meier-Ewert HK. Cardiovascular, inflammatory, and metabolic consequences of sleep deprivation. Progress in Cardiovascular Diseases. 51:294-302, 2009.
Nunes JG, Tufik S. Validation of modified multiple platform methods (MPM) of paradoxical sleep deprivation in rats. Sleep Research. 23:419, 1994.
NTSB. Factors that affect fatigue in heavy truck accidents. National Transportation Safety Board, Safety Study. NTSB/SS-95/01. 1995.
NTSB. Fatigue, alchohol, other drugs, and medical factors in fatal-to-the-driver heavy truck crashes. National Transportation and Safety Board, Safety Study. NTST/SS-90/01. 1990.
Palma BD, Gabriel A Jr, Colugnati FA, Tufik S. Effects of sleep deprivation on the development of autoimmune disease in an experimental model of systemic lupus erythematosus. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 291:1527-1532, 2006.
Philip P, Akerstedt T. Transport and industrial safety, how are they affected by sleepiness and sleep restriction? Sleep Medicine Reviews. 10:347-356, 2006.
Poli G, Cutrin JC, Biasi F. Lipid peroxidation in the reperfusion injury of liver. Free Radical Research. 28:547-551, 1998.
Qian XX, Chen YM, Wu WX, et al. Effect of Baoxin capsule on nitric oxide and endothelin in acute myocardial ischemia dogs. Chinese Journal of Clinical Pharmacy. 9:280-281, 2000.
Rechtschaffen A, Gilliland MA, Bergmann BM, Winter JB. Physiological correlates of prolonged sleep deprivation in rats. Science. 221:182-184, 1983.
Robb G, Sultana S, Ameratunga S, Jackson R. A systematic review of epidemiological studies investigating risk factors for work-related road traffic crashes and injuries. Injury Prevention. 14:51-58, 2008.
Roehrs T, Roth T. Medication and substance abuse. In: Kryger MH, Roth T, Dement WC, editors. Principles and Practice of Sleep Medicine. 5. Philadelphia: WB Saunders; pp. 1512-1523, 2009.
Roffwarg HP. Association of Sleep Disorders Centers: Diagnostic Classification of Sleep and Arousal Disorders. Prepared by the Sleep Disorders Classification Committee. Sleep. 2:1-137, 1979.
Rosso GL, Zanelli R, Bruno S, Feola M, Bobbio M. Professional driving and safety, a target for occupational medicine. Medicina del Lavoro. 98:355-373, 2007.
Sahan-Firat S, Canacankatan N, Korkmaz B, Yildirim H, Tamer L, Buharalioglu CK, et al. Increased production of nitric oxide mediates selective organ-specific effects of endotoxin on oxidative stress. Anti-inflammatory and Anti-allergy Agents in Medicinal Chemistry. 11:161-172, 2012.
Schwierin B, Borbély AA, Tobler I. Effects of N6-cyclopentyladenosine and caffeine on sleep regulation in the rat. European Journal of Pharmacology. 300:163-171, 1996.
Sharma PR, Jain S, Tiwari PK. Elevated level of serum LDH2 and LDH3 in sputum three positive TB patients of Sahariya tribe: a preliminary study. Clinical Biochemistry. 40:1414-1419, 2007.
Shewfelt RL, Purvis AC. Toward a comprehensive model for lipid peroxidation in plant tissue disorders. Horticultural Science. 30:213-218, 1995.
Shvedova AA, Yanamala N, Murray AR, Kisin ER, Khaliullin T, Hatfield MK, et al. Oxidative stress, inflammatory biomarkers, and toxicity in mouse lung and liver after inhalation exposure to 100% biodiesel or petroleum diesel emissions. Journal of Toxicology and Environmental Health Part A. 76:907-921, 2013.
Sies H. Oxidative stress: from basic research to clinical application. The American Journal of Medicine. 91:31-38, 1991.
Silva RH, Abilio VC, Takatsu AL, Kameda SR, Grassl C, Chehin AB, et al. Role of hippocampal oxidative stress in memory deficits induced by sleep deprivation in mice. Neuropharmacology. 46:895-903, 2004.
Silva RH, Abílio VC, Kameda SR, Takatsu-Coleman AL, Carvalho RC, Ribeiro Rde A, et al. Effects of 3-nitropropionic acid administration on memory and hippocampal lipid peroxidation in sleep-deprived mice. Progress in Neuro-Psychopharmacology and Biological Psychiatry 31:65-70, 2007.
Silva JS, Vespa GN, Cardoso MA, Aliberti JC, Cunha FQ. Tumor necrosis factor alpha mediates resistance to Trypanosoma cruzi infection in mice by inducing nitric oxide production in infected gamma interferon-activated macrophages. Infection and Immunity. 63:4862-4867, 1995.
Solarz DE, Mullington JM, Meier-Ewert HK. Sleep, inflammation and cardiovascular disease. Front Biosci(Elite Ed). 1:2490-2501, 2012.
Sosroseno W. The effect of L-arginine on Porphyromonas gingivalis-induced phagocytosis of a murine macrophage-like RAW264.7 cell line. Immunopharmacology and Immunotoxicology. 26:309-313, 2004.
Stamler JS, Singel DJ, Loscalzo J. Biochemistry of nitric oxide and its redox-activated forms. Science. 258:1898-1902, 1992.
Steptoe A , Peacey V, Wardle J. Sleep duration and health in young adults. Archives of Internal Medicine. 166:1689-1692, 2006.
Suchecki D, Hipólide DC, Lobo LL, Tufik S. ACTH and corticosterone responses to multiple and single platform techniques-induced REM sleep deprivation. Sleep Research. 24: 455, 1995.
Sunbul M, Kanar BG, Durmus E, Kivrak T, Sari I. Acute sleep deprivation is associated with increased arterial stiffness in healthy young adults. Sleep and Breathing. 18:215-220, 2014.
Takagi K, Nukaya I, Yasukawa K, Suketa Y. Inhibitory mechanisms of antibody production by nitrogen oxides released from activated macrophages during the immune response: relationship to energy consumption. Immunology and Cell Biology. 72:241-248, 1994.
Tanaka T, Fujii M, Nishikawa A, Bunai Y, Obayashi F, Sugie S, et al. A cytochemical study of lactic dehydrogenase (LDH) isoenzymes in human lung cancer. Cancer Detection and Prevention. 7:65-71, 1984.
Titheradge MA. Nitric oxide in septic shock. Biochimica et Biophysica Acta. 1411:437-455, 1999.
Uehli K, Mehta AJ, Miedinger D, Hug K, Schindler C, Holsboer-Trachsler E, et al. Sleep problems and work injuries: a systematic review and meta-analysis. Sleep Medicine Reviews. 18:61-73, 2014.
Van Hulzen ZJM, Coenen AML. Paradoxical sleep deprivation and locomotor activity in rats. Physiology and Behavior. 27:741-744, 1981.
Ventegodt S , Kandel I , Merrick J . Quality of life and philosophy of life determines physical and mental health: status over research findings from the Quality of Life Research Center, Copenhagen, 1991-2007. Scientific World Journal. 7:1743-1751, 2007.
Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Wong C, et al. Sleep deprivation decreases binding of [11C]raclopride to dopamine D2/D3 receptors in the human brain. The Journal of Neuroscience. 28:8454-8461, 2008.
Vriend JL, Davidson FD, Corkum PV, Rusak B, Chambers CT, McLaughlin EN. Manipulating sleep duration alters emotional functioning and cognitive performance in children. Journal of Pediatric Psychology. 38:1058-1069, 2013.
Weingarten JA, Collop NA. Air travel: effects of sleep deprivation and jet lag. Chest. 144:1394-401, 2013.
Williamson A, Lombardi DA, Folkard S, Stutts J, Courtney TK, Connor JL. The link between fatigue and safety. Accident Analysis and Prevention. 43:498-515, 2011.
Wright JL, Postma DS, Kerstjens HA, Timens W, Whittaker P, Churg A. Airway remodeling in the smoke exposed guinea pig model. Inhalation Toxicology. 19:915-923, 2007.
馬旭輝，張杰。中藥對內皮素及一氧化氮的調控作用研究進展。中西醫結合學報，2004年3月第2卷第2期。