臺灣博碩士論文加值系統

睡眠呼吸中止症如同間歇性低氧之狀態，經常伴隨產生呼吸道反應亢進。雖然睡眠呼吸中止病患伴隨產生呼吸道反應亢進的病生理機制仍不清楚，但據推測呼吸道的發炎反應似乎在此過程中扮演著重要角色。因此，本實驗我們探討1)長期暴露間歇性低氧是否導致呼吸道反應亢進和呼吸道發炎；假設可以，則進一步探討2)發炎介質，如活性氧物種、環氧合酶的代謝產物是否參與在此反應中。實驗採用雄性Brown Norway大鼠，暴露於間歇性低氧每1.25分鐘一個循環(30秒氮氣+45秒空氣)，每天暴露六小時且連續14天，控制組則暴露在外界正常氧濃度下。在第15天以右頸靜脈插管注射methacholine，測量總肺阻力和動態肺順應性的變化情形，作為呼吸道反應亢進的指標。呼吸道發炎指標則測量肺泡灌洗液當中的總細胞數、蛋白質含量、細胞分類、化學介質和細胞激素的分析。實驗結果顯示，基礎值的總肺阻力和動態肺順應性在兩組之間並沒有顯著差異；然而暴露間歇性低氧的大鼠注射methacholine卻引起更強烈的支氣管平滑肌的收縮。在肺泡灌洗液分析可發現間歇性低氧暴露的大鼠產生呼吸道發炎反應，包括嗜中性白血球、巨噬細胞、淋巴球、嗜酸性白血球的數量提高，前列腺素E2、白細胞介素-6、單核球趨化蛋白-1的含量也增加。此外，於每天間歇性低氧暴露之前，以腹腔注射N-acetyl-L-cysteine(NAC; 抗氧化劑, 300 mg/kg)、apocynin(NADPH oxidase的抑制劑)和ibuprofen (環氧合酶抑制劑, 50 mg/kg)等藥物，皆可減弱methacholine誘發的氣道收縮反應和呼吸道發炎現象，而合併給予NAC和Ibuprofen所造成的抑制作用也與單獨藥物給予的反應相類似。根據上述的實驗結果得知，十四天之慢性間歇性低氧暴露的大鼠可引發呼吸道反應亢進和呼吸道發炎，且內源性的活性氧物種和環氧合酶的代謝產物參與此反應中。

Obstructive sleep apnea (OSA), manifested by intermittent hypoxia (IH), is associated with airway hyperresponsiveness (AHR). Although the pathophysiological mechanism of OSA-associated AHR remains unclear, airway inflammation is likely to play a critical role. In this study, we investigated 1) whether long-term exposure to IH causes AHR and airway inflammation, and if so, 2) whether inflammatory mediators, such as reactive oxygen species (ROS) and cyclooxygenase products, are involved in the response. Male Brown Norway rats were exposed to repetitive 1.25-min cycles (30 s of N2 + 45 s of 21% O2) of IH for 6 h/day for 14 consecutive days and matching control animals (receiving room air exposure). On day 15, total lung resistance (RL) and dynamic lung compliance (Cdyn) to right atrial injection of methacholine were measured as an index for AHR. Total cell counts, protein levels, differential cell counts, inflammatory mediator and cytokines in bronchoalveolar lavage fluid (BALF) were measured to serve as indices of airway inflammation. The baseline RL and Cdyn were not significantly different between the two groups; however, the methacholine injection induced a significantly more intense bronchoconstriction in IH-exposed rats. IH exposure evoked airway inflammation as shown by an elevation of the levels of neutrophils, macrophages, lymphocytes, and eosinophils, PGE2, IL-6, and monocyte chemoattractant protein-1 (MCP-1) in BALF. Furthermore, the increase in bronchomotor responses to methacholine injection and elevated airway inflammation caused by IH exposure were significantly attenuated by N-acetyl-L-cysteine (NAC; an antioxidant, 300 mg/kg), apocynin (an inhibitor of NADPH oxidase, 50 mg/kg) and ibuprofen (a cyclooxygenase inhibitor, 50 mg/kg), and was nearly abolished by a combination of NAC and ibuprofen. These results suggest that IH exposure induces AHR and airway inflammation in rats, and that the endogenous ROS and cyclooxygenase products are responsible for these responses.

目錄
壹、 文獻回顧與研究目的 3
一、 背景知識 3
(一) 間歇性低氧對呼吸系統之影響 3
(二) 間歇性低氧誘使反應性氧衍生物產生 5
(三) 呼吸系統的發炎反應 7
(四) 呼吸道反應亢進 9
二、 研究目的 13
貳、 實驗材料與方法 15
三、 研究方法 15
(一) 實驗動物 15
(二) 間歇性低氧模式 15
(三) 動物的麻醉及插管 16
(四) 開胸手術 16
(五) 生理參數測量 17
(六) 支氣管肺泡灌洗液分析 18
(七) 肺組織脂質過氧化反應之測定 20
四、 藥物製備 23
五、 實驗步驟 25
六、 資料分析與統計 26
參、 實驗結果 27
肆、 討論 32
伍、 結論 37
陸、 圖表及說明 38
柒、 參考文獻 56

Almendros I, Montserrat JM, Ramirez J, Torres M, Duran-Cantolla J, Navajas D, Farre R (2012) Intermittent hypoxia enhances cancer progression in a mouse model of sleep apnoea. The European Respiratory Journal 39:215-217.
Aoki H, Mogi C, Hisada T, Nakakura T, Kamide Y, Ichimonji I, Tomura H, Tobo M, Sato K, Tsurumaki H, Dobashi K, Mori T, Harada A, Yamada M, Mori M, Ishizuka T, Okajima F (2013) Proton-sensing ovarian cancer g protein-coupled receptor 1 on dendritic cells is required for airway responses in a murine asthma model. Plos One 8:79985.
Araneda OF, Tuesta M (2012) Lung oxidative damage by hypoxia. Oxidative Medicine and Cellular Longevity 2012:856918.
Armour CL, Black JL, Johnson PR (1988) A role for inflammatory mediators in airway hyper-responsiveness. Progress in Clinical and Biological Research 263:99-108.
Bai TR, Knight DA (2005) Structural changes in the airways in asthma: observations and consequences. Clinical Science 108:463-477.
Bell EL, Klimova TA, Eisenbart J, Schumacker PT, Chandel NS (2007) Mitochondrial reactive oxygen species trigger hypoxia-inducible factor-dependent extension of the replicative life span during hypoxia. Molecular and Cellular Biology 27:5737-5745.
Borchers MT, Biechele T, Justice JP, Ansay T, Cormier S, Mancino V, Wilkie TM, Simon MI, Lee NA, Lee JJ (2003) Methacholine-induced airway hyperresponsiveness is dependent on Galphaq signaling. American Journal of Physiology Lung Cellular and Molecular Physiology 285:28.
Brusasco V, Crimi E, Pellegrino R (1998) Airway hyperresponsiveness in asthma: not just a matter of airway inflammation. Thorax 53:992-998.
Carpagnano GE, Spanevello A, Sabato R, Depalo A, Palladino GP, Bergantino L, Foschino Barbaro MP (2010) Systemic and airway inflammation in sleep apnea and obesity: the role of ICAM-1 and IL-8. Translational Research: the Journal of Laboratory and Clinical Medicine 155:35-43.
Chandel NS, Trzyna WC, McClintock DS, Schumacker PT (2000) Role of oxidants in NF-kappa B activation and TNF-alpha gene transcription induced by hypoxia and endotoxin. Journal of Immunology 165:1013-1021.
Chiang LL, Kuo CT, Wang CH, Chen TF, Ho YS, Kuo HP, Lin CH (2003) Involvement of nuclear factor-kappaB in lipoteichoic acid-induced cyclooxygenase-2 expression in RAW 264.7 macrophages. The Journal of Pharmacy and Pharmacology 55:115-123.
Chizzolini C, Brembilla NC (2009) Prostaglandin E2: igniting the fire. Immunology and Cell Biology 87:510-511.
Cockcroft DW, Davis BE (2006) Mechanisms of airway hyperresponsiveness. The Journal of Allergy and Clinical Immunology 118:551-559
Coleridge JC, Coleridge HM (1984) Afferent vagal C fibre innervation of the lungs and airways and its functional significance. Reviews of Physiology, Biochemistry and Pharmacology 99:1-110.
Conti P, DiGioacchino M (2001) MCP-1 and RANTES are mediators of acute and chronic inflammation. Allergy and Asthma Proceedings 22:133-137.
Ebina M, Takahashi T, Chiba T, Motomiya M (1993) Cellular hypertrophy and hyperplasia of airway smooth muscles underlying bronchial asthma. A 3-D morphometric study. The American Review of Respiratory Disease 148:720-726.
Elwood W, Sakamoto T, Barnes PJ, Chung KF (1985) Allergen-induced airway hyperresponsiveness in Brown-Norway rat: role of parasympathetic mechanisms. Journal of Applied Physiology 75:279-284.
Emerson PA, Torres GE, Lyons HA (1960) The effect of intermittent positive pressure breathing on the lung compliance and intrapulmonary mixing of gases. Thorax 15:125-131.
Fabbri LM, Aizawa H, Alpert SE, Walters EH, O'Byrne PM, Gold BD, Nadel JA, Holtzman MJ (1984) Airway hyperresponsiveness and changes in cell counts in bronchoalveolar lavage after ozone exposure in dogs. American Review of Respiratory Disease 129:288-291.
Feghali CA, Wright TM (1997) Cytokines in acute and chronic inflammation. Frontiers in Bioscience 2:d12-26.
Fernandes DJ, Mitchell RW, Lakser O, Dowell M, Stewart AG, Solway J (2003) Do inflammatory mediators influence the contribution of airway smooth muscle contraction to airway hyperresponsiveness in asthma? Journal of Applied Physiology 95:844-853.
Fielding CA, McLoughlin RM, McLeod L, Colmont CS, Najdovska M, Grail D, Ernst M, Jones SA, Topley N, Jenkins BJ (2008) IL-6 regulates neutrophil trafficking during acute inflammation via STAT3. Journal of Immunology 181:2189-2195.
Fletcher BL, Dillard CJ, Tappel AL (1973) Measurement of fluorescent lipid peroxidation products in biological systems and tissues. Analytical Biochemistry 52:1-9.
Fredenburgh LE, Liang OD, Macias AA, Polte TR, Liu X, Riascos DF, Chung SW, Schissel SL, Ingber DE, Mitsialis SA, Kourembanas S, Perrella MA (2008) Absence of cyclooxygenase-2 exacerbates hypoxia-induced pulmonary hypertension and enhances contractility of vascular smooth muscle cells. Circulation 117:2114-2122.
Habre W, Janosi TZ, Fontao F, Meyers C, Albu G, Pache JC, Petak F (2010) Mechanisms for lung function impairment and airway hyperresponsiveness following chronic hypoxia in rats. American Journal of Physiology Lung Cellular and Molecular Physiology 298:5.
Hirshman CA, Austin DR, Klein W, Hanifin JM, Hulbert W (1986) Increased metachromatic cells and lymphocytes in bronchoalveolar lavage fluid of dogs with airway hyperreactivity. American Review of Respiratory Disease 133:482-487.
Hirst SJ, Twort CH, Lee TH (2000) Differential effects of extracellular matrix proteins on human airway smooth muscle cell proliferation and phenotype. American Journal of Respiratory Cell and Molecular Biology 23:335-344.
Holtzman MJ, Fabbri LM, O'Byrne PM, Gold BD, Aizawa H, Walters EH, Alpert SE, Nadel JA (1983) Importance of airway inflammation for hyperresponsiveness induced by ozone. American Review of Respiratory Disease 127:686-690.
Honjo A, Ogawa H, Azuma M, Tezuka T, Sone S, Biragyn A, Nishioka Y (2013) Targeted reduction of CCR4(+) cells is sufficient to suppress allergic airway inflammation. Respiratory Investigation 51:241-249.
Hopfenspirger MT, Parr SK, Hopp RJ, Townley RG, Agrawal DK (2001) Mycobacterial antigens attenuate late phase response, airway hyperresponsiveness, and bronchoalveolar lavage eosinophilia in a mouse model of bronchial asthma. International Immunopharmacology 1:1743-1751.
Itoh M, Tsuji T, Nemoto K, Nakamura H, Aoshiba K (2013) Undernutrition in patients with COPD and its treatment. Nutrients 5:1316-1335.
Jacobson J, Duchen MR (2002) Mitochondrial oxidative stress and cell death in astrocytes--requirement for stored Ca2+ and sustained opening of the permeability transition pore. Journal of Cell Science 115:1175-1188.
Kanehiro A, Ikemura T, Makela MJ, Lahn M, Joetham A, Dakhama A, Gelfand EW (2001) Inhibition of phosphodiesterase 4 attenuates airway hyperresponsiveness and airway inflammation in a model of secondary allergen challenge. American Journal of Respiratory and Critical Care Medicine 163:173-184.
Kaplanski G, Marin V, Montero-Julian F, Mantovani A, Farnarier C (2003) IL-6: a regulator of the transition from neutrophil to monocyte recruitment during inflammation. Trends in Immunology 24:25-29.
Keshavan P, Deem TL, Schwemberger SJ, Babcock GF, Cook-Mills JM, Zucker SD (2005) Unconjugated bilirubin inhibits VCAM-1-mediated transendothelial leukocyte migration. The Journal of Immunology 174:3709-3718.
Kim SY, Moon KA, Jo HY, Jeong S, Seon SH, Jung E, Cho YS, Chun E, Lee KY (2012) Anti-inflammatory effects of apocynin, an inhibitor of NADPH oxidase, in airway inflammation. Immunology and Cell Biology 90:441-448.
Kladna A, Aboul-Enein HY, Kruk I, Lichszteld K, Michalska T (2006) Scavenging of reactive oxygen species by some nonsteroidal anti-inflammatory drugs and fenofibrate. Biopolymers 82:99-105.
Kou YR, Kwong K, Lee LY (2011) Airway inflammation and hypersensitivity induced by chronic smoking. Respiratory Physiology & Neurobiology 178:395-405.
Kuhn C, Homer RJ, Zhu Z, Ward N, Flavell RA, Geba GP, Elias JA (2000) Airway hyperresponsiveness and airway obstruction in transgenic mice. Morphologic correlates in mice overexpressing interleukin (IL)-11 and IL-6 in the lung. American Journal of Respiratory Cell and Molecular Biology 22:289-295.
Lee IT, Yang CM (2012) Role of NADPH oxidase/ROS in pro-inflammatory mediators-induced airway and pulmonary diseases. Biochemical Pharmacology 84:581-590.
Lee LY (2009) Respiratory sensations evoked by activation of bronchopulmonary C-fibers. Respiratory Physiology and Neurobiology 167:26-35.
Leigh R, Ellis R, Wattie J, Donaldson DD, Inman MD (2004) Is interleukin-13 critical in maintaining airway hyperresponsiveness in allergen-challenged mice? American Journal of Respiratory and Critical Care Medicine 170:851-856.
Lin AM, Yang CH, Chai CY (1998) Striatal dopamine dynamics are altered following an intranigral infusion of iron in adult rats. Free Radical Biology and Medicine 24:988-993.
Lin AM, Chen CF, Ho LT (2002) Neuroprotective effect of intermittent hypoxia on iron-induced oxidative injury in rat brain. Experimental Neurology 176:328-335.
Lin C-C, Lee IT, Yang Y-L, Lee C-W, Kou YR, Yang C-M (2010) Induction of COX-2/PGE2/IL-6 is crucial for cigarette smoke extract-induced airway inflammation: Role of TLR4-dependent NADPH oxidase activation. Free Radical Biology and Medicine 48:240-254.
Lin CC, Lin CY (1995) Obstructive sleep apnea syndrome and bronchial hyperreactivity. Lung 173:117-126.
Makwana R, Gozzard N, Spina D, Page C (2012) TNF-alpha-induces airway hyperresponsiveness to cholinergic stimulation in guinea pig airways. British Journal of Pharmacology 165:1978-1991.
Manuyakorn W, Howarth PH, Holgate ST (2013) Airway remodelling in asthma and novel therapy. Asian Pacific Journal of Allergy and Immunology 31:3-10.
Mates JM, Sanchez-Jimenez FM (2000) Role of reactive oxygen species in apoptosis: implications for cancer therapy. The International Journal of Biochemistry and Cell Biology 32:157-170.
McNicholas WT (2009) Chronic obstructive pulmonary disease and obstructive sleep apnea: overlaps in pathophysiology, systemic inflammation, and cardiovascular disease. American Journal of Respiratory and Critical Care Medicine 180:692-700.
Neveu WA, Allard JL, Raymond DM, Bourassa LM, Burns SM, Bunn JY, Irvin CG, Kaminsky DA, Rincon M (2010) Elevation of IL-6 in the allergic asthmatic airway is independent of inflammation but associates with loss of central airway function. Respiratory Research 11:28.
Oishi K, Machida K (1997) Some plasma component is essential for IL-6 secretion by Neutrophils. Environmental Health and Preventive Medicine 2:89-92.
Pare PD (2003) Airway hyperresponsiveness in asthma: geometry is not everything! American Journal of Respiratory and Critical Care Medicine 168:913-914.
Peebles RS, Jr., Dworski R, Collins RD, Jarzecka K, Mitchell DB, Graham BS, Sheller JR (2000) Cyclooxygenase inhibition increases interleukin 5 and interleukin 13 production and airway hyperresponsiveness in allergic mice. American Journal of Respiratory and Critical Care Medicine 162:676-681.
Peebles RS, Jr., Hashimoto K, Sheller JR, Moore ML, Morrow JD, Ji S, Elias JA, Goleniewska K, O'Neal J, Mitchell DB, Graham BS, Zhou W (2005) Allergen-induced airway hyperresponsiveness mediated by cyclooxygenase inhibition is not dependent on 5-lipoxygenase or IL-5, but is IL-13 dependent. Journal of Immunology 175:8253-8259.
Petak F, Babik B, Hantos Z, Morel DR, Pache JC, Biton C, Suki B, Habre W (2004) Impact of microvascular circulation on peripheral lung stability. American Journal of Physiology: Lung Cellular and Molecular Physiology 287:18.
Pierson DJ (2000) Pathophysiology and clinical effects of chronic hypoxia. Respiratory Care 45:39-51.
Polito AJ, Proud D (1998) Epithelia cells as regulators of airway inflammation. The Journal of Allergy and Clinical Immunology 102:714-718.
Postma DS, Kerstjens HA (1998) Characteristics of airway hyperresponsiveness in asthma and chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 158:S187-192.
Prasad B, Nyenhuis SM, Weaver TE (2013) Obstructive sleep apnea and asthma: Associations and treatment implications. Sleep Medicine Reviews. 3:1087-1092
Profita M, Montuschi P, Bonanno A, Riccobono L, Cibella F, Ciabattoni G, Albano GD, Gjomarkaj M, Pace E, Grutta SL Biomarkers of oxidative stress in the upper and lower airways of atopic children. American Thoracic Society 179:A5711:
Rahman I, MacNee W (2000) Oxidative stress and regulation of glutathione in lung inflammation. The European Respiratory Journal 16:534-554.
Reeves SR, Gozal D (2006) Respiratory and metabolic responses to early postnatal chronic intermittent hypoxia and sustained hypoxia in the developing rat. Pediatric Research 60:680-686.
Renz H (2001) The role of neurotrophins in bronchial asthma. European Journal of Pharmacology 429:231-237.
Reynolds SD, Giangreco A, Hong KU, McGrath KE, Ortiz LA, Stripp BR (2004) Airway injury in lung disease pathophysiology: selective depletion of airway stem and progenitor cell pools potentiates lung inflammation and alveolar dysfunction. American Journal of Physiology: Lung Cellular and Molecular Physiology 287:L1256-1265.
Sabato R, Guido P, Salerno FG, Resta O, Spanevello A, Barbaro MP (2006) Airway inflammation in patients affected by obstructive sleep apnea. Respiratory Medicine 98:25-28.
Sant'Ambrogio FB, Sant'Ambrogio G, Fisher JT (1988) Lung mechanics and activity of slowly adapting airway stretch receptors. The European Respiratory Journal 1:685-690.
Sariman N, Levent E, Cubuk R, Yurtlu S, Benli Aksungar F (2011) Bronchial hyperreactivity and airway wall thickening in obstructive sleep apnea patients. Sleep and Breathing 15:341-350.
Schepetkin IA, Cherdyntseva NV, Kagiya VT (2001) Sanazole as substrate of xanthine oxidase and microsomal NADPH/cytochrome P450 reductase. Pathophysiology 8:119-127.
Shen MY, Luo YL, Yang CH, Ruan T, Lai CJ (2012) Hypersensitivity of lung vagal C fibers induced by acute intermittent hypoxia in rats: role of reactive oxygen species and TRPA1. The American Journal of Physiology Regulatory Integrative and Comparative Physiology 303:17.
Shen Y, Yang T, Guo S, Li X, Chen L, Wang T, Wen F (2013) Increased serum ox-LDL levels correlated with lung function, inflammation, and oxidative stress in COPD. Mediators of Inflammation 2013:972347.
Sheu SS, Nauduri D, Anders MW (2006) Targeting antioxidants to mitochondria: a new therapeutic direction. Biochimica et Biophysica acta 1762:256-265.
Sohn HY, Krotz F, Gloe T, Keller M, Theisen K, Klauss V, Pohl U (2003) Differential regulation of xanthine and NAD(P)H oxidase by hypoxia in human umbilical vein endothelial cells. Role of nitric oxide and adenosine. Cardiovascular Research 58:638-646.
Steevels TA, van Avondt K, Westerlaken GH, Stalpers F, Walk J, Bont L, Coffer PJ, Meyaard L (2013) Signal inhibitory receptor on leukocytes-1 (SIRL-1) negatively regulates the oxidative burst in human phagocytes. European Journal of Immunology 43:1297-1308.
Stewart JC, Hyde RW, Boscia J, Chow MY, O'Mara RE, Perillo I, Pietropaoli A, Smith CJ, Torres A, Utell MJ, Frampton MW (2006) Changes in markers of epithelial permeability and inflammation in chronic smokers switching to a nonburning tobacco device. Nicotine and Tobacco Research 8:773-783.
Suarez-Sipmann F, Bohm SH, Tusman G, Pesch T, Thamm O, Reissmann H, Reske A, Magnusson A, Hedenstierna G (2007) Use of dynamic compliance for open lung positive end-expiratory pressure titration in an experimental study. Critical Care Medicine 35:214-221.
Swedin L, Neimert-Andersson T, Hjoberg J, Jonasson S, van Hage M, Adner M, Ryrfeldt A, Dahlen SE (2009) Dissociation of airway inflammation and hyperresponsiveness by cyclooxygenase inhibition in allergen challenged mice. The European Respiratory Journal 34:200-208.
Tagaya E, Tamaoki J (2007) Mechanisms of airway remodeling in asthma. Allergology International 56:331-340.
Tirmenstein MA, Pierce CA, Leraas TL, Fariss MW (1998) A fluorescence plate reader assay for monitoring the susceptibility of biological samples to lipid peroxidation. Analytical Biochemistry 265:246-252.
Tuder RM, Yun JH, Bhunia A, Fijalkowska I (2007) Hypoxia and chronic lung disease. Journal of Molecular Medicine 85:1317-1324.
Turrens JF (2003) Mitochondrial formation of reactive oxygen species. The Journal of Physiology 552:335-344.
Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M (2006) Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chemico Biological Interactions 160:1-40.
Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J (2007) Free radicals and antioxidants in normal physiological functions and human disease. The International Journal of Biochemistry and Cell Biology 39:44-84.
Williams CS, Mann M, DuBois RN (1999) The role of cyclooxygenases in inflammation, cancer, and development. Oncogene 18:7908-7916.
Wilson JW, Li X (1997) The measurement of reticular basement membrane and submucosal collagen in the asthmatic airway. Clinical and Experimental Allergy 27:363-371.
Wu ZX, Zhou D, Chen G, Lee LY (2000) Airway hyperresponsiveness to cigarette smoke in ovalbumin-sensitized guinea pigs. American Journal of Respiratory and Critical Care Medicine 161:73-80.
Xie X, Pan L, Ren D, Du C, Guo Y (2013) Effects of continuous positive airway pressure therapy on systemic inflammation in obstructive sleep apnea: A meta-analysis. Sleep Medicine 14:1139-1150.
Zhao L, Wu Y, Xu Z, Wang H, Zhao Z, Li Y, Yang P, Wei X (2012) Involvement of COX-2/PGE2 signalling in hypoxia-induced angiogenic response in endothelial cells. Journal of Cellular and Molecular Medicine 16:1840-1855.
Zweier JL, Talukder MA (2006) The role of oxidants and free radicals in reperfusion injury. Cardiovascular Research 70:181-190.