Nursing Research and Practice

Nursing Research and Practice / 2011 / Article

Review Article | Open Access

Volume 2011 |Article ID 260482 |

William J. Mach, Amanda R. Thimmesch, J. Thomas Pierce, Janet D. Pierce, "Consequences of Hyperoxia and the Toxicity of Oxygen in the Lung", Nursing Research and Practice, vol. 2011, Article ID 260482, 7 pages, 2011.

Consequences of Hyperoxia and the Toxicity of Oxygen in the Lung

Academic Editor: Alan Pearson
Received14 Dec 2010
Revised29 Mar 2011
Accepted04 Apr 2011
Published05 Jun 2011


Oxygen (O2) is life essential but as a drug has a maximum positive biological benefit and accompanying toxicity effects. Oxygen is therapeutic for treatment of hypoxemia and hypoxia associated with many pathological processes. Pathophysiological processes are associated with increased levels of hyperoxia-induced reactive O2 species (ROS) which may readily react with surrounding biological tissues, damaging lipids, proteins, and nucleic acids. Protective antioxidant defenses can become overwhelmed with ROS leading to oxidative stress. Activated alveolar capillary endothelium is characterized by increased adhesiveness causing accumulation of cell populations such as neutrophils, which are a source of ROS. Increased levels of ROS cause hyperpermeability, coagulopathy, and collagen deposition as well as other irreversible changes occurring within the alveolar space. In hyperoxia, multiple signaling pathways determine the pulmonary cellular response: apoptosis, necrosis, or repair. Understanding the effects of O2 administration is important to prevent inadvertent alveolar damage caused by hyperoxia in patients requiring supplemental oxygenation.

1. Introduction

When administering supplemental oxygen (O2) to treat hypoxemia associated with acute and chronic conditions, O2 toxicity by overexposure may be present. Annually, the need for supplemental O2 is projected to be around 800,000 individuals at a cost of 1.8 billion dollars [1]. Suboptimal use of O2 is reflected in prescription and treatment errors that exceed those related to antibiotics [24].

The alveolar epithelial and alveolar capillary endothelial cells are vulnerable targets for O2-free-radical-induced injury caused by hyperoxia. In acute lung injury (ALI) caused by hyperoxia, hyperpermeability of the pulmonary microvasculature causes flooding of the alveolus with plasma extravasations leading to pulmonary edema and abnormalities in the coagulation and fibrinolysis pathways promoting fibrin deposition [5, 6]. Type II alveolar epithelial cells are injured by O2 free radicals leading to impairment of surfactant production [7]. Thus, the maximum positive biological benefit for this life essential but toxic molecule exists along a dose-response, deficiency–toxicity continuum.

2. Pathophysiology of Oxygen Toxicity

Hyperoxia is a state of excess supply of O2 in tissues and organs. Oxygen toxicity occurs when the partial pressure of alveolar O2 (PAO2) exceeds that which is breathed under normal conditions. With continuous exposure to supraphysiologic concentrations of O2, a state of hyperoxia develops. Under hyperoxic pathological conditions, a large influx of reactive O2 species (ROS) are produced. In intracellular and extracellular biological systems, the mass effect of ROS elevation, caused by O2 overexposure, disrupts the balance between oxidants and antioxidants, and this disruption of homeostasis can result in damage to cells and tissues [811].

Exposure time, atmospheric pressure, and fraction of inspired O2 (FIO2) determine the cumulative O2 dose leading to toxicity. Oxygen is toxic to the lungs when high FIO2 (>0.60) is administered over extended exposure time (≥24 hours) at normal barometric pressure (1 atmospheres absolute (ATA)). This type of exposure is referred to as low pressure O2 poisoning, pulmonary toxicity, or the Lorraine Smith effect. Oxygen exposure after approximately 12 hours leads to lung passageway congestion, pulmonary edema, and atelectasis caused by damage to the linings of the bronchi and alveoli. The formation of fluid in the lungs causes a feeling of shortness of breath combined with a burning of the throat and chest, and breathing becomes very painful [12]. The reason for this effect in the lungs but not in other tissues is that the air spaces of the lungs are directly exposed to the high O2 pressure. Oxygen is delivered to the other body tissues at almost normal partial pressure of O2 (PO2) because of the hemoglobin-O2 buffer system [1315]. Toxicity also occurs when the ATA is high (1.6–4) and the high FIO2 exposure time is short. This type of exposure is referred to as high pressure O2 poisoning or the Paul Bert effect and is toxic to the central nervous system (CNS). Central nervous system toxicity results in seizures followed by coma in most people within 30 to 60 minutes. Seizures often occur without warning and are likely to be lethal. Other symptoms include nausea, muscle twitching, dizziness, disturbances of vision, irritability, and disorientation [13, 1620]. Oceanic divers are more likely to experience CNS toxicity [17].

Pulmonary capillary endothelial and alveolar epithelial cells are targets for ROS resulting in injury-induced lung edema, alveolar flooding, hemorrhage, and collagen, elastin, and hyaline membrane deposits [11, 21, 22]. Above a critical PAO2, the hemoglobin-O2 buffering mechanism fails and the tissue PO2 can rise to hundreds or thousands of mm Hg. At high levels of O2, protective endogenous antioxidant enzyme systems become consumed by ROS leading to cell death [16, 23].

Oxygen toxicity caused by ROS progresses in overlapping phases based on degree of severity and reversibility of injury. The phases are initiation, inflammation, proliferation, and fibrosis. Initially, there are increased ROS and depleted antioxidant levels, and the lung fails to clear itself of mucous. The inflammation phase or exudative phase is characterized by the destruction of the pulmonary lining and migration of leukocyte derived inflammatory mediators to the sites of injury. The proliferative phase is subacute and there are cellular hypertrophy, increased secretions from surfactant secreting alveolar type II cells, and increased monocytes. The final terminal phase is the fibrotic phase in which the changes to the lung are irreversible and permanent. There is collagen deposition and thickening of the pulmonary interstitial space and the lung becomes fibrotic [2427].

Clinically, progressive hypoxemia, or high O2 tension in the blood, requires increased FIO2 and assisted ventilation, which further aggravate the pathophysiological changes associated with O2 toxicity. Chest X-rays may show an alveolar interstitial pattern in an irregular distribution with evidence of a moderate loss of volume from atelectasis, however there is no clinical way of diagnosing O2 toxicity. Lung biopsy specimens may show changes consistent with O2 toxicity but the primary value of the biopsy is to exclude other causes of lung injury. Air pressure changes within the enclosed lung cavity and ventilator-induced injury may accompany and be indistinguishable from O2 toxicity. Oxygen toxicity can be minimized by keeping the PAO2 less than 80 mm Hg or the FIO2 below 0.40 to 0.50 [12].

The pulmonary cellular response to hyperoxic exposure and increased ROS is well described. Anatomically, the pulmonary epithelial surface is vulnerable to a destructive inflammatory response. This inflammation damages the alveolar capillary barrier leading to impaired gas exchange and pulmonary edema. Reactive O2 species induces pulmonary cell secretion of chemoattractants, and cytokines stimulate macrophage and monocyte mobilization and accumulation into the lungs, leading to additional ROS. The ROS leukocyte interaction further exacerbates injury. Research has shown that as these highly reduced cell layers become increasingly oxidized and levels of antioxidants fall, ROS-induced activation of multiple upstream signal transduction pathways regulates the cellular response: adaptation, repair, or cell death by apoptosis, oncosis, or necrosis [28, 29].

Mitogen-activated protein kinase (MAPK), toll-like receptor 4 (TLR4), signal transducers and activators of transcription (STAT), and nuclear factor kappa beta (NF kβ) are a few well-researched protein pathways that communicate the receptor signal to the deoxyribonucleic acid (DNA) of the cell thereby determining the cellular response. The MAPK pathway is a regulator of cell death genes, stress, and transformation and growth regulation. Mitogen-activated protein kinase activation precedes extracellular signal regulated kinase (ERK1/2), a promoter of cell proliferation. C-Jun-terminal protein kinase (JNK1/2) and p38 kinase both induce cell death and inflammation [30]. The TLR4, STAT, and nuclear regulatory factor 2 (Nrf2) pathways are associated with survival gene expression such as caspase-3 proteins and antioxidant response element (ARE) [31, 32]. The NF kβ pathway is an up-stream signal for inflammation and survival genes: anti-oxidant enzymes (AOE), Bcl-2, AKT, heme oxygenase (HO-1), and heat shock proteins (HSPs). The AKT1-4 family of signals plays an important role in glucose metabolism, cell proliferation, apoptosis, transcription, and cell migration. The Bcl-2 proteins are antiapoptotic while HO-1 and HSPs are ubiquitous stress-response proteins [33]. These signaling pathways are regulators of the pulmonary epithelial cell response to increases in ROS and hyperoxia [18, 34]. Cytokine and chemokine overexpression in response to hyperoxic stress can be protective. Tumor necrosis factor alpha (TNFα), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), chemokine receptor 2 (CXCR2), interleukin 11 (IL-11), insulin and keratinocyte growth factor expression, and the beta subunit of Na, K-ATPase have been shown to attenuate death signals [3537].

3. The Formation of Free Radicals

Oxygen is a requirement for cellular respiration in the metabolism of glucose and the majority of O2 consumed by the mitochondria is utilized for adenosine triphosphate (ATP) generation [38, 39]. The mitochondrial electron transport chain reduces the elemental molecular O2 to ionic O2 by the relay of electrons making O2 usable for ATP generation, during this process, oxidizing free radicals are generated [40, 41]. Toxic levels of O2 lead to the formation of additional ROS, which can impose damage to lipid membranes, proteins, and nucleic acids. Reactive O2 species mediate physiological and pathophysiological roles within the body [42].

Free radicals are a type of unstable, reactive, short-lived chemical species that have one or more unpaired electrons and may possess a net charge or be neutral. The species is termed free because the unpaired electron in the outer orbit is free to interact with surrounding molecules [42, 43]. Cells generate free radicals, or ROS, by the reduction of molecular O2 to water (H2O) (Figure 1) [44, 45].

Chemically, three types of reactions lead to the formation of ROS. The one-electron reduction of molecular O2 to the superoxide anion () is catalyzed by transition metals including iron (Fe) and copper (Cu) such as

 The simultaneous oxidation reduction reaction of to hydrogen peroxide (H2O2) and the addition of an electron to produce the hydroxyl radical (HO). The in biological membranes can act in four different modes: electron transfer, nucleophilic substitution, deprotonation, and a hydrogen atom abstraction as in

 A initiated Fenton-type reaction and the decomposition of H2O2 requires and H2O2 as precursors and Fe and Cu presence for completion. The HO is the most injury producing in biological systems, reacting with molecules in close proximity. These reactions are called Fenton-like reactions generating O2 and HO when Fe II or Cu I reacts with H2O2

The sum of reactions (3) and (4), or the Haber-Weiss reaction shown in (5) above demonstrates HO formation by the metal-catalyzed decomposition of H2O2. The interaction between and H2O2 is the source of the majority of damage to biological systems due to the reactivity of continuously produced, highly toxic HO [18, 46, 47]. These ROS-producing reactions occur endogenously involving enzymes, neutrophils, and organelles such as the mitochondria and exogenously induced by radiation, pollutants, xenobiotics, and toxins. Cellular survival and adaptation in an oxidative atmosphere are dependent upon sufficient antioxidant defenses to counteract the effects of ROS on cells and tissues [48].

4. Functions and Classifications of Antioxidants

Oxidant antioxidant homeostasis is highly regulated and essential for maintaining cellular and biochemical functions [49]. A change in the balance toward an increase in the oxidant over the capacity of the antioxidant defines oxidative stress and can lead to oxidative damage. Changing the balance toward an increase in the reducing power of the antioxidant can also cause damage and is defined as reductive stress [5052]. Reduction, antioxidant and oxidation, or pro-oxidant reactions result from a gain or a loss of electrons and a loss or a gain in O2 [50, 53, 54].

An antioxidant (a reductant or reducing agent) is anything that can prevent or inhibit oxidation [5557]. Delay of oxidation can be achieved by preventing the generation or inactivating ROS [58]. Prevention, diversion, dismutation (decay), scavenging, and quenching are specialized antioxidant properties (Table 1). Antioxidant defenses may be classified as nonenzymatic and enzymatic or endogenous and dietary. Examples of nonenzymatic antioxidants are glutathione (GSH), ascorbic acid, vitamin E, beta-carotene, and uric acid. Major enzymatic antioxidants are superoxide dismutase (SOD), catalase, and GSH peroxidase which divert or dismutate ROS into harmless products. Endogenous or dietary antioxidants are based on the ability of the antioxidant to be synthesized by humans. Endogenous antioxidants are SOD, catalase, GSH peroxidase, uric acid, and bilirubin. Dietary antioxidants are ascorbic acid, vitamin E, and beta-carotene [59, 60]. Ascorbic acid, vitamin E, uric acid, bilirubin, and GSH scavenge ROS by expendable, replaceable, or recyclable substrates. Vitamin E and beta-carotene quench ROS by absorption of electrons and/or energy.

Enzymatic antioxidants located in mitochondria and cytosol

Glutathione peroxidase (GSH)Removal of H2O2, hydroperoxides
Superoxide dismutase (SOD)Catalytic removal of O2
Catalase (CAT)Catalytic reduction of H2O2 to H2O

Nonenzymatic antioxidants located in cell membrane, exogenous dietary source
Vitamin E (α tocopherol)Chain-breaking antioxidant
β-caroteneScavenger of ROS, singlet O2 quencher
Co-enzyme QRegenerates vitamin E

Compounds that reduce the availability of transition metals, Fenton reactions
TransferrinSequesters iron and copper ions
LactoferrinSequesters iron at lower pH
AlbuminSequesters heme and copper
Ceruloplasmin (ferroxidase)Scavenges superoxide radical, binds copper ions

Scavengers, products of metabolism, exogenous dietary source
BilirubinScavenges peroxyl radical
Uric acidScavenges hydroxyl radical
Vitamin C (ascorbic acid)Scavenges hydroxyl radical, recycles vitamin E

Thiol group donors
Reduced glutathione (GSSH)Binds free radicals, SH group oxidized to disulfide group (GSSG)
α-lipoic acidRecycles vitamin C, glutathione substitute

Antioxidants can be classified into four categories based on function. (1) Preventive antioxidants which suppress formation of ROS, (2) radical scavenging antioxidants which suppress chain initiation and/or break chain propagation reactions, (3) the repair and de novo antioxidants such as proteolytic enzymes and the repair enzymes of DNA, and (4) antioxidants which allow for adaptation that occurs when the signal for the production and reactions of ROS induces oxidant formation and transport [10, 61].

Superoxide dismutase converts to H2O2 and has three isoforms widely distributed in mammalian organisms. (1) Cytoplasmic SOD (SOD1 or Cu zinc (CuZn) SOD) is located in the cytoplasm, nucleus, and peroxisomes, (2) mitochondrial SOD (SOD2 or MnSOD) is located in the mitochondrial matrix near the electron transport chain, and (3) extracellular SOD (SOD3 or EcSOD) is found in the extracellular fluids and extracellular matrix of all human tissues especially the heart, placenta, pancreas, and lung [6264]. The protective effects of EcSOD in the lungs are extremely important and well-established [6568].

Catalase, one of the most potent catalysts found mostly in the peroxisome, functions to decompose H2O2 to H2O. Catalase defense from oxidant injury to lung epithelial cells exists in the cytosol or the mitochondria.

Glutathione reductase is an important antioxidant enzyme for maintaining the intracellular reducing environment. This enzyme catalyzes the reduction of glutathione disulfide (GSSG) to GSH [69]. Glutathione disulfide is produced through the oxidation of GSH by ROS that arise during conditions of oxidative stress. Due to the high concentrations of GSH, GSH/GSSG is considered to be the principal redox buffer of the cell and the ratio of GSH/GSSG is viewed as a major indicator of the cellular redox status. The ratio of GSH/GSSG decreases under an oxidative stress condition [70, 71]. Tissue damage may develop when an oxidant/antioxidant imbalance occurs as a consequence of hyperoxia [72, 73]. The damaging effects of hyperoxia can lead to O2 toxicity, cell death, and can be a triggering factor in ALI [22].

5. Clinical Presentation of Hyperoxic Acute Lung Injury

Acute lung injury and acute respiratory distress syndrome (ARDS) are secondarily occurring, inflammatory syndromes caused by triggers or risk factors described as direct or indirect, pulmonary or extrapulmonary. The pathological changes associated with HALI mimic the ALI triggered by other conditions such as hemorrhagic shock, reperfusion injury, pneumonia, sepsis, or paraquat inhalation [23, 33, 74, 75]. The risk of developing ALI or ARDS after inhalation injury is dependent on the toxicity and concentration of the inhaled substance [17]. For example, the cells and structure of the alveolar capillary membrane are highly susceptible to damage by toxic levels of O2 [76]. Both ALI and ARDS are the same clinical disorder, differing only in severity of hypoxemia. The ratio between arterial pressure of O2 (PaO2) and the FIO2 concentration delivered by ventilator support distinguishes the two syndromes. For ALI, the PaO2/FIO2 is ≤300 mm Hg and for ARDS, the PaO2/FIO2 is ≤200 mm Hg [74, 75, 77].

The injury to the alveolus is thought to develop when pulmonary or systemic inflammation leads to systemic release of cytokines and other proinflammatory molecules. Mast cells, which express mediators that exert effects on lung vasculature, are also increased after hyperoxic exposure [78]. Cytokine release activates alveolar macrophages and recruits neutrophils to the lungs. Subsequent activation of leukotrienes, oxidants, platelet activating factor, and protease occurs. These substances damage capillary endothelium and alveolar epithelium, disrupting the barriers between the capillaries and air spaces. Edema fluid, proteins, and cellular debris flood the air spaces and interstitium, causing disruption of surfactant, airspace collapse, ventilation-perfusion mismatch, shunting, and stiffening of the lungs with decreased compliance and pulmonary hypertension. There is no pattern to the injury; however, dependant lung areas are most frequently affected [74, 79].

Tissue examination reveals that surfactant disruption, epithelial injury, and sepsis initiate the increased expression of cytokines that sequester and activate inflammatory cells. Increased release of ROS alters normal endothelial function. Microarray analysis has revealed increased expression of genes related to oxidative stress, antiproteolytic function, and extracellular matrix repair as well as decreased surfactant proteins in ozone-induced ALI [80]. Diffuse alveolar damage results with intra-alveolar neutrophils indicating the presence of an inflammatory response in the alveoli. Red blood cells, cellular fragments, and eroded epithelial basement membranes are present with formation of hyaline membranes, indicating that serum proteins have entered and precipitated in the air spaces due to disruption of the alveolar capillary barrier. Formation of microthrombi indicates the presence of endothelial injury and activation of the coagulation cascade [81].

Acute lung injury syndrome presents within 24 to 48 hours after the direct or indirect trigger. Initially, the patient may experience dyspnea, cough, chest pain, tachypnea, tachycardia, accessory muscle use, cyanosis, mottled skin, and abnormal breath sounds (crackles, rhonchi, and wheezing). Blood gas analysis reveals progressive worsening of hypoxemia, leading to respiratory failure. Bilateral infiltrates are seen on a chest X-ray and are consistent with pulmonary edema but without the cardiac component of elevated left atrial pressure. Treatment includes mechanical ventilation, supportive care, and treatment of the underlying causes [16]. The mortality of ALI has improved over the past decade; however, it still ranges from 30% to 75% [75, 77, 82, 83] and occurs in about 86 of 100,000 individuals per year [84].

6. Conclusion

Oxygen, often used to treat hypoxemia in the clinical setting, is itself a triggering factor in HALI given that the exposure is sufficiently concentrated and of adequate duration. The lung is a vulnerable target for oxidant-induced injury, initiating a cascade of protein signals that determine the cellular response. The alveolar epithelial and alveolar capillary endothelial surfaces are injured. Hyperpermeability, microthrombi (resulting from altered coagulation and fibrinolysis), collagen deposition, and fibrosis alter alveolar structure and function. Understanding precise mechanisms of injury and pulmonary cellular responses to hyperoxia is essential evidence for expert practice.


This project was sponsored by the TriService Nursing Research Program (TSNRP) (N08-012, HU0001-08-1-TS08). The information or content and conclusions do not necessarily represent the official position or policy of, nor should any official endorsement be inferred by, the TSNRP, the Department of Defense, or the US Government.


  1. V. Kim, J. O. Benditt, R. A. Wise, and A. Sharafkhaneh, “Oxygen therapy in chronic obstructive pulmonary disease,” Proceedings of the American Thoracic Society, vol. 5, no. 4, pp. 513–518, 2008. View at: Publisher Site | Google Scholar
  2. H. Brokalaki, V. Matziou, S. Zyga et al., “Omissions and errors during oxygen therapy of hospitalized patients in a large city of Greece,” Intensive and Critical Care Nursing, vol. 20, no. 6, pp. 352–357, 2004. View at: Publisher Site | Google Scholar
  3. S. Hickey, “An audit of oxygen therapy on a respiratory ward,” British Journal of Nursing, vol. 16, no. 18, pp. 1132–1136, 2007. View at: Google Scholar
  4. M. Boyle and J. Wong, “Prescribing oxygen therapy. An audit of oxygen prescribing practices on medical wards at north shore hospital, auckland, new zealand,” New Zealand Medical Journal, vol. 119, no. 1238, U2080, 2006. View at: Google Scholar
  5. S. Shetty, J. Padijnayayveetil, T. Tucker, D. Stankowska, and S. Idell, “The fibrinolytic system and the regulation of lung epithelial cell proteolysis, signaling, and cellular viability,” American Journal of Physiology, vol. 295, no. 6, pp. L967–L975, 2008. View at: Publisher Site | Google Scholar
  6. S. Idell, “Coagulation, fibrinolysis, and fibrin deposition in acute lung injury,” Critical Care Medicine, vol. 31, no. 4, supplement, pp. S213–S220, 2003. View at: Google Scholar
  7. L. N. Johnson and M. Koval, “Cross-talk between pulmonary injury, oxidant stress, and gap junctional communication,” Antioxidants and Redox Signaling, vol. 11, no. 2, pp. 355–367, 2009. View at: Publisher Site | Google Scholar
  8. J. Ciencewicki, S. Trivedi, and S. R. Kleeberger, “Oxidants and the pathogenesis of lung diseases,” Journal of Allergy and Clinical Immunology, vol. 122, no. 3, pp. 456–470, 2008. View at: Publisher Site | Google Scholar
  9. T. L. Clanton, “Hypoxia-induced reactive oxygen species formation in skeletal muscle,” Journal of Applied Physiology, vol. 102, no. 6, pp. 2379–2388, 2007. View at: Publisher Site | Google Scholar
  10. I. Rahman, S. K. Biswas, and A. Kode, “Oxidant and antioxidant balance in the airways and airway diseases,” European Journal of Pharmacology, vol. 533, no. 1–3, pp. 222–239, 2006. View at: Publisher Site | Google Scholar
  11. M. Yee, P. F. Vitiello, J. M. Roper et al., “Type II epithelial cells are critical target for hyperoxia-mediated impairment of postnatal lung development,” American Journal of Physiology, vol. 291, no. 5, pp. L1101–L1111, 2006. View at: Publisher Site | Google Scholar
  12. R. Mason, C. Broaddus, and J. Murray, Murray & Nadel's Textbook of Respiratory Medicine, vol. 2, 2nd edition, 2005.
  13. H. Zhou, G. M. Saidel, and M. E. Cabrera, “Multi-organ system model of O2 and CO2 transport during isocapnic and poikilocapnic hypoxia,” Respiratory Physiology and Neurobiology, vol. 156, no. 3, pp. 320–330, 2007. View at: Publisher Site | Google Scholar
  14. R. K. Dash and J. B. Bassingthwaighte, “Simultaneous blood-tissue exchange of oxygen, carbon dioxide, bicarbonate, and hydrogen ion,” Annals of Biomedical Engineering, vol. 34, no. 7, pp. 1129–1148, 2006. View at: Publisher Site | Google Scholar
  15. N. L. Jones, “An obsession with CO2,” Applied Physiology, Nutrition and Metabolism, vol. 33, no. 4, pp. 641–650, 2008. View at: Publisher Site | Google Scholar
  16. A. C. Guyton and J. E. Hall, Textbook of Medical Physiology, Elsevier Saunders, Philadelphia, Pa, USA, 11th edition, 2006.
  17. J. Joiner, NOAA Diving Manual: Diving for Science and Technology, Best Publishing Company, Flagstaff, Ariz, USA, 4th edition, 2001.
  18. B. Halliwell, “Reactive species and antioxidants. Redox biology is a fundamental theme of aerobic life,” Plant Physiology, vol. 141, no. 2, pp. 312–322, 2006. View at: Publisher Site | Google Scholar
  19. J. Hedley-Whyte, “Pulmonary oxygen toxicity: investigation and mentoring,” Ulster Medical Journal, vol. 77, no. 1, pp. 39–42, 2008. View at: Google Scholar
  20. B. W. Allen, I. T. Demchenko, and C. A. Piantadosi, “Two faces of nitric oxide: implications for cellular mechanisms of oxygen toxicity,” Journal of Applied Physiology, vol. 106, no. 2, pp. 662–667, 2009. View at: Publisher Site | Google Scholar
  21. K. W. Kang, S. J. Lee, and S. G. Kim, “Molecular mechanism of Nrf2 activation by oxidative stress,” Antioxidants and Redox Signaling, vol. 7, no. 11-12, pp. 1664–1673, 2005. View at: Publisher Site | Google Scholar
  22. A. Pagano and C. Barazzone-Argiroffo, “Alveolar cell death in hyperoxia-induced lung injury,” Annals of the New York Academy of Sciences, vol. 1010, pp. 405–416, 2003. View at: Publisher Site | Google Scholar
  23. L. L. Mantell, S. Horowitz, J. M. Davis, and J. A. Kazzaz, “Hyperoxia-induced cell death in the lung—the correlation of apoptosis, necrosis, and inflammation,” Annals of the New York Academy of Sciences, vol. 887, pp. 171–180, 1999. View at: Google Scholar
  24. J. D. Crapo, “Morphologic changes in pulmonary oxygen toxicity,” Annual Review of Physiology, vol. 48, pp. 721–731, 1986. View at: Google Scholar
  25. J. D. Crapo, B. E. Barry, L. Y. Chang, and R. R. Mercer, “Alterations in lung structure caused by inhalation of oxidants,” Journal of Toxicology and Environmental Health, vol. 13, no. 2-3, pp. 301–321, 1984. View at: Google Scholar
  26. J. D. Crapo and D. F. Tierney, “Superoxide dismutase and pulmonary oxygen toxicity,” American Journal of Physiology, vol. 226, no. 6, pp. 1401–1407, 1974. View at: Google Scholar
  27. S. M. Mensack and R. Murtaugh, “Oxygen toxicity,” Compendium on Continuing Education for the Practicing Veterinarian, vol. 21, no. 4, pp. 341–351, 1999. View at: Google Scholar
  28. J. Romashko III, S. Horowitz, W. R. Franek et al., “MAPK pathways mediate hyperoxia-induced oncotic cell death in lung epithelial cells,” Free Radical Biology and Medicine, vol. 35, no. 8, pp. 978–993, 2003. View at: Publisher Site | Google Scholar
  29. S. Kannan, H. Pang, D. C. Foster, Z. Rao, and M. Wu, “Human 8-oxoguanine DNA glycosylase increases resistance to hyperoxic cytotoxicity in lung epithelial cells and involvement with altered MAPK activity,” Cell Death and Differentiation, vol. 13, no. 2, pp. 311–323, 2006. View at: Publisher Site | Google Scholar
  30. L. F. Li, S. K. Liao, Y. S. Ko, C. H. Lee, and D. A. Quinn, “Hyperoxia increases ventilator-induced lung injury via mitogen-activated protein kinases: a prospective, controlled animal experiment,” Critical Care, vol. 11, no. 1, Article ID R25, 2007. View at: Publisher Site | Google Scholar
  31. S. Papaiahgari, S. R. Kleeberger, H. Y. Cho, D. V. Kalvakolanu, and S. P. Reddy, “NADPH oxidase and ERK signaling regulates hyperoxia-induced Nrf2-ARE transcriptional response in pulmonary epithelial cells,” Journal of Biological Chemistry, vol. 279, no. 40, pp. 42302–42312, 2004. View at: Publisher Site | Google Scholar
  32. S. T. Qureshi, X. Zhang, E. Aberg et al., “Inducible activation of TLR4 confers resistance to hyperoxia-induced pulmonary apoptosis,” Journal of Immunology, vol. 176, no. 8, pp. 4950–4958, 2006. View at: Google Scholar
  33. L. L. Mantell and P. J. Lee, “Signal transduction pathways in hyperoxia-induced lung cell death,” Molecular Genetics and Metabolism, vol. 71, no. 1-2, pp. 359–370, 2000. View at: Publisher Site | Google Scholar
  34. T. E. Zaher, E. J. Miller, D. M. Morrow, M. Javdan, and L. L. Mantell, “Hyperoxia-induced signal transduction pathways in pulmonary epithelial cells,” Free Radical Biology and Medicine, vol. 42, no. 7, pp. 897–908, 2007. View at: Publisher Site | Google Scholar
  35. A. B. Waxman and N. Kolliputi, “IL-6 protects against hyperoxia-induced mitochondrial damage via BCL-2 induced BAK interactions with mitofusions,” American Journal of Respiratory Cell and Molecular Biology, vol. 41, no. 4, pp. 385–396, 2009. View at: Publisher Site | Google Scholar
  36. D. Barlos, E. A. Deitch, A. C. Watkins et al., “Trauma-hemorrhagic shock-induced pulmonary epithelial and endothelial cell injury utilizes different programmed cell death signaling pathways,” American Journal of Physiology, vol. 296, no. 3, pp. L404–L417, 2009. View at: Publisher Site | Google Scholar
  37. G. R. Budinger and J. I. Sznajder, “To live or die: a critical decision for the lung,” Journal of Clinical Investigation, vol. 115, no. 4, pp. 828–830, 2005. View at: Publisher Site | Google Scholar
  38. A. C. Kulkarni, P. Kuppusamy, and N. Parinandi, “Oxygen, the lead actor in the pathophysiologic drama: enactment of the trinity of normoxia, hypoxia, and hyperoxia in disease and therapy,” Antioxidants and Redox Signaling, vol. 9, no. 10, pp. 1717–1730, 2007. View at: Publisher Site | Google Scholar
  39. L. Min and X. Jian-xing, “Detoxifying function of cytochrome c against oxygen toxicity,” Mitochondrion, vol. 7, no. 1-2, pp. 13–16, 2007. View at: Publisher Site | Google Scholar
  40. M. Czarna and W. Jarmuszkiewicz, “Role of mitochondria in reactive oxygen species generation and removal; relevance to signaling and programmed cell death,” Postepy Biochemii, vol. 52, no. 2, pp. 145–156, 2006. View at: Google Scholar
  41. P. Jezek and L. Hlavata, “Mitochondria in homeostasis of reactive oxygen species in cell, tissues, and organism,” International Journal of Biochemistry and Cell Biology, vol. 37, no. 12, pp. 2478–2503, 2005. View at: Publisher Site | Google Scholar
  42. M. Valko, D. Leibfritz, J. Moncol, M. T. Cronin, M. Mazur, and J. Telser, “Free radicals and antioxidants in normal physiological functions and human disease,” International Journal of Biochemistry and Cell Biology, vol. 39, no. 1, pp. 44–84, 2007. View at: Publisher Site | Google Scholar
  43. V. Tandon, B. M. Gupta, and R. Tandon, “Free radicals/reactive oxygen species,” JK Practitioner, vol. 12, no. 3, pp. 143–148, 2005. View at: Google Scholar
  44. K. Apel and H. Hirt, “Reactive oxygen species: metabolism, oxidative stress, and signal transduction,” Annual Review of Plant Biology, vol. 55, pp. 373–399, 2004. View at: Publisher Site | Google Scholar
  45. V. Sakac and M. Sakac, “Free oxygen radiacals and kidney diseases—part I,” Medicinski Pregled, vol. 53, no. 9-10, pp. 463–474, 2000. View at: Google Scholar
  46. E. Cadenas, “Biochemistry of oxygen toxicity,” Annual Review of Biochemistry, vol. 58, pp. 79–110, 1989. View at: Google Scholar
  47. E. Cadenas and K. J. Davies, “Mitochondrial free radical generation, oxidative stress, and aging,” Free Radical Biology and Medicine, vol. 29, no. 3-4, pp. 222–230, 2000. View at: Publisher Site | Google Scholar
  48. S. A. Comhair, P. R. Bhathena, C. Farver, F. B. Thunnissen, and S. C. Erzurum, “Extracellular glutathione peroxidase induction in asthmatic lungs: evidence for redox regulation of expression in human airway epithelial cells,” FASEB Journal, vol. 15, no. 1, pp. 70–78, 2001. View at: Publisher Site | Google Scholar
  49. K. J. Davies, “Oxidative stress: the paradox of aerobic life,” Biochemical Society Symposium, vol. 61, pp. 1–31, 1995. View at: Google Scholar
  50. R. Kohen and A. Nyska, “Oxidation of biological systems: oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantification,” Toxicologic Pathology, vol. 30, no. 6, pp. 620–650, 2002. View at: Publisher Site | Google Scholar
  51. L. A. Pham-Huy, H. He, and C. Pham-Huy, “Free radicals, antioxidants in disease and health,” International Journal of Biomedical Science, vol. 4, no. 2, pp. 89–96, 2008. View at: Google Scholar
  52. M. Nishikawa and M. Inoue, “Oxidative stress and tissue injury,” Japanese Journal of Anesthesiology, vol. 57, no. 3, pp. 321–326, 2008. View at: Google Scholar
  53. R. Chang, Chemistry, McGraw Hill, Boston, Mass, USA, 9th edition, 2007.
  54. W. Droge, “Free radicals in the physiological control of cell function,” Physiological Reviews, vol. 82, no. 1, pp. 47–95, 2002. View at: Google Scholar
  55. D. Hernandez-Saavedra and J. M. McCord, “Evolution and free radicals. Importance of oxidative stress in human pathology,” Revista Medica del Instituto Mexicano del Seguro Social, vol. 45, no. 5, pp. 477–484, 2007. View at: Google Scholar
  56. B. Halliwell, R. Aeschbach, J. Loliger, and O. I. Aruoma, “The characterization of antioxidants,” Food and Chemical Toxicology, vol. 33, no. 7, pp. 601–617, 1995. View at: Publisher Site | Google Scholar
  57. B. Halliwell, “How to characterize a biological antioxidant,” Free Radical Research Communications, vol. 9, no. 1, pp. 1–32, 1990. View at: Google Scholar
  58. L. J. Buccellato, M. Tso, O. I. Akinci, N. S. Chandel, and G. R. Budinger, “Reactive oxygen species are required for hyperoxia-induced Bax activation and cell death in alveolar epithelial cells,” Journal of Biological Chemistry, vol. 279, no. 8, pp. 6753–6760, 2004. View at: Publisher Site | Google Scholar
  59. E. M. Bulger and R. V. Maier, “Antioxidants in critical illness,” Archives of Surgery, vol. 136, no. 10, pp. 1201–1207, 2001. View at: Google Scholar
  60. S. Yamaoka, H. S. Kim, T. Ogihara et al., “Severe vitamin E deficiency exacerbates acute hyperoxic lung injury associated with increased oxidative stress and inflammation,” Free Radical Research, vol. 42, no. 6, pp. 602–612, 2008. View at: Publisher Site | Google Scholar
  61. N. Noguchi, A. Watanabe, and H. Shi, “Diverse functions of antioxidants,” Free Radical Research, vol. 33, no. 6, pp. 809–817, 2000. View at: Google Scholar
  62. M. F. Tsan, “Superoxide dismutase and pulmonary oxygen toxicity: lessons from transgenic and knockout mice (Review),” International Journal of Molecular Medicine, vol. 7, no. 1, pp. 13–19, 2001. View at: Google Scholar
  63. J. M. van Raamsdonk and S. Hekimi, “Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in caenorhabditis elegans,” PLoS Genetics, vol. 5, no. 2, Article ID e1000361, 2009. View at: Publisher Site | Google Scholar
  64. R. L. Auten, M. A. O'Reilly, T. D. Oury, E. Nozik-Grayck, and M. H. Whorton, “Transgenic extracellular superoxide dismutase protects postnatal alveolar epithelial proliferation and development during hyperoxia,” American Journal of Physiology, vol. 290, no. 1, pp. L32–L40, 2006. View at: Publisher Site | Google Scholar
  65. R. P. Bowler, J. Arcaroli, J. D. Crapo, A. Ross, J. W. Slot, and E. Abraham, “Extracellular superoxide dismutase attenuates lung injury after hemorrhage,” American Journal of Respiratory and Critical Care Medicine, vol. 164, no. 2, pp. 290–294, 2001. View at: Google Scholar
  66. F. Gao, V. L. Kinnula, M. Myllarniemi, and T. D. Oury, “Extracellular superoxide dismutase in pulmonary fibrosis,” Antioxidants and Redox Signaling, vol. 10, no. 2, pp. 343–354, 2008. View at: Publisher Site | Google Scholar
  67. E. Nozik-Grayck, H. B. Suliman, and C. A. Piantadosi, “Extracellular superoxide dismutase,” International Journal of Biochemistry and Cell Biology, vol. 37, no. 12, pp. 2466–2471, 2005. View at: Publisher Site | Google Scholar
  68. R. J. Folz, A. M. Abushamaa, and H. B. Suliman, “Extracellular superoxide dismutase in the airways of transgenic mice reduces inflammation and attenuates lung toxicity following hyperoxia,” Journal of Clinical Investigation, vol. 103, no. 7, pp. 1055–1066, 1999. View at: Google Scholar
  69. D. J. O'Donovan and C. J. Fernandes, “Mitochondrial glutathione and oxidative stress: implications for pulmonary oxygen toxicity in premature infants,” Molecular Genetics and Metabolism, vol. 71, no. 1-2, pp. 352–358, 2000. View at: Publisher Site | Google Scholar
  70. A. R. Smith, F. Visioli, and T. M. Hagen, “Vitamin C matters: increased oxidative stress in cultured human aortic endothelial cells without supplemental ascorbic acid,” FASEB Journal, vol. 16, no. 9, pp. 1102–1104, 2002. View at: Google Scholar
  71. H. Shi and K. J. Liu, “Effects of glucose concentration on redox status in rat primary cortical neurons under hypoxia,” Neuroscience Letters, vol. 410, no. 1, pp. 57–61, 2006. View at: Publisher Site | Google Scholar
  72. M. K. Misra, M. Sarwat, P. Bhakuni, R. Tuteja, and N. Tuteja, “Oxidative stress and ischemic myocardial syndromes,” Medical Science Monitor, vol. 15, no. 10, pp. RA209–RA219, 2009. View at: Google Scholar
  73. J. Tkaczyk and M. VIzek, “Oxidative stress in the lung tissue—sources of reactive oxygen species and antioxidant defence,” Prague Medical Report, vol. 108, no. 2, pp. 105–114, 2007. View at: Google Scholar
  74. L. B. Ware, “Pathophysiology of acute lung injury and the acute respiratory distress syndrome,” Seminars in Respiratory and Critical Care Medicine, vol. 27, no. 4, pp. 337–349, 2006. View at: Publisher Site | Google Scholar
  75. F. Frutos-Vivar, N. D. Ferguson, and A. Esteban, “Epidemiology of acute lung injury and acute respiratory distress syndrome,” Seminars in Respiratory and Critical Care Medicine, vol. 27, no. 4, pp. 327–336, 2006. View at: Publisher Site | Google Scholar
  76. K. Nagata, Y. Iwasaki, T. Yamada et al., “Overexpression of manganese superoxide dismutase by N-acetylcysteine in hyperoxic lung injury,” Respiratory Medicine, vol. 101, no. 4, pp. 800–807, 2007. View at: Publisher Site | Google Scholar
  77. E. Manteiga Riestra, O. Martinez Gonzalez, and F. Frutos Vivar, “Epidemiology of acute pulmonary injury and acute respiratory distress syndrome,” Medicina Intensiva, vol. 30, no. 4, pp. 151–161, 2006. View at: Publisher Site | Google Scholar
  78. T. G. Brock and C. Di Giulio, “Prolonged exposure to hyperoxia increases perivascular mast cells in rat lungs,” Journal of Histochemistry and Cytochemistry, vol. 54, no. 11, pp. 1239–1246, 2006. View at: Publisher Site | Google Scholar
  79. L. Wang, J. A. Bastarache, N. Wickersham, X. Fang, M. A. Matthay, and L. B. Ware, “Novel role of the human alveolar epithelium in regulating intra-alveolar coagulation,” American Journal of Respiratory Cell and Molecular Biology, vol. 36, no. 4, pp. 497–503, 2007. View at: Publisher Site | Google Scholar
  80. G. D. Leikauf, S. A. McDowell, C. J. Bachurski et al., “Functional genomics of oxidant-induced lung injury,” Advances in Experimental Medicine and Biology, vol. 500, pp. 479–487, 2001. View at: Google Scholar
  81. G. Matute-Bello, C. W. Frevert, and T. R. Martin, “Animal models of acute lung injury,” American Journal of Physiology, vol. 295, no. 3, pp. L379–L399, 2008. View at: Publisher Site | Google Scholar
  82. M. A. Matthay, G. A. Zimmerman, C. Esmon et al., “Future research directions in acute lung injury: summary of a national heart, lung, and blood institute working group,” American Journal of Respiratory and Critical Care Medicine, vol. 167, no. 7, pp. 1027–1035, 2003. View at: Publisher Site | Google Scholar
  83. C. Flores, S. F. Ma, K. Maresso, O. Ahmed, and J. G. N. Garcia, “Genomics of acute lung injury,” Seminars in Respiratory and Critical Care Medicine, vol. 27, no. 4, pp. 389–395, 2006. View at: Publisher Site | Google Scholar
  84. G. D. Rubenfeld, E. Caldwell, E. Peabody et al., “Incidence and outcomes of acute lung injury,” New England Journal of Medicine, vol. 353, no. 16, pp. 1685–1693, 2005. View at: Publisher Site | Google Scholar

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