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Purpose of Review: Low-dose oxygen (LDO) supplementation is used by millions of COPD patients worldwide. The therapeutic benefits of LDO supplementation are well known. There are also several concerns regarding the potential for cellular harm from LDO in COPD patients. This review summarizes the current arguments and evidence pertaining to this important topic., Recent Findings: LDO therapy has been used in COPD patients for more than 50 years. Over the years, data from randomized controlled trials has confirmed that LDO provides survival benefit in COPD patients with severe hypoxemia. Recent data, however, show that LDO does not provide any morality benefit for patients with a less severe degree of hypoxemia. There are several theoretical concerns regarding use of LDO in COPD patients, including radiation-like cellular risks because of oxygen toxicity. However, none of these have been validated in human clinical trials and remain somewhat peripheral to the clinician deciding whether or not to initiate LDO in a hypoxemic COPD patient., Summary: There is high-quality evidence that LDO is both well tolerated and highly efficacious for patients with COPD. There are several theoretical concerns regarding damage from oxygen free radicals from LDO in COPD patients. However, none of these have been validated or confirmed in human clinical trial data. Thus, the benefits of LDO clearly outweigh the risks from any theoretical concerns about oxygen toxicity.

Accumulation of molecular damage and increased molecular heterogeneity are hallmarks of photoaged skin and pathogenesis of human cutaneous disease. Growing evidence demonstrates the ability of molecular chaperone proteins and of pharmacologic chaperones to decrease the environmental stress and ameliorate the oxidation stress-related and glycation disease phenotypes, suggesting that the field of chaperone therapy might hold novel treatments for skin diseases and aging. In this review, we examine the evidence suggesting a role for molecular chaperone proteins in the skin and their inducer and protecting agents: pharmacologic chaperone imidazole dipeptide-based agents (carcinine and related compounds) in cosmetics and dermatology. Furthermore, we discuss the use of chaperone therapy for the treatment of skin photoaging diseases and other skin pathologies that have a component of increased glycation and/or free radical-induced oxidation in their genesis. We examine biologic activities of molecular and pharmacologic chaperones, including strategies for identifying potential chaperone compounds and for experimentally demonstrating chaperone activity in in vitro and in vivo models of human skin disease. This allows the protein to function and traffic to the appropriate location in the skin, thereby increasing protein activity and cellular function and reducing stress on skin cells. The benefits of imidazole dipeptide antioxidants with transglycating activity (such as carcinine) in skin care are that they help protect and repair cell membrane damage and help retain youthful, younger-looking skin. All skin types will benefit from daily, topical application of pharmacologic chaperone antioxidants, anti-irritants, in combination with water-binding protein agents that work to mimic the structure and function of healthy skin. General strategies are presented addressing ground techniques to improve absorption of usually active chaperone proteins and dipeptide compounds, include encapsulation into hydrophobic carriers, a combination with penetration enhancers, active electrical transport, or chemical modification to increase hydrophobicity.

Globally, tobacco use is associated with 5 million deaths per annum and is regarded as one of the leading causes of premature death. Major chronic disorders associated with smoking include cardiovascular diseases, several types of cancer, and chronic obstructive pulmonary disease (lung problems). Cigarette smoking (CS) generates a cumulative oxidative stress, which may contribute to the pathogenesis of chronic diseases. Mainstream and side stream gas-phase smoke each have about the same concentration of reactive free radical species, about 1 × 10(16) radicals per cigarette (or 5 × 10(14) per puff). This effect is critical in understanding the biologic effects of smoke. Several lines of evidence suggest that cigarette smoke constituents can directly activate vascular reactive oxygen species production. In this work we present multiple evidence that CS provide the important risk factors in many age-related diseases, and is associated with increased cumulative and systemic oxidative stress and inflammation. The cited processes are marked by increased white blood cell (leucocytes, WBCs) turnover. The data suggest an alteration of the circulating WBCs by CS, resulting in increased adherence to endothelial cells. Telomeres are complex DNA-protein structures located at the end of eukaryotic chromosomes. Telomere length shortens with biologic age in all replicating somatic cells. It has been shown that tobacco smoking enhances telomere shortening in circulating human WBCs. Telomere attrition (expressed in WBCs) can serve as a biomarker of the cumulative oxidative stress and inflammation induced by smoking and, consequently, show the pace of biologic aging. We originally propose that patented specific oral formulations of nonhydrolized carnosine and carcinine provide a powerful tool for targeted therapeutic inhibition of cumulative oxidative stress and inflammation and protection of telomere attrition associated with smoking. The longitudinal studies of the clinical population groups described in this study including elderly support the hypothesis that telomere length is a predictor of survival and therapeutic treatment requirement associated with smoking behavior.

Purpose of Review: Photosensitivity disorders are cutaneous reactions caused or amplified in their severity by sunlight, normally ultraviolet radiation (UVA or UVB). These reactions appear when xenobiotics are topically or systemically administered, and the individuals are exposed to solar or artificial light., Recent Findings: Photoallergic reactions seem to be initiated by covalent binding of the photosensitizer to a skin protein, forming adducts capable of interacting with the immune system. The most frequent reactions of this type (photoallergic dermatitis) are induced by drugs and mediated by T cells. Diagnosis of photoallergy requires identification of the responsible agent, which is not always clear-cut. Photopatch testing is the method of choice for definitive diagnosis., Summary: In the current review, some specific examples of photoallergic xenobiotics are given. They include nonsteroidal anti-inflammatory drugs, antibiotics, platelet aggregation inhibitors, and sunscreens. In general, they are taken from the scientific literature published during the last decade, with particular emphasis on the most recent articles. The focus is on the mechanistic aspects, specifically on the generation of reactive intermediates capable of reacting with proteins.

Background: Mild to moderate hypothermia (32-35 degrees C) is the first treatment with proven efficacy for postischemic neurological injury. In recent years important insights have been gained into the mechanisms underlying hypothermia's protective effects; in addition, physiological and pathophysiological changes associated with cooling have become better understood., Objective: To discuss hypothermia's mechanisms of action, to review (patho)physiological changes associated with cooling, and to discuss potential side effects., Design: Review article., Interventions: None., Main Results: A myriad of destructive processes unfold in injured tissue following ischemia-reperfusion. These include excitotoxicty, neuroinflammation, apoptosis, free radical production, seizure activity, blood-brain barrier disruption, blood vessel leakage, cerebral thermopooling, and numerous others. The severity of this destructive cascade determines whether injured cells will survive or die. Hypothermia can inhibit or mitigate all of these mechanisms, while stimulating protective systems such as early gene activation. Hypothermia is also effective in mitigating intracranial hypertension and reducing brain edema. Side effects include immunosuppression with increased infection risk, cold diuresis and hypovolemia, electrolyte disorders, insulin resistance, impaired drug clearance, and mild coagulopathy. Targeted interventions are required to effectively manage these side effects. Hypothermia does not decrease myocardial contractility or induce hypotension if hypovolemia is corrected, and preliminary evidence suggests that it can be safely used in patients with cardiac shock. Cardiac output will decrease due to hypothermia-induced bradycardia, but given that metabolic rate also decreases the balance between supply and demand, is usually maintained or improved. In contrast to deep hypothermia (

Background: Ischemic preconditioning (IP) renders tissues more tolerant to subsequent longer episodes of ischemia. This study tested whether IP attenuates injury of small-for-size liver grafts by preventing free radical production and mitochondrial dysfunction., Methods: IP was induced by clamping the portal vein and hepatic artery for 9 min. Livers were harvested 5 min after releasing the clamp. Mitochondrial polarization and cell death were assessed by intravital confocal/multiphoton microscopy of rhodamine 123 (Rh123) and propidium iodide. Free radicals were trapped with alpha-(4-pyridyl 1-oxide)-N-tert-butylnitrone and measured using electron spin resonance., Results: After quarter-size liver transplantation, alanine aminotransferase, serum bilirubin, necrosis, and apoptosis all increased. IP blocked these increases by more than 58%. 5-Bromo-2'-deoxyuridine labeling and increases of graft weight were only approximately 3% and 0.2% in quarter-size grafts without IP, respectively, but increased to 32% and 60% in ischemic-preconditioned grafts, indicating better liver regeneration. Eighteen hours after implantation, viable cells with depolarized mitochondria in quarter-size grafts were 15 per high power field, and dead cells were less than 1 per high power field, indicating that depolarization preceded necrosis. A free radical adduct signal was detected in bile from quarter-size grafts. IP decreased this free radical formation and prevented mitochondrial depolarization. IP did not increase heat shock proteins 10, 27, 32, 60, 70, 72, 75 and Cu/Zn-superoxide dismutase (SOD) but increased heat shock protein-90, a chaperone that facilitates protein import into mitochondria, and mitochondrial Mn-SOD., Conclusion: Taken together, IP decreases injury and improves regeneration of small-for-size liver grafts, possibly by increasing mitochondrial Mn-SOD, thus protecting against free radical production and mitochondrial dysfunction.

Purpose of Review: This review summarizes the role of free radicals and oxidative stress in the pathophysiology of human reproduction., Recent Findings: An extensive review of the literature on the role of oxidative stress in influencing assisted reproduction and its outcome is described in this article. Free radicals or reactive oxygen species mediate their action through many of the proinflammatory cytokines and this mechanism has been proposed as a common underlying factor for endometriosis, ovarian cancer, polycystic ovary disease, and various other pathologies affecting the female reproductive process, as highlighted in this review. Oxidative stress, sperm DNA damage, and apoptosis have been implicated in male infertility. Elevated reactive oxygen species levels correlate with the poor fertility outcomes seen in the assisted reproductive technology setting., Summary: Oxidative stress has been implicated in male and female infertility, including fetal dysmorphogenesis, abortions, and intrauterine growth restriction. Accurate evaluation of seminal oxidative stress by standardized assays may help in the diagnosis and management of male infertility. There is evidence in the literature on the beneficial effects of oral antioxidant supplementation in male infertility. Current ongoing trials will provide answers on the safety and effectiveness of antioxidants in improving maternal and fetal outcomes. Further studies need to be conducted to determine if antioxidant supplementation will prevent fetal developmental defects in high-risk pregnancy with diabetes.

Purpose of Review: Hypersensitivity pneumonitis is a group of immunologically mediated diseases caused by an abnormal response to a wide variety of inhaled antigens. Its pathogenesis is complex and involves many immunological concepts. This review discusses recent advances in our understanding of the pathogenesis of hypersensitivity pneumonitis., Recent Findings: Over the last 3 years, several studies on the pathogenesis of hypersensitivity pneumonitis have been published. New antigens have been identified. We now have a better understanding of the role of inflammatory cells and mediators, and promoting and protective factors have been suggested., Summary: Most of the mechanisms involved in the pathogenesis of hypersensitivity pneumonitis remain incompletely understood. Current and future findings will not only help our understanding of the disease and its prevention, but also improve its treatment.

Experimental studies and few human reports demonstrate that hyperoxia increases the level of reactive oxygen-derived free radicals and that these substances can produce oxidative cellular injury. However, available data suggest that the human lung is more resistant to hyperoxic oxidative damage than previously expected and demonstrate that absorption atelectasis is the most frequently pulmonary effect of inhalation of a high inspired oxygen fraction. Practically, the therapeutic use of high inspired oxygen fractions is limited to patients with acute lung injury and severe hypoxemia. Recent studies demonstrated that ventilator-induced lung injury is a more important cause of pulmonary damage in these patients than hyperoxic toxicity. New protective ventilatory strategies are associated with increased survival.

In human ageing and with many pathologies correlated to the senile functional decay of cells, membrane damage often occurs in some organ or tissue, which provokes lipid peroxidation in the membrane and accelerates the disorder in structure and function of the membrane. When lipid peroxides accumulate sufficiently, they leak from the organ or tissue into the bloodstream and increase the lipid peroxide level in blood lipoproteins. The increased lipid peroxides in the blood attack the blood vessel and promote atherogenesis. This paper describes the possible involvement of free radicals in this damage, both to tissues and to blood vessels, which contributes to the senile functional decay of the tissues.

Epidemiological evidence increasingly points to exogenous or endogenous oestrogens as a risk factor for breast cancer. However, it is unlikely that induction of oestrogen-dependent tumour growth is the sole contribution of oestrogens to tumour development in the mammary gland, because oestrogen receptors are barely detectable in normal mammary epithelial cells. In this review, I examine a mechanism for mammary carcinogenesis, which emphasizes tumour initiation by metabolic activation of oestrogens in combination with cell transformation and growth stimulation by oestrogen receptor-mediated processes. Catecholestrogen metabolites are capable of metabolic redox cycling between quinone and hydroquinone forms, a mechanism of free radical generation. Several types of direct and indirect free radical-mediated DNA damage are induced by oestrogens in vitro and in vivo, such as DNA single strand breaks, 8-hydroxylation of guanine bases, and DNA adduct formation by malondialdehyde, a decomposition product of free radical-induced lipid peroxides. The substrate for redox cycling and free radical generation may be 4-hydroxoestradiol, because this metabolite is formed from oestradiol by a specific oestrogen 4-hydroxylase detected in several human organs including mammary tissue. It has also been formed in organs of rodents where oestrogens induce tumours, with the exception of the liver. 4-Hydroxyoestradiol is a potent, long-acting oestrogen and may complete the carcinogenic process by stimulating receptor-mediated proliferation. An understanding of a possible mechanism of mammary carcinogenesis as a result of oestrogen-mediated initiation means that several prevention strategies, based on inhibiting metabolic activation of oestrogens or free radical action, can be developed.

Background and Purpose: Oxygen free radicals or oxidants have been proposed to be involved in acute central nervous system injury that is produced by cerebral ischemia and reperfusion. Because of the transient nature of oxygen radicals and the technical difficulties inherent in accurately measuring their levels in the brain, experimental strategies have been focused on the use of pharmacological agents and antioxidants to seek a correlation between the exogenously supplied specific radical scavengers (ie, superoxide dismutase and catalase) and the subsequent protection of cerebral tissues from ischemic injury. However, this strategy entails problems (hemodynamic, pharmacokinetic, toxicity, blood-brain barrier permeability, etc) that may cloud the data interpretation. This mini-review will focus on the oxidant mechanisms in cerebral ischemic brain injury by using transgenic and knockout mice as an alternative approach., Methods: Transgenic and knockout mutants that either overexpress or are deficient in antioxidant enzyme/protein levels have been successfully produced. The availability of these genetically modified animals has made it possible to investigate the role of certain oxidants in ischemic brain cell damage in molecular fashion., Results: It has been shown that an increased level of CuZn-superoxide dismutase and antiapoptotic protein Bcl-2 in the brains of transgenic mice protects neurons from ischemic/reperfusion injury, whereas a deficiency in CuZn-superoxide dismutase or mitochondrial Mn-superoxide dismutase exacerbates ischemic brain damage. Target disruption of neuronal nitric oxide synthase in mice also provides neuronal protection against permanent and transient focal cerebral ischemia., Conclusions: I conclude that molecular genetic approaches in modifying antioxidant levels in the brain offer a unique tool for understanding the role of oxidants in ischemic brain damage.

Resuscitative (postinsult) hypothermia is less well studied than protective-preservative (pre- and intra-arrest) hypothermia. The latter is in wide clinical use, particularly for protecting the brain during cardiac surgery. Resuscitative hypothermia was explored in the 1950s and then lay dormant until the 1980s when it was revived. This change occurred through the discoveries of brain damage mitigating effects after cardiac arrest in dogs, and after forebrain ischemia in rats, of mild (34 degrees C) hypothermia (which is safe), and of benefits derived from moderate hypothermia (30 degrees C) after traumatic brain injury or focal brain ischemia in various species. The idea that protection-preservation or resuscitation by hypothermia is mainly explained by its ability to reduce cerebral oxygen demand has been replaced by an increasingly documented synergism of many beneficial mechanisms. Deleterious chemical cascades during and after these insults are suppressed even by mild hypothermia. Prolonged moderate hypothermia carries some risks, e.g., arrhythmias, infection and coagulopathies. These side effects need further study. In global brain ischemia, protective-preservative mild hypothermia provides lasting mitigation of brain damage. Resuscitative mild hypothermia, however, may be beneficial in terms of long-term outcome or may merely delay the inevitable loss of selectively vulnerable neurons. Even if the latter is true, mild hypothermia may extend the therapeutic window for other interventions. This extension of the therapeutic window requires further documentation. After normothermic cardiac arrest of 11 mins in dogs, mild resuscitative hypothermia from 15 mins to 12 hours after reperfusion plus cerebral blood flow promotion normalized functional recovery with the least histologic damage seen thus far. Optimal duration of, and rewarming methods from, resuscitative hypothermia need clarification. The earliest possible induction of mild hypothermia after cardiac arrest seems desirable. Head-neck surface cooling alone is too slow. Among many clinically feasible rapid cooling methods, carotid cold flush and peritoneal cooling look promising. After traumatic brain injury or focal brain ischemia, which seem to still benefit from even later cooling, surface cooling methods may be adequate. Resuscitative hypothermia after cardiac arrest, traumatic brain injury, or focal brain ischemia should be considered for clinical trials.

Substantial evidence has accumulated implicating metals and free radicals in the pathogenesis of the major neurodegenerative disorders (Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis). Metal-induced oxidant stress can damage critical biological molecules and initiate a cascade of events including mitochondrial dysfunction, excitotoxicity, and a rise in cytosolic free calcium, leading to cell death. In Parkinson's disease and Alzheimer's disease there is evidence of oxidative stress in affected brain regions, as indicated by increased metal accumulation (which promotes free radical formation), decreased antioxidant levels (which protect against free radical formation), and oxidative damage. Recently, studies of the familial form of amyotrophic lateral sclerosis have detected mutations in the gene that encodes superoxide dismutase, which is one of the body's primary oxidant defense mechanisms. Mice that are transfected with the human mutant superoxide dismutase gene develop an amyotrophic lateral sclerosis syndrome. These studies demonstrate that oxidant stress can initiate the development of a chronic progressive neurodegenerative disorder.

Background: Free-radical generation after successful thrombolysis in acute myocardial infarction may jeopardize ischaemic but viable myocardium, thus limiting the optimal benefits of reperfusion., Methods: Circulating free-radical activity was assessed in 25 consecutive patients with acute myocardial infarction. Those who successfully reperfused (Group A) were compared with those who did not (Group B). We also compared patients who had or had not developed Q waves and patients with and without previous angina or myocardial infarction. All patients presented within 6 h of the onset of chest pain and received standard intravenous streptokinase therapy. Free-radical activity in serial serum samples collected over 72 h was measured using the percentage molar ratio (PMR) of the concentrations of 9,11-linoleic acid to 9,12-linoleic acid, and malonaldehyde concentration., Results: Throughout the study period Group A (n = 11) showed significantly greater change in serum PMR and malonaldehyde levels compared with Group B (n = 14) (P < 0.01). PMR differences between the two groups were most pronounced at 3 and 12 h (P < 0.001). Patients with non-Q-wave myocardial infarction (n = 5) showed significantly greater changes in serum PMR and malonaldehyde levels (P < 0.01) compared with those with Q-wave infarction (n = 20). A history of previous infarction or angina had no apparent effects on the changes in serum free-radical activity., Conclusions: Successful early reperfusion and non-Q-wave myocardial infarction are both associated with a significantly greater increase in the levels of markers of serum free-radical activity immediately after infarction. The results support present concepts of free-radical-mediated reperfusion injury. Use of these assays may identify those patients who may be at risk from free-radical-mediated reperfusion injury.

Oxygen-derived free radicals may contribute to tissue injury in myocardial ischemia although the mechanism is unclear. Catecholamines possibly could be involved in the genesis of free radicals because it has been demonstrated that oxygen free radicals may be generated by autooxidation of noradrenaline. Superoxide dismutase (SOD) protects the myocardium against injury by superoxide anion radicals. We, therefore, examined whether the cardioprotective effect of superoxide dismutase still could be demonstrated after depletion of catecholamine stores by reserpine (7 mg/kg intraperitoneally 24 h premortem). We used electrically paced isolated hearts perfused according to Langendorff (Tyrode's solution, Ca2+ 1.8 mmol/L, constant perfusion pressure: 70 cm H2O, 3 Hz). Myocardial ischemia was induced by occlusion of a left coronary artery branch. Epicardial NADH-fluorescence was used for quantitation of the myocardial ischemia. SOD (48 U/mL) did not influence global coronary flow or left ventricular pressure significantly (P > 0.05). In control hearts, SOD significantly diminished both size and intensity of epicardial NADH-fluorescence after repetitive coronary ligatures (-45%) (P < 0.05). In hearts with depleted catecholamine stores, this cardioprotection by SOD was no longer observed (P > 0.05). Stimulation of noradrenaline overflow by increasing the pacing rate of control hearts from 180/min up to 300/min after coronary occlusion also significantly enlarged myocardial ischemia (P < 0.05). This pacing rate-dependent growth of myocardial ischemia could be prevented completely by either prior depletion of catecholamine stores with reserpine or SOD. Therefore, noradrenaline seems to be the most important source for the generation of oxygen free radicals during myocardial ischemia in isolated saline-perfused rabbit hearts.

Background: Oxygen radicals have been implicated in the pathogenesis of reperfusion arrhythmias. However, the basic electrophysiological alterations accompanying the effects of oxygen radicals on action potential (AP) are poorly understood., Methods and Results: We investigated the effects of oxygen radicals generated by dihydroxyfumarate (DHF, 5 mM) on AP parameters and on ionic currents in patch-clamped guinea pig ventricular myocytes. DHF consistently caused a marked prolongation of AP duration, which was already significant after 60 seconds of exposure and continued to increase over time. Within 5 minutes, the majority of cells developed early afterdepolarizations (EADs) or became unexcitable. Both AP prolongation and occurrence of EADs were completely prevented in the presence of the oxygen radical scavengers superoxide dismutase (SOD) and catalase (CAT). Prolongation of AP duration was accompanied by a marked decreased in time-dependent potassium current (IK) and calcium current (ICa). The inward rectifier K current (IK1) was unaffected, suggesting no widespread changes in membrane properties. IK and ICa alterations were also significantly reduced by SOD and CAT. In additional experiments, intracellular calcium levels were kept constantly low by addition of 200 microM ethyleneglycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetra-acetic acid (EGTA) to the pipette solution. Under these conditions, the effects of DHF on AP duration and the occurrence of EADs were largely prevented. However, EGTA did not prevent cells from becoming unexcitable, nor did it affect the decrease in both IK and ICa upon exposure to DHF., Conclusions: Exposure to an exogenous source of oxygen radicals may induce major electrophysiological alterations in isolated myocytes, which might be related to changes in specific ionic currents and in level of intracellular calcium. These alterations occur with a time course consistent with the rapid onset of ventricular arrhythmias in reperfused hearts.

Magnetic resonance imaging (MRI) identified a paramagnetic substance in the hyaline cartilage of the hips and knees in a patient with ochronosis. Chemical studies characterized the paramagnetic agent as melanin. The free radicals contained in melanin were shown to initiate cytotoxicity. The loss of cartilage in ochronotic arthropathy now can be explained at the electron level using the superoxide theory of oxygen toxicity. Inappropriate metabolism of oxygen also may explain early cartilage degeneration in hemochromatosis, hemosiderosis, and Wilson's disease.