Lipid peroxidation or oxidative rancification represents one form of tissue damage associated with disease states and drug-induced toxicity that proceeds by free radical-initiated chain reactions. In the presence of endogenous hydroperoxides, peroxides, and antioxidants, hemoglobin and oxyhemoglobin will be oxidized to methemoglobin, and/or to oxoferryl hemoglobin. The reactions and accumulation of their products can lead to oxidative stress, causing antioxidant depletion and lipid peroxidation. The impulse as well as the damage to both soft tissues of human or animal bodies and solid structures from complex blast waves is usually greater than that caused by simple waves. The common feature in all these events is that they produce a region of instantaneous rise in atmospheric pressure that is termed blast overpressure. Concomitant with a decrease in antioxidant contents, lipid peroxidation measured as conjugated diene in lipid extract and as total thiobarbituric acid-reactive substances in whole lung tissue homogenate increased significantly with increased blast peak pressure.

Primary immunodeficiencies (PID) are a group of heterogeneous diseases with more then 200 type described. Databases worldwide show geographical variation. Data captured form interviews and a retrospective chart review for all PID patients managed at King Faisal Specialist Hospital & Research Center (KFSHRC) from May 2010 to April 2012(ongoing). A software was designed for data entry. Microsoft SQL Server was used to develop and administer the database. 357 cases encountered (54% male and 46% female).age range: <1 to 45 years. Consanguinity in 76 %. 205 patients of combined B & T-cell defect (T- B+ SCID 9, T-B-SCID 51, ADA 7, PNP 3, Reticular dysgenesis 3, Omenn Syndrome 12, CID 7, SCID NOS 37, Hyper IgM syndrome 18, MHC II deficiency 42, Hyper IgE Syndrome 16). Predominantly antibody defect in 55 patients (CVID 26, Agammaglobulinemia 10, and Hypogammaglobulinemia 19). 21 patients in other well defined PID (Wiskott Aldrich syndrome 12, DiGeorge Syndrome 3, Ataxia Telangeictasia 4, ICF 1, Dyskeratosis congenital 1). 23 with Immune Dysregulation (Chediak Higashi 7, Griscelli Syndrome 15, EBV related LPS 1). 37 patients had phagocytic defect (Chronic Granulomatous Disease 26, leukocyte adhesion deficiency 11). 16 patients with complement deficiencies (HAE 14, C5 deficiency 2). 178 patients underwent hematopoietic stem cell transplantation (HSCT) (143allogenic & 35cord). 10 patients died (5 SCID, 1 CID, 2 MHCII deficiency,1 Griscelli syndrome and 1 Dyskeratosis congenital). The high incidence and the pattern of PIDs with higher percentage of combined B & T-cell defects could be due to the genetic backgrounds and the higher consanguinity in the Saudi population.

Antioxidants, whether from diet or pharmacological supplementation, gained significant popularity among scientists and lay public in recent years, and was claimed to protect or treat numerous ailments. [...].

Blast overpressure (BOP), also known as high energy impulse noise, is a damaging outcome of explosive detonations and firing of weapons. Exposure to BOP shock waves alone results in injury predominantly to the hollow organ systems such as auditory, respiratory, and gastrointestinal systems. In recent years, the hazards of BOP that once were confined to military and professional settings have become a global societal problem as terrorist bombings and armed conflicts involving both military and civilian populations increased significantly. We have previously investigated the effects of single BOP exposures at different peak pressures. In this study, we examined the effects of repeated exposure to a low-level BOP and whether the number of exposures or time after exposure would alter the injury outcome. We exposed deeply anesthetized rats to simulated BOP at 62 +/- 2 kPa peak pressure. The lungs were examined immediately after one exposure (1 + 0), or 1 h after one (1 + 1), two (2 + 1), or three (3 + 1) consecutive exposures at 3-min interval. In one group of animals, we examined the effects of repeated exposure on lung weight, methemoglobin, transferrin, antioxidants, and lipid peroxidation. In a second group, the lungs were fixed inflated at 25 cm water, sectioned, and examined histologically after one to three repeated exposures, or after one exposure at 1, 6, and 24 h. We found that single BOP exposure causes notable changes after 1 h, and that repeating BOP exposure did not add markedly to the effect of the first one. However, the effects increased significantly with time from 1 to 24 h. These observations have biological and occupational implications, and emphasize the need for protection from low-level BOP, and for prompt treatment within the first hour following BOP exposure.

Sulfur mustard (HD) is a vesicant-type chemical warfare agent (CWA) introduced in World War I which continues to be produced, stockpiled, and occasionally deployed by some countries, and could be used potentially by terrorists. Exposure to HD can cause erythema, blisters, corneal opacity, and airway damage. We have reported previously that subcutaneous (SC) injection of immunodeficient athymic nude mice with the half mustard butyl 2-chloroethyl sulfide (BCS) causes systemic biochemical changes in several organs distal to the exposure site. In the present study, we examined the response of non-immunodeficient Swiss Webster mice to the mustard, 2-chloroethyl 4-chlorobutyl sulfide (CECBS). In a pilot study, we found that a single SC injection of 20–25μl/mouse causes death within 24h. Consequently, we used 5μl/mouse (approx. 0.017mg/kg body weight) of neat CECBS or an equal volume of saline as control. We examined the lungs after 1, 24, and 48h for biochemical changes including total and oxidized glutathione, protein, DNA, and lipid peroxidation contents in tissue homogenate, and superoxide dismutase, catalase, glucose-6-phosphate dehydrogenase, and glutathione S-transferases activities in the cytosol. After 1h and/or 24h, we found statistically significant changes that were resolved by 48h. These changes mimicked those of HD and BCS and were generally consistent with free radical-mediated oxidative stress. The implications of these observations are two-fold. First, dermal exposure to low-dose mustard gas could elicit systemic changes impacting distal organs such as the lungs. It also suggests that antioxidants could potentially modulate the response and reduce the damage. Second, although the use of known CWAs such as HD is prohibited, analogs that are not recognized as agents are as toxic and could be dangerous if acquired and used by potential terrorists.

High-energy impulse noise (BLAST) is a physical event characterized by an abrupt rise in atmospheric pressure above ambient lasting for a very short period, but potentially causing significant material and biological damage. Exposure to high-level BLAST can be destructive and lethal. Low-level BLAST similar to what is encountered repeatedly by military personnel during training and combat from detonation of munitions and firing of large caliber weapons, and during occupational use of explosives and some heavy machinery, can also cause significant injury. Globally, civilians are increasingly exposed to BLAST resulting from terrorist bombings or abandoned unmarked mines following numerous wars and conflicts. We have shown previously in several animal models that exposure to non-lethal BLAST results in pathological changes, mostly to the hollow organs characterized in the lungs, the most sensitive organ, by rupture of alveolar septa, and pulmonary hemorrhage and edema. These events potentially can cause alveolar flooding, respiratory insufficiency and adult respiratory distress syndrome (ARDS), leading to varying degrees of hypoxia, antioxidant depletion and oxidative damage. We have also observed progressive formation of nitric oxide in blood and other tissues. The totality of these observations supports our general hypothesis that exposure to BLAST can lead to antioxidant depletion and oxidative damage. Understanding the mechanism(s) of BLAST-induced oxidative stress may have important implications that include a potential beneficial role for antioxidants as a prophylaxis or as secondary treatment of injury after exposure alongside other protective and therapeutic modalities. In addition, it suggests a role for endogenous nitric oxide in the injury. This report reviews experimental evidence of BLAST-induced antioxidant depletion, and the potential benefit from antioxidant supplementation before exposure.

Brief, high-level nitrogen dioxide (NO(2)) exposures are major hazards during fires and heat-generating explosions. To characterize the lung response to a brief high-level NO(2) exposure, we exposed two groups (n = 5) of 325-375 g, male, Sprague-Dawley rats to either 200 +/- 5 ppm (376 +/- 9 mg/m(3)) NO(2) or room air for 15 min. The rats were nose-only exposed in a multiport exposure chamber fitted with pressure transducers to monitor their respiration during exposure. One hour after exposure, we euthanized the rats, collected blood samples, lavaged the lungs with warm saline, and then excised them. One lung lobe was cooled to -196 degrees C and used for low-temperature electron paramagentic resonance (EPR) analysis. The remainder was homogenized and used for biochemical analyses. Inspired minute ventilation (V(i)) during exposure decreased 59% (p < 0.05). Calculated total inspired dose was 0.880 mg NO(2). In lung lavage, both total and alveolar macrophage cell counts declined (approximately 75%, p < 0.05), but epithelial cell count increased 8.5-fold. Lung weight increased 40% (p < 0.05) after exposure. In the blood, potassium and methemoglobin increased 45 and 18% (p < 0.05), respectively; glucose, lactate, and total hemoglobin were not altered significantly. EPR analysis of lung tissue revealed hemoglobin oxidation and carbon-centered radical formation. Vitamins E and C and uric acid were depleted, and lipid peroxidation measured by three different methods (TBARS, conjugated dienes, and fluorescent peroxidation end products) was elevated, but total protein, DNA, and lipid contents were unchanged. These observations combined demonstrate that a brief (15 min) high-level (200 ppm) NO(2) exposure of rats was sufficient to cause significant damage. However, comparison of the exposure dose normalized to rat body weight with previously reported sheep and estimated human values revealed significant differences. This raises a question about interspecies dosimetry and species-specific responses when animal data are extrapolated to humans and used for safety standard setting, particularly with high-level brief exposures.

Ozone (O(3)) is a powerful oxidant component of photochemical smog polluting the air of urban cities. Exposure to low-level O(3) causes lung injury and increased morbidity of the sensitive segment of population, and exposure to high levels can be lethal to experimental animals. Injury from O(3) exposure is generally associated with free radical formation and oxidative stress. Because diet restriction is proposed to enhance antioxidant status, we examined whether it would influence the response to inhaled O(3). Twenty-four Sprague-Dawley rats, 1 month old, weighing 150 g, were divided into two dietary regimens (12 rats/regimen); one was freely-fed (FF), and the second was diet-restricted (DR) to 20% the average daily intake of the FF. After 60 days of dietary conditioning, the body weight of DR rats was reduced to 50% that of FF rats. Then, in one experiment, two groups (six rats/group), one FF and the other DR, were exposed to 0.8+/-0.1 p.p.m. (1570+/-196 microg/m(3)) O(3), continuously for 3 days. Another two similar groups of rats were exposed to filtered room air and served as matched controls. After exposure, all rats were euthanized and the lungs analyzed for biochemical markers of oxidative stress. In a second experiment, 24 rats were divided into two groups (12 rats/group), one FF and the other DR, then exposed to high-level O(3) for 8 h (4 p.p.m., 7848+/-981 microg/m(3)) and the mortality noted during exposure and for 16 h post-exposure. Following low-level O(3), inhalation, greater alterations were observed in FF rats compared with DR rats. With high-level O(3) exposure, DR rats exhibited a much greater survivability compared with FF rats (90% versus 8%, respectively). These observations suggest that diet restriction leading to significant reduction of body weight is beneficial, and may play a role in the resistance to the adverse effects of O(3).

Cigarette smoking is the most popular form of smoking, and is one of the most prevalent social habits worldwide. It has been estimated that almost 1.1 billion people are classified as smokers of whom over 2 million are expected to die every year. This makes smoking the leading preventable cause of death and disability in the world. In addition to mortality, smoking was shown to deplete the body of its endogenous antioxidants such as vitamins C and E, β-carotene, ubiquinol, glutathione and α-lipoic acid. Antioxidant depletion was shown to increase individual vulnerability to free radicals and other oxidant species produced by cigarette smoking and therefore leads to elevated morbidity, aging, and death. Dietary supplementation with antioxidants can reduce the overall oxidative burden that is increased by cigarette smoking. However, supplementation can not substitute for the greater benefits of smoking cessation.

In today’s society, human activities and lifestyles generate numerous forms of environmental oxidative stress. Oxidative stress is defined as a process in which the balance between oxidants and antioxidants is shifted toward the oxidant side. This shift can lead to antioxidant depletion and potentially to biological damage if the body has an insufficient reserve to compensate for consumed antioxidants. This report focuses on the observation that oxidative stress resulting from inhalation of oxidant air pollutants mobilized vitamin E to the lung. A review of the literature showed that this mobilization is not limited to the lung; rather, a variety of situations in which oxidative stress occur can mobilize antioxidants. This antioxidant mobilization shows that a high antioxidant capacity in the body must be maintained for it to cope efficiently with environmental oxidative stress. Maintaining a high-antioxidant capacity in the body with the use of dietary supplementation was a convenient and acceptable method by test subjects, human or non-human. One mechanism that might explain the antioxidant mobilization is a dynamic interaction between environment and nutrition. In that mechanism, oxidative stress would alter certain bioactive molecules, followed by activation of signal transduction pathways that in turn would mobilize antioxidants to the target organ of the oxidant attack.

Detonation of explosives, firing of large caliber weapons and occupational explosions, professional or accidental, produce high-energy impulse noise (blast) waves characterized by a rapid rise in atmospheric pressure (overpressure) followed by gradual decay to ambient level. Exposure to blast waves causes injury, predominantly to the hollow organs such as ears and lungs. We have previously reported that blast exposure can induce free radical-mediated oxidative stress in the lung characterized by antioxidant depletion, lipid peroxidation, and hemoglobin (Hb) oxidation. In this study, we examined whether pre-loading, adequately fed rats, with pharmacological doses of antioxidants would reduce the response to blast. Sprague-Dawley rats weighing 300-350 g were loaded with either 800 IU vitamin E (VE), 1000 mg vitamin C (VC) or 25 mg lipoic acid (LA) for 3 consecutive days by gavage before exposure to blast. Both VE, and LA were dissolved in 2 ml corn oil, but VC in 2 ml water. After the 3-day antioxidant loading, the rats were divided into six groups (five rats per group), deeply anesthetized with sodium pentobarbital (60 mg/kg body weight), then exposed to a low-level blast (62+/-2 kPa peak pressure and 5 ms duration). A matched number of groups were sham exposed and served as controls. One hour after exposure, all rats were euthanized then blood, and lung tissue was analyzed. We found that antioxidant loading resulted in restored Hb oxygenation, and reduced lipid peroxidation. Lung tissue VE content was elevated after loading but VC did not change possibly due to their different bioavailability and saturation kinetics. These observations, suggest that brief antioxidant loading with pharmacological doses can reduce blast-induced oxidative stress, and may have occupational and clinical implications.

We studied protective effects of nitric oxide against tert-butyl hydroperoxide-induced oxidative damage to cardiac myocytes. Two distinct free radicals species--alkoxyl radicals associated with non-heme iron catalytic sites and myoglobin protein-centered peroxyl radicals--were found in low-temperature EPR spectra of cardiac myocytes exposed to t-BuOOH. The t-BuOOH-induced radical formation was accompanied by site-specific oxidative stress in membrane phospholipids (peroxidation of phosphatidylserine) assayed by fluorescence HPLC after metabolic labeling of cell phospholipids with oxidation-sensitive cis-parinaric acid. An NO-donor, (Z)-1-[N-(3-ammonio-propyl)-N-(n-propyl) amino]-diazen-1-ium-1,2-diolate], protected cardiac myocytes against tert-butyl hydroperoxide-induced: (i) formation of non-protein- and protein-centered free radical species and (ii) concomitant peroxidation of phosphatidylserine. Thus nitric oxide can act as an effective antioxidant in live cardiomyocytes.