Analysis of air pollution particulate-mediated oxidant stress in alveolar macrophages

Adverse health effects of urban air pollution particulates may be attributable to particle-mediated oxidant stress and inflammation. Intracellular oxidant production in normal hamster alveolar macrophages (AMs) was measured upon exposure to concentrated ambient particulates (CAPs), residual oil fly ash (ROFA), and their water-soluble and particulate fractions. ROFA and CAPs caused increases in dichlorofluorescin (DCFH) oxidation, a fluorescent measure of intracellular reactive oxygen species (ROS) production, comparable to the positive control, phorbol myristate acetate (PMA). The water-soluble component of both CAPs and ROFA (CAPs, S and ROFA, S) significantly increased AM oxidant production over negative control. CAPs samples and components showed substantial day-to-day variability in their oxidant effects. Metal chelation by desferrioxamine (DF, 1 mM) caused significant inhibition of particulate-induced AM oxidant production. ROFA exposure resulted in increased macrophage inflammatory protein-2 (MIP-2) message in AMs and in increased tumor necrosis factor alpha (TNF-alpha) production by the monocyte-macrophage cell line, RAW 264.7. TNF-alpha production was inhibitable by the antioxidant N-acetylcysteine (NAC). The data suggest that metal components adsorbed to urban air pollution particulates can significantly contribute to particulate ability to cause oxidant stress and cytokine production in AMs.     

Asthma and oxidant stress: nutritional, environmental, and genetic risk factors

A considerable body of evidence suggests that oxidant stress results in inflammation and tissue damage in the respiratory system, and later in immune damage, and that individuals with lowered cellular reducing capacity are at increased risk to develop asthma. Reducing capacity in the erythrocyte is generated through the pentose phosphate pathway and this pathway also generates a major portion of the reducing capacity in all cells of the body. Therefore, dietary, environmental, and genetic factors which diminish cellular reducing capacity will increase tissue vulnerability to oxidant stress and are likely to increase asthma risk. Dietary selenium deficiency lowers red cell glutathione peroxidase activity and is associated with an increased risk for asthma, and low dietary intakes of vitamins C and E also appear to increase asthma risk. High body iron stores increase free radical production and may also elevate asthma risk. Environmental lead exposure depresses the activities of a several enzyme systems that influence cellular reducing capacity (glucose-6-phosphate dehydrogenase, NAD synthetase, glutathione peroxidase, superoxide dismutase, catalase) and consequently may increase asthma risk. Genetically-determined low activity of glucose-6-phosphate dehydrogenase lowers cellular reducing capacity and may also heighten asthma risk. Simple dietary and environmental interventions may significantly reduce oxidant stress and prevent or minimize the development of asthmatic symptoms and should prove to be a cost effective approach to asthma management in addition to current pharmacological strategies.     

Regional drug delivery I: permeability characteristics of the rat 6-day-old air pouch model of inflammation

PURPOSE: To determine the permeability characteristics of the rat air pouch model of inflammation using permeability extremes within which the NSAIDs S[+] ibuprofen, piroxicam and diclofenac could be evaluated. METHODS: Permeability was calculated using concentration data obtained following intrapouch and intravenous administration of [3H]-water, [14C]-urea, [14C]-inulin and [125I]-albumin and compared to similar data obtained for the three NSAIDs. RESULTS: Similar permeability values (5-6.5 ml hr-1) were obtained for the three NSAIDS which fell between the permeability extremes of the molecular weight markers [3H]-water (9.7 ml hr-1), [14C]-urea (6.8 ml hr-1), [14C]-inulin (1.0 ml hr-1) and [125I]-albumin (0.6 ml hr-1). Coadministration of equipotent anti-inflammatory doses of the NSAIDs did not affect local blood flow to the air pouch (as assessed by urea kinetics) but did reduced vascular permeability (as assessed by albumin flux into the pouch). CONCLUSIONS: Comparison of the NSAIDs with the permeabilities of the molecular weight markers indicates that a perfusion rate limitation probably exists. Systemic absorption is complete over the first two hours following intrapouch administration of the NSAIDs, therefore albumin flux into the pouch is insufficient to materially affect the permeability of the NSAIDs. However, subsequently (post 5hr) albumin concentration in the pouch rises sufficiently to lower the effective flux of the NSAIDs.     

Markers of platelet activation and oxidant stress in atherothrombotic disease

Several new approaches to the study of platelet activation have been developed. Logically, these should be combined with novel indices of coagulant function (60,61) to select rational targets for antithrombotic drugs. They may also be invaluable in dose-finding, which has been a particular weakness in this area of drug development (62,63). While activation of platelets and the coagulation cascade are virtually simultaneous events, markers of the atherosclerosis are also artificially segregated from those of the complicating thrombotic process. Oxidant stress has been implicated in both platelet activation (64) and atherogenesis (65), yet our ability to study this system has been so constrained that we are unsure of appropriate doses of antioxidant vitamins. Novel approaches to this problem promise the ability to study oxidative modification of proteins (46,66,67), lipids (57) and DNA (45,68) in clinical studies.     

Intestinal permeability and inflammation in patients on NSAIDs

PURPOSE: The purpose of this study was to determine whether high frequency fatigue was present in the diaphragm after intense whole body endurance exercise. METHODS: We used bilateral phrenic nerve stimulation (BPNS) before and during recovery from whole body exercise to detect fatigue in the diaphragm. To detect high frequency fatigue we used paired stimuli at 10, 20, 50, 70, and 100 Hz frequency and determined the transdiaphragmatic pressure (Pdi) response to the second stimulation (T2). RESULTS: The subjects (N = 10) exercised at 93.3 +/- 2.3% of their VO2max for 9.9 +/- 0.5 min. The Pdi response to "twitch" and 10 Hz "tetanic" stimulation was decreased immediately after exercise versus pre-exercise values (-23.4 +/- 3.3%). The T2 amplitude was substantially reduced at all frequencies immediately after exercise (-28.0%), but by 30 min into recovery the T2 amplitude at 70 and 100 Hz was not different from pre-exercise values. In contrast, at 10 and 20 Hz the T2 response was still significantly reduced. CONCLUSIONS: We interpret these data to mean that high frequency fatigue as well as low frequency fatigue were present in the diaphragm after intense whole body endurance exercise.     

Epithelial antibiotics induced at sites of inflammation

The role of antimicrobial peptides in epithelial defense is not fully understood. An epithelial beta-defensin, lingual antimicrobial peptide (LAP), was isolated from bovine tongue and the corresponding complementary DNA cloned. LAP showed a broad spectrum of antibacterial and antifungal activities. LAP messenger RNA abundance was markedly increased in the epithelium surrounding naturally occurring tongue lesions. This increase coincided with the cellular hallmarks of acute and chronic inflammation in the underlying lamina propria, supporting a role for epithelial antimicrobial peptides as integral components of the inflammatory response.     

Successful treatment of habitual smokers with warm, smoky air and rapid smoking.

Presented either warm smoky air or warm mentholated air to 28 undergraduate habituated smokers and required them to smoke until they could tolerate no further cigarettes. Both groups smoked at a rapid rate, received considerable social reinforcement, and were given comparable expectation of success. All Ss were abstinent at termination after an average of 8 sessions, and 16 of 25 Ss followed up for 6 mo. remained abstinent. The warm smoky air and menthol air groups did not differ, but paradoxically, Ss followed up at 4-wk intervals were more successful than Ss contacted every 2 wk. (24 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Attentional bias in active smokers, abstinent smokers, and nonsmokers

Pure autonomic failure is characterized by orthostatic hypotension, sweating disorder, urinary incontinence, and syncope. A 64 year-old man with pure autonomia failure was scheduled for suprapubic prostatectomy. We monitoring direct arterial pressure and inserted pulmonary artery catheter prior to the induction of anesthesia. General anesthesia was induced with diazepam 10 mg, fentanyl 0.3 mg, and vecuronium 8 mg for tracheal intubation. Anesthesia was maintained with sevoflurane (0.2-1.5%), 60% nitrous oxide in oxygen supplemented with intermittent epidural anesthesia. During anesthesia, blood loss was immediately replaced with banked blood because autonomic failure could not compensate hypovolemia well. Epidural anesthesia in this patient was considered to cause less hypotension than in patients with normal autonomic function. Therefore, we think epidural anesthesia is a useful anesthesia method for patients with pure autonomic failure. The emergence from anesthesia was smooth and no complications were seen during the perioperative period.     

Adenovirus-mediated catalase gene transfer reduces oxidant stress in human, porcine and rat pancreatic islets

Susceptibility of pancreatic islets to oxidant stress may affect islet viability and contribute to primary non function of allo- or xenogenic grafts. We investigated the influence of overexpression of catalase (CAT) on the viability of human, porcine and rat islets, as well as INS-1 beta-cell line. Islets were transfected with a replication-deficient adenovirus vector containing human CAT cDNA under the control of the adenovirus major late promoter (AdCAT) or a vector containing no foreign gene (AdNull) and used as a control. Oxidant stress was induced 48 h later by xanthine oxidase-hypoxanthine (XO 25 mU/ml, HX 0.5 mmol/l) or hydrogen peroxide (100 or 250 micromol/l). Islet cell viability was assessed 72 h after CAT transfer by 4-[3-(4-Idophenyl)-2-(4 nitrophenyl)-2H-5-tetrazolio]-1,2,benzene disulphonate (WST-1) test. Baseline catalase activity was three to fourfold lower in porcine than in human islets. CAT activity was reproducibly increased 2.5- to 7-fold in AdCAT infected islets, at least for 13 days. Overall, AdCAT conferred on human and pig islets a protection of 26.1 +/- 6.1 and 21.2 +/- 9.8% on XOHX injury and 35.4 +/- 4.2 and 57.9 +/- 10.5% on H2O2 stress. Similarly, rat islet cells and INS-1 cells were protected on XOHX stress by 17.8 +/- 2.3 and 30.8 +/- 8.7%, respectively. AdNull had no effect. Basal and stimulated insulin secretion was preserved in AdCAT-transfected human islets despite a XOHX challenge. This study validates adenovirus-mediated catalase gene transfer as a realistic approach to reduce non specific inflammation effects on human or porcine islet grafts. Moreover the relevance of defense mechanisms, previously suggested in human islets, is here illustrated in porcine islets.     

Probucol suppresses oxidant stress in hypertensive arteries. Immunohistochemical evidence

Oxy-free radicals may be involved in the pathogenesis of accelerated atherosclerosis in hypertension. We evaluated the direct antioxidant potential of probucol in hypertensive arteries by studying the spatial immunohistochemical distribution of three primary antioxidant enzymes (AEs). Nineteen normocholesterolemic New Zealand White rabbits were divided into two groups: normotensive controls (NT; n = 6) and 13 animals rendered hypertensive by surgical coarctation of abdominal aorta. The hypertensive group was subdivided into hypertensive alone (HT; n = 8) and hypertensive treated with 1% probucol (PO) for 9 weeks (HT-P; n = 5). Blood pressure rose significantly in both hypertensive groups (P < .005). At autopsy, both hypertensive groups showed similarly significant increases in mean arterial intima-media thickness (IMT) whether or not they were treated with probucol. However, only HT rabbits revealed significant increases in the intima-media depth penetration of glutathione peroxidase, superoxide dismutase, and catalase AEs. By contrast, in HT-P animals probucol produced significant reductions of immunostaining of all three AEs compared to the HT group (P < .05). Additionally, specific macrophage immunostaining revealed that the arterial wall of HT rabbits had numerous (10 to 12 per high power field) subintimal and medial macrophages as compared to the HT-P animals (1 to 2 per high power field). The blood pressure level correlated significantly with IMT in all three groups, but with depth penetration of the three AEs only in the NT and HT groups. Probucol, therefore, appears to act in concert with the native arterial antioxidant enzymes as a potent free radical scavenger to reduce oxidative stress and thus attenuate the macrophage invasive response in hypertensive arteries.     

Investigation of oxidant stress and vasodepression to glyceryl trinitrate in the obese Zucker rat in vivo

OBJECTIVE: To describe risk factors and explore mechanisms of ischemic strokes after general surgery. BACKGROUND: Strokes follow general surgery in about 0.08% to 2.9% of cases. Patients with previous cerebrovascular disease, atrial fibrillation, hypertension, advanced age, or atherosclerosis were found to have an increased risk. Knowledge of factors involved may guide physicians in determining the overall risk of surgery. METHODS: This case-control study was performed in a referral center. A total of 61 patients identified through a computerized database with ischemic strokes after surgical procedures-excluding heart, brain, vessels, or neck-between July 1986 and July 1996 were studied. Procedures included 11 urogenital, 16 gastrointestinal, 17 orthopedic, 12 pulmonary, and 5 other. A total of 122 randomly selected controls were matched for age, sex, procedure, and year of procedure. Main outcome measures included arterial territory, timing, risk factors, and perioperative events. Differences were expressed as adjusted odds ratios (AOR) with 95% confidence limits (CL), using multivariate conditional logistic analyses for matched case-control design. RESULTS: Arterial territory included 37 middle cerebral artery, 11 posterior circulation, 7 borderzone, and 6 multiple. Median procedure to stroke interval was 2 days (range, 0 to 16); 10 patients had intraoperative strokes. Three major risk factors emerged: previous cerebrovascular disease (AOR 12.57, 95% CL 2.14/73.70), chronic obstructive pulmonary disease (COPD) (7.51, 1.87/30.12), and peripheral vascular disease (PVD) (5.35, 1.25/22.94). After adding stroke-related factors, PVD (14.70, 2.01/107.71) and COPD (10.04, 1.90/53.14) remained the strongest variables; blood pressure (1.05, 1.01/1.10) and urea (1.04, 1.01/1.07) contributed slightly. Hypotension did not contribute. Four patients (6.6%) and no controls had diffuse intravascular coagulation (p = 0.01). Four stroke patients had myocardial infarction (6.6% versus 0%; p = 0.01). CONCLUSIONS: Ischemic strokes after general surgery most commonly occur after an asymptomatic interval. Previous cerebrovascular disease, COPD, and PVD greatly increase the risk. Hypotension rarely accounts for postoperative strokes. Major comorbidity of the patient at risk seems more important than complicating events during surgery.     

Regular smokers, lifetime very light smokers, and reduced smokers: Comparison of psychosocial and smoking characteristics in women.

This study compared stable very light smokers ([VLS]; less than 6 cigarettes a day) with regular smokers ([RS]; greater than 14 cigarettes a day) in a cohort of women followed up for 1 yr. The VLS showed evidence of inhaling the cigarette smoke. They were not novice smokers, nor were they under particular pressure to limit their smoking. Among the 61 VLS, 34 had at one time smoked more than 10 cigarettes per day. These "reduced smokers" were broadly similar to the lifetime VLS, who differed from RS in several important respects. In a multiple logistic regression, education and smoking patterns in relatives were independently associated with very light versus regular smoking. Familial factors and personal resources may protect against dependence among those who use tobacco. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Is hemin responsible for the susceptibility of Plasmodia to oxidant stress?

Based on the unusually high and stage-dependent susceptibility of Plasmodia to oxidant stress it has been proposed that during parasite development, increasing levels of redox-active forms of iron are gradually released. The purpose of this study was to examine this proposal by using an assay monitoring the levels of available forms of iron for redox reactions. Ascorbate-driven and iron-mediated degradation of adventitious DNA served as the basis for this functional assay. Incubation of DNA with lysate from infected RBC caused massive degradation, which was dose, time- and parasite-stage dependent. In contrast, lysate from non-infected RBC did not induce DNA degradation. Likewise, lysate only from infected RBC enhanced the aerobic oxidation of ascorbate. These effects on both reaction, DNA degradation and ascorbate oxidation, could be reconstructed with hemin, instead of lysate. Also, chelators exerted similar effects on both reactions. The results suggest that increased levels of redox-active forms of iron are liberated during parasite development. We propose that hemin or hemin-like structures are the appropriate candidates which could catalyze oxidative stress and deregulate the delicate redox balance of the host-parasite system.     

Psychosocial stress and coping in smokers who relapse or quit.

Selected responses and coping skills in 23 male and 21 female adult smokers and ex-smokers were evaluated in 4 situational contexts: general social competence, smoking-specific high-risk-for-relapse situations, social anxiety, and relaxation. Results show that quitters coped better than relapsers with intrapersonal (e.g., negative mood) smoking-specific situations. Quitters had lower heart rates than relapsers during relaxation and intrapersonal situations and had lower anxiety scores at the end of the procedures. Women showed more stress and less confidence in their ability to cope than men. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Respiratory function and symptoms in urban office workers in relation to oxidant air pollution exposure

Similar populations of male and female office workers in San Francisco, which has little air pollution, and in Los Angeles, which experiences frequent photochemical smog episodes, were surveyed in an attempt to document excess respiratory symptoms and dysfunction in Los Angeles relatable to air pollution. Most results of forced expiratory tests, single-breath N2 tests, and questionnaire interviews did not differ significantly between cities. Los Angeles women reported nonpersistent cough and phlegm more often than did San Francisco women. Smokers in both cities showed increased functional abnormalities. These results suggested that Los Angeles oxidant exposure is far less significant than smoking as a risk factor in development of chronic respiratory disease in sedentary indoor workers in good general health. Oxidant exposure has not been ruled out as a significant risk to more heavily exposed on more highly susceptible persons.     

Severity of airflow limitation is associated with severity of airway inflammation in smokers

To investigate the relationship between airflow limitation and airway inflammation in smokers, we examined paraffin-embedded bronchial biopsies obtained from 30 smokers: 10 with severe airflow limitation, eight with mild/moderate airflow limitation, and 12 control smokers with normal lung function. Histochemical and immunohistochemical methods were performed to assess the number of inflammatory cells in the subepithelium and the expression of CC chemokines macrophage inflammatory protein (MIP)-1alpha and -1beta in the bronchial mucosa. Compared with control smokers, smokers with severe airflow limitation had an increased number of neutrophils (p < 0.02), macrophages (p < 0.03), and NK lymphocytes (p < 0.03) in the subepithelium, and an increased number of MIP-1alpha+ epithelial cells (p < 0.02). When all smokers were considered together, the value of FEV1 was inversely correlated with the number of neutrophils (r = -0.59, p < 0.002), macrophages (r = -047, p < 0. 012), NK-lymphocytes (r = -0.51, p < 0.006) in the subepithelium, and with the number of MIP-1alpha+ epithelial cells (r = -0.61, p < 0.003). We conclude that in smokers the severity of airflow limitation is correlated with the severity of airway inflammation and that severe airflow limitation is associated with an increased number of neutrophils, macrophages, NK lymphocytes, and MIP-1alpha+ cells in the bronchial mucosa.     

No evidence for systemic oxidant stress in Parkinson's or Alzheimer's disease

Oxidant stress secondary to dopamine metabolism has been proposed as a pathogenic factor in the development of Parkinson's disease. Biochemical abnormalities extending beyond the central nervous system have been identified in patients with this condition. Previous investigators have found abnormally elevated concentrations of the lipid peroxidation product, malondialdehyde, in the plasma and serum of patients with Parkinson's disease. We attempted to replicate these findings but controlled for other factors that could influence malondialdehyde levels. We detected no significant elevations in mean serum malondialdehyde concentrations in either levodopa-treated or untreated patients with Parkinson's disease, compared to normal controls; similarly, no elevation was found in a group of patients with dementia of Alzheimer's type. On the other hand, a group of subjects with diabetes mellitus but no neurodegenerative disease had significantly elevated mean serum malondialdehyde levels, consistent with previous studies of diabetic patients. Autoxidation is one of the two major routes by which dopamine and dopa metabolism may generate oxygen free radicals. We analyzed the autoxidation product of dopa, 5-S-cysteinyl-dopa, in the plasma of these same groups of patients with neurodegenerative disease and normal controls; no significant differences were identified. Serum concentrations of two other antioxidant substances, alpha-tocopherol and uric acid, were also statistically similar in these groups. In conclusion, analysis of several blood products relevant to oxidant stress, including malondialdehyde, 5-S-cysteinyl-dopa, alpha-tocopherol, and uric acid, failed to distinguish patients with Parkinson's disease or dementia of Alzheimer's type from controls.