dinoprost and Pneumonia

N-acetylcysteine has been used to treat a variety of lung diseases, where is it thought to have an antioxidant effect. In a randomized placebo-controlled double-blind study, the effect of N-acetylcysteine on systemic inflammation and oxidative damage was examined in patients undergoing lung resection, a human model of acute lung injury.. Eligible adults were randomized to receive preoperative infusion of N-acetylcysteine (240 mg/kg over 12 h) or placebo. Plasma thiols, interleukin-6, 8-isoprostane, ischaemia-modified albumin, red blood cell glutathione and exhaled breath condensate pH were measured pre- and post-operatively as markers of local and systemic inflammation and oxidative stress.. Patients undergoing lung resection and one-lung ventilation exhibited significant postoperative inflammation and oxidative damage. Postoperative plasma thiol concentration was significantly higher in the N-acetylcysteine-treated group. However, there was no significant difference in any of the measured biomarkers of inflammation or oxidative damage, or in clinical outcomes, between N-acetylcysteine and placebo groups.. Preoperative administration of N-acetylcysteine did not attenuate postoperative systemic or pulmonary inflammation or oxidative damage after lung resection.. NCT00655928 at ClinicalTrials.gov.

Topics: Acetylcysteine; Aged; Antioxidants; Biomarkers; Breath Tests; Dinoprost; Double-Blind Method; Female; Glutathione; Humans; Interleukin-6; Lung; Male; Middle Aged; Oxidative Stress; Pneumonectomy; Pneumonia; Postoperative Complications; Preoperative Care; Serum Albumin; Serum Albumin, Human; Treatment Outcome

Induced sputum 8-iso-prostaglandin F(2alpha) (PGF(2alpha)) concentrations may be a useful marker of oxidative stress in airways disease. This study examines oxidative stress (measured by 8-iso-PGF(2alpha)) in airway disease according to disease type (asthma and bronchiectasis), disease activity (stable and acute asthma), and disease pattern (intermittent, mild, moderate, and severe persistent asthma). We compared subjects with stable asthma (n = 71) and bronchiectasis (n = 23) with healthy control subjects (n = 29). Another group of patients with asthma (n = 39) were assessed during and after acute exacerbation. Induced sputum 8-iso-PGF(2alpha) concentrations were validated and found to be elevated in subjects with stable asthma and bronchiectasis versus control subjects (median [interquartile range] 216 [103-389] and 698 [264-1,613] ng/L vs. 123 [41-290] ng/L, p < 0.001) and increased as clinical asthma pattern worsened (intermittent 115 [42-153], mild persistent 116 [89-229] ng/L, moderate persistent 183 [110-317] ng/L, severe persistent 387 [102-587] ng/L; p = 0.010). Sputum 8-iso-PGF(2alpha) concentrations were elevated during acute asthma and decreased with recovery (458 [227-950] ng/L vs. 214 [148-304] ng/L, p = 0.0002). We conclude that 8-iso-PGF(2alpha) is involved in the pathophysiology of inflammatory airway diseases, being related to disease type, pattern, and activity. Analysis of 8-iso-PGF(2alpha) concentrations in induced sputum provides a useful tool for monitoring oxidative stress and investigating strategies aimed at reducing oxidative stress in airways disease.

Topics: Adult; Age Factors; Asthma; Biomarkers; Bronchiectasis; Dinoprost; Eosinophils; Female; Humans; Leukocyte Count; Male; Middle Aged; Multivariate Analysis; Neutrophils; Oxidative Stress; Pneumonia; Respiratory Function Tests; Sex Factors; Sputum

Water pipe smoking is a tobacco smoking method commonly used in Eastern countries and is gaining popularity in Europe and North America, in particular among adolescents and young adults. Several clinical and experimental studies have reported that exposure to water pipe smoke (WPS) induces lung inflammation and impairment of pulmonary function. However, the mechanisms of such effects are not understood, as are data on the possible palliative effect of exercise training. The present study evaluated the effects of regular aerobic exercise training (treadmill: 5 days/week, 40 min/day) on subchronic exposure to WPS (30 minutes/day, 5 days/week for 2 months). C57BL/6 mice were exposed to air or WPS with or without exercise training. Airway resistance measured using forced oscillation technique was significantly and dose-dependently increased in the WPS-exposed group when compared with the air-exposed one. Exercise training significantly prevented the effect of WPS on airway resistance. Histologically, the lungs of WPS-exposed mice had focal moderate interstitial inflammatory cell infiltration consisting of neutrophil polymorphs, plasma cells, and lymphocytes. There was a mild increase in intra-alveolar macrophages and a focal damage to alveolar septae in some foci. Exercise training significantly alleviated these effects and also decreased the WPS-induced increase of tumor necrosis factor

Topics: Animals; Dinoprost; Interleukin-6; Lung; Methacholine Chloride; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; NF-kappa B; Physical Conditioning, Animal; Pneumonia; Water Pipe Smoking

Inflammatory processes, including respiratory symptoms, can be induced among workers in composting plants exposed to bioaerosols containing microorganisms and their compounds. We evaluated inflammatory processes in the lower respiratory tract via cellular and soluble mediator profiles in induced sputum (IS). IS samples of 140 current (35% smokers) and 49 former compost workers (29% smokers) as well as 29 white-collar workers (17% smokers) were collected and analyzed for the cell count and composition, and for soluble biomarkers. Significant differences between current and former compost workers and white-collar workers were detected for total cell count (p=0.0004), neutrophils (p=0.0045), sCD14 (p=0.008), and 8-isoprostane (p<0.0001). IS of non-smoking former compost workers showed lower concentrations of IL-8, total protein, immunoreactive MMP-9 and sCD14, compared with non-smoking current compost workers. 10.1% of the study population was suffering from chronic bronchitis with significant differences (p=0.018) between former compost workers (24.5%), current workers (5%), and white-collar workers (10.3%). Significantly lower IL-8 (p=0.0002), neutrophils (p=0.001), and MMP-9 (p=0.0023) values were measured in healthy subjects compared with subjects with chronic bronchitis. In conclusion, changes in lower airways were detected by analysis of biomarkers in IS of current exposed and, to a lesser extent, in IS of former compost workers. These effects are especially pronounced in subjects with chronic bronchitis.

Topics: Adult; Air Pollutants, Occupational; Biomarkers; Blood Proteins; Bronchitis; Cell Count; Chronic Disease; Cross-Sectional Studies; Dinoprost; Female; Humans; Interleukin-8; Lipopolysaccharide Receptors; Male; Matrix Metalloproteinase 9; Middle Aged; Neutrophils; Occupational Exposure; Pneumonia; Smoking; Soil; Sputum

Occupational bioaerosol exposures are capable to cause respiratory diseases. We studied the relationship between exposure to bioaerosols and biomarkers' concentration in exhaled breath condensate (EBC) and fractional exhaled nitric oxide (FeNO) in 119 bioaerosol-exposed compost workers taking into account atopy and smoking habits. Atopy was classified according to specific IgE concentrations to common inhalant allergens (sx1). Bioaerosol exposure was estimated according to job title, duration of employment, results of ambient monitoring at the workplaces, and shift time worked under protection of filtered air supply. Concentrations of 8-iso-prostaglandin F2α (8-iso-PGF2α), prostaglandin E2 (PGE2), leukotriene B4 (LTB4), and acid-base balance (pH) in EBC and FeNO were assessed in 59 never-smoking (NS) and 60 smoking (S) compost workers. We found that atopic subjects were equally distributed among NS and S (n=16 each). Levels of 8-iso-PGF2α were significantly higher in workers considered highly exposed to bioaerosols than in low exposed workers (86.6 (66.1; 128.8) pg/mL vs. 74.4 (56.3; 96.7) pg/mL, p=0.047). No associations could be observed between exposures and biomarkers concerning compost workers in total, but there were some in atopic workers (duration of employment and FeNO: r=0.376, p=0.041; filtered air supply and FeNO: r=-0.335, p=0.071). Smokers had significantly lower pH values compared to NS (non-atopic, p=0.041; atopic p=0.050). In conclusion, EBC and FeNO might be useful tools for monitoring of inflammation due to bioaerosol exposures, especially in atopic subjects. Besides smoking also atopy should be considered when investigating airway inflammation.

Topics: Acid-Base Equilibrium; Adult; Aerosols; Air Pollutants, Occupational; Biomarkers; Cross-Sectional Studies; Dinoprost; Dinoprostone; Exhalation; Female; Humans; Hypersensitivity, Immediate; Immunoglobulin E; Leukotriene B4; Male; Middle Aged; Nitric Oxide; Occupational Exposure; Pneumonia; Smoking; Soil

Several epidemiological studies have shown the impact on respiratory health of pollution of nitrogen dioxide (NO2), particulate matter (PM10), and ozone (O3) as an environmental mixture. However, the influence of individual components of airborne pollutants is less well known. Our study examined the cumulative effects of a single pollutant, NO2, on sensitized rats by measurement of isoprostane release in exhaled breath condensate (EBC). Three groups of six rats were used: (1) controls (only exposed to air), (2) sensitized and challenged by ovalbumin and exposed to air, and (3) sensitized, challenged by ovalbumin, and exposed to NO(2). There was no marked change in 8-isoprostane levels in EBC of sensitized rats, whereas a significant increase of 8-isoprostane was found in rats sensitized and exposed to NO2. Data indicate effect of exposure to NO2 is evident as increased 8-isoprostane levels in EBC, a relevant marker for assessment of pulmonary inflammation or oxidant stress and conventionally found in EBC of asthmatic subjects.

Topics: Air Pollutants; Animals; Biomarkers; Breath Tests; Dinoprost; Environmental Exposure; Environmental Monitoring; Male; Nitrogen Dioxide; Oxidative Stress; Particulate Matter; Pneumonia; Rats

The ″in situ burning" of trapped crude oil on the surface of Gulf waters during the 2010 Deepwater Horizon (DWH) oil spill released numerous pollutants, including combustion-generated particulate matter (PM). Limited information is available on the respiratory impact of inhaled in situ burned oil sail particulate matter (OSPM). Here we utilized PM collected from in situ burn plumes of the DWH oil spill to study the acute effects of exposure to OSPM on pulmonary health. OSPM caused dose-and time-dependent cytotoxicity and generated reactive oxygen species and superoxide radicals in vitro. Additionally, mice exposed to OSPM exhibited significant decreases in body weight gain, systemic oxidative stress in the form of increased serum 8-isoprostane (8-IP) levels, and airway inflammation in the form of increased macrophages and eosinophils in bronchoalveolar lavage fluid. Further, in a mouse model of allergic asthma, OSPM caused increased T helper 2 cells (Th2), peribronchiolar inflammation, and increased airway mucus production. These findings demonstrate that acute exposure to OSPM results in pulmonary inflammation and alteration of innate/adaptive immune responses in mice and highlight potential respiratory effects associated with cleaning up an oil spill.

Topics: Adaptive Immunity; Animals; Asthma; Cell Death; Cell Line; Cell Survival; Dinoprost; Disease Models, Animal; Electron Spin Resonance Spectroscopy; Environmental Exposure; Female; Mice, Inbred BALB C; Mucus; Oxidative Stress; Particulate Matter; Petroleum; Petroleum Pollution; Pneumonia; Superoxides; Time Factors

In the present study, we tested the hypothesis that oxidative stress could be implicated in myocardial damage during the acute phase of pneumonia. NOX2 activation, the catalytic subunit of NADPH oxidase, and high-sensitivity cardiac troponin T (hs-cTnT) elevation have been analyzed in two hundred forty-eight consecutive patients hospitalized for community-acquired pneumonia. Serum NOX2-derived peptide (sNOX2-dp), a marker of NOX2 activation, and 8-isoprostaglandin F2α (8-iso-PGF2α), a marker of oxidative stress, were measured upon admission; serum hs-cTnT and ECG were measured every 12 and 24 h, respectively. One hundred thirty-five patients (54%) showed elevated serum levels of hs-cTnT (>0.014 μg/L). A logistic regression analysis showed sNOX2-dp (p<0.001), Pneumonia Severity Index score (p<0.001), renal failure (p=0.024), and ejection fraction (p<0.001) as independent predictors of elevated serum levels of hs-cTnT. Serum sNOX2-dp was linearly correlated with hs-cTnT (Rs=0.538; p<0.001) and 8-iso-PGF2α (Rs=0.354; p<0.001). The study provides the first evidence of a significant association between serum cardiac Troponin T elevation and NOX2 upregulation in patients with pneumonia. This finding raises the hypothesis that NOX2-derived oxidative stress may be implicated in myocardial injury and that its inhibition could be a novel therapeutic strategy to limit it.

Topics: Aged; Aged, 80 and over; Biomarkers; Cohort Studies; Community-Acquired Infections; Dinoprost; Female; Humans; Logistic Models; Male; Membrane Glycoproteins; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Myocardium; NADPH Oxidase 2; NADPH Oxidases; Odds Ratio; Oxidative Stress; Pneumonia; Reactive Oxygen Species; Severity of Illness Index; Troponin T; Up-Regulation

The importance of the lung parenchyma in the pathophysiology of asthma has previously been demonstrated. Considering that nitric oxide synthases (NOS) and arginases compete for the same substrate, it is worthwhile to elucidate the effects of complex NOS-arginase dysfunction in the pathophysiology of asthma, particularly, related to distal lung tissue. We evaluated the effects of arginase and iNOS inhibition on distal lung mechanics and oxidative stress pathway activation in a model of chronic pulmonary allergic inflammation in guinea pigs.. Guinea pigs were exposed to repeated ovalbumin inhalations (twice a week for 4 weeks). The animals received 1400 W (an iNOS-specific inhibitor) for 4 days beginning at the last inhalation. Afterwards, the animals were anesthetized and exsanguinated; then, a slice of the distal lung was evaluated by oscillatory mechanics, and an arginase inhibitor (nor-NOHA) or vehicle was infused in a Krebs solution bath. Tissue resistance (Rt) and elastance (Et) were assessed before and after ovalbumin challenge (0.1%), and lung strips were submitted to histopathological studies.. Ovalbumin-exposed animals presented an increase in the maximal Rt and Et responses after antigen challenge (p<0.001), in the number of iNOS positive cells (p<0.001) and in the expression of arginase 2, 8-isoprostane and NF-kB (p<0.001) in distal lung tissue. The 1400 W administration reduced all these responses (p<0.001) in alveolar septa. Ovalbumin-exposed animals that received nor-NOHA had a reduction of Rt, Et after antigen challenge, iNOS positive cells and 8-isoprostane and NF-kB (p<0.001) in lung tissue. The activity of arginase 2 was reduced only in the groups treated with nor-NOHA (p <0.05). There was a reduction of 8-isoprostane expression in OVA-NOR-W compared to OVA-NOR (p<0.001).. In this experimental model, increased arginase content and iNOS-positive cells were associated with the constriction of distal lung parenchyma. This functional alteration may be due to a high expression of 8-isoprostane, which had a procontractile effect. The mechanism involved in this response is likely related to the modulation of NF-kB expression, which contributed to the activation of the arginase and iNOS pathways. The association of both inhibitors potentiated the reduction of 8-isoprostane expression in this animal model.

Topics: Administration, Inhalation; Animals; Arginase; Chronic Disease; Dinoprost; Disease Models, Animal; Guinea Pigs; Hypersensitivity; Lung; Male; NF-kappa B; Nitric Oxide Synthase Type II; Ovalbumin; Oxidative Stress; Pneumonia; Respiratory Mechanics

Mechanisms involved in stress-induced asthmatic alterations have been poorly characterised. We assessed whether inducible nitric oxide synthase (iNOS) inhibition modulates the stress-amplified lung parenchyma responsiveness, oxidative stress and extracellular matrix remodelling that was previously increased by chronic lung inflammation. Guinea pigs were subjected to 7 exposures to ovalbumin (1-5 mg/ml) or saline (OVA and SAL groups) over 4 weeks. To induce behavioural stress, animals were subjected to a forced swimming protocol (5 times/week, over 2 weeks; SAL-Stress and OVA-Stress groups) 24 h after the 4th inhalation. 1400W (iNOS-specific inhibitor) was administered intraperitoneally in the last 4 days of the protocol (SAL-1400W, OVA-1400W, SAL-Stress+1400W and OVA-Stress+1400W groups). Seventy-two hours after the last inhalation, animals were anaesthetised and exsanguinated, and adrenal glands were removed. Lung tissue resistance and elastance were evaluated by oscillatory mechanics and submitted for histopathological evaluation. Stressed animals had higher adrenal weights compared to non-stressed groups, which were reduced by 1400W treatment. Behavioural stress in sensitised animals amplified the resistance and elastance responses after antigen challenge, numbers of eosinophils and iNOS+ cells, actin content and 8-iso-PGF2α density in the distal lung compared to the OVA group. 1400W treatment in ovalbumin-exposed and stressed animals reduced lung mechanics, iNOS+ cell numbers and 8-iso-PGF2α density compared to sensitised and stressed animals that received vehicle treatment. We concluded that stress amplifies the distal lung constriction, eosinophilic inflammation, iNOS expression, actin content and oxidative stress previously induced by chronic lung inflammation. iNOS-derived NO contributes to stress-augmented lung tissue functional alterations in this animal model and is at least partially due to activation of the oxidative stress pathway.

Topics: Actins; Adrenal Glands; Animals; Collagen; Dinoprost; Eosinophils; Guinea Pigs; Hydrocortisone; Lung; Male; Nitric Oxide Synthase Type II; Organ Size; Oxidative Stress; Pneumonia; Stress, Physiological

Mechanisms linking behavioral stress and inflammation are poorly understood, mainly in distal lung tissue.. We have investigated whether the forced swim stress (FS) could modulate lung tissue mechanics, iNOS, cytokines, oxidative stress activation, eosinophilic recruitment, and remodeling in guinea pigs (GP) with chronic pulmonary inflammation.. The GP were exposed to ovalbumin or saline aerosols (2×/wk/4wks, OVA, and SAL). Twenty-four hours after the 4th inhalation, the GP were submitted to the FS protocol (5×/wk/2wks, SAL-S, and OVA-S). Seventy-two hours after the 7th inhalation, lung strips were cut and tissue resistance (Rt) and elastance (Et) were obtained (at baseline and after OVA and Ach challenge). Strips were submitted to histopathological evaluation.. The adrenals' weight, the serum cortisol, and the catecholamines were measured. There was an increase in IL-2, IL-5, IL-13, IFN-γ, iNOS, 8-iso-PGF2α, and in %Rt and %Et after Ach challenge in the SAL-S group compared to the SAL one. The OVA-S group has had an increase in %Rt and %Et after the OVA challenge, in %Et after the Ach and in IL-4, 8-iso-PGF2α, and actin compared to the OVA. Adrenal weight and cortisol serum were increased in stressed animals compared to nonstressed ones, and the catecholamines were unaltered.. Repeated stress has increased distal lung constriction, which was associated with an increase of actin, IL-4, and 8-iso-PGF2α levels. Stress has also induced an activation of iNOS, cytokines, and oxidative stress pathways.

Topics: Actins; Adrenal Glands; Airway Resistance; Animals; Catecholamines; Chronic Disease; Cytokines; Dinoprost; Eosinophils; Guinea Pigs; Hydrocortisone; Lung; Male; Nitric Oxide Synthase Type II; Organ Size; Oxidative Stress; Pneumonia; Stress, Psychological; Swimming

The imbalance between oxidants and antioxidants is referred to as oxidative stress and has been associated with various respiratory disorders. The aim of this study was the assessment of 8-isoprostane (8-iso-PGF(2α)) and Cu/Zn superoxide dismutase (Cu/Zn SOD) in exudative pleural effusions in order to examine the diagnostic accuracy of these markers in the differentiation between complicated and uncomplicated parapneumonic effusions.. The study included 214 consecutive patients with pleural effusions [68 parapneumonic (31 uncomplicated parapneumonic, 20 complicated parapneumonic, 17 empyemas), 24 tuberculous, 88 malignant and 34 transudates]. 8-Isoprostane and Cu/Zn SOD were determined by ELISA in pleural fluid and serum.. Parapneumonic effusions were characterized by higher pleural fluid 8-isoprostane levels compared to transudative, malignant and tuberculous effusions. Pleural fluid Cu/Zn SOD levels were lower in transudates, while serum levels were higher in transudative compared to all exudative pleural effusions. Both pleural fluid 8-isoprostane and Cu/Zn SOD were higher in complicated parapneumonic effusions and empyemas compared to uncomplicated parapneumonic effusions. Pleural fluid 8-isoprostane was the most accurate test to differentiate between complicated and uncomplicated parapneumonic pleural effusions with a sensitivity of 100% and a specificity of 58·1% at a cut-off point of 35·1 (AUC = 0·848).. Pleural fluid 8-isoprostane and Cu/Zn SOD may provide useful information for the differentiation between uncomplicated and complicated parapneumonic effusions and empyemas.

Topics: Aged; Aged, 80 and over; Biomarkers; Diagnosis, Differential; Dinoprost; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Oxidative Stress; Pleural Effusion; Pneumonia; Predictive Value of Tests; Prospective Studies; Superoxide Dismutase

Swimming in chlorinated pools involves exposure to disinfection by-products (DBPs) and has been associated with impaired respiratory health.. We evaluated short-term changes in several respiratory biomarkers to explore mechanisms of potential lung damage related to swimming pool exposure.. We measured lung function and biomarkers of airway inflammation [fractional exhaled nitric oxide (FeNO), eight cytokines, and vascular endothelial growth factor (VEGF) in exhaled breath condensate], oxidative stress (8-isoprostane in exhaled breath condensate), and lung permeability [surfactant protein D (SP-D) and the Clara cell secretory protein (CC16) in serum] in 48 healthy nonsmoking adults before and after they swam for 40 min in a chlorinated indoor swimming pool. We measured trihalomethanes in exhaled breath as a marker of individual exposure to DBPs. Energy expenditure during swimming, atopy, and CC16 genotype (rs3741240) were also determined.. Median serum CC16 levels increased from 6.01 to 6.21 microg/L (average increase, 3.3%; paired Wilcoxon test p = 0.03), regardless of atopic status and CC16 genotype. This increase was explained both by energy expenditure and different markers of DBP exposure in multivariate models. FeNO was unchanged overall but tended to decrease among atopics. We found no significant changes in lung function, SP-D, 8-isoprostane, eight cytokines, or VEGF.. We detected a slight increase in serum CC16, a marker of lung epithelium permeability, in healthy adults after they swam in an indoor chlorinated pool. Exercise and DBP exposure explained this association, without involving inflammatory mechanisms. Further research is needed to confirm the results, establish the clinical relevance of short-term serum CC16 changes, and evaluate the long-term health impacts.

Topics: Adult; Biomarkers; Breath Tests; Chlorine Compounds; Dinoprost; Disinfectants; Female; Halogenation; Humans; Inhalation Exposure; Linear Models; Male; Multivariate Analysis; Pneumonia; Pulmonary Surfactant-Associated Protein D; Respiratory Function Tests; Swimming Pools; Uteroglobin; Vascular Endothelial Growth Factor A; Water Pollutants, Chemical; Water Pollution, Chemical

One host susceptibility factor for ozone identified in epidemiologic studies is NAD(P)H quinone oxidoreductase 1 (NQO1). We hypothesized that after ozone exposure, NQO1 is required to increase 8-isoprostane (also known as F(2)-isoprostane) production, a recognized marker of ozone-induced oxidative stress, and to enhance airway inflammation and hyperresponsiveness. In this report, we demonstrate that in contrast to wild-type mice, NQO1-null mice are resistant to ozone and have blunted responses, including decreased production of F(2)-isoprostane and keratinocyte chemokine, decreased airway inflammation, and diminished airway hyperresponsiveness. Importantly, these results in mice correlate with in vitro findings in humans. In primary human airway epithelial cells, inhibition of NQO1 by dicumarol blocks ozone-induced F(2)-isoprostane production and IL-8 gene expression. Together, these results demonstrate that NQO1 modulates cellular redox status and influences the biologic and physiologic effects of ozone.

Topics: Animals; Bronchi; Bronchial Hyperreactivity; Bronchial Provocation Tests; Cells, Cultured; Chemokines; Dicumarol; Dinoprost; Enzyme Inhibitors; Epithelial Cells; Humans; Interleukin-8; Mice; Mice, Inbred C57BL; Mice, Knockout; NAD(P)H Dehydrogenase (Quinone); NADPH Dehydrogenase; Oxidants; Oxidation-Reduction; Oxidative Stress; Ozone; Pneumonia; Time Factors

We report here that 4-dibenzo[a,d]cyclohepten-5-ylidene-1-[4-(2H-tetrazol-5-yl)-butyl]-piperidine (AT-56) is an orally active and selective inhibitor of lipocalin-type prostaglandin (PG) D synthase (L-PGDS). AT-56 inhibited human and mouse L-PGDSs in a concentration (3-250 microm)-dependent manner but did not affect the activities of hematopoietic PGD synthase (H-PGDS), cyclooxygenase-1 and -2, and microsomal PGE synthase-1. AT-56 inhibited the L-PGDS activity in a competitive manner against the substrate PGH(2) (K(m) = 14 microm) with a K(i) value of 75 microm but did not inhibit the binding of 13-cis-retinoic acid, a nonsubstrate lipophilic ligand, to L-PGDS. NMR titration analysis revealed that AT-56 occupied the catalytic pocket, but not the retinoid-binding pocket, of L-PGDS. AT-56 inhibited the production of PGD(2) by L-PGDS-expressing human TE-671 cells after stimulation with Ca(2+) ionophore (5 microm A23187) with an IC(50) value of about 3 microm without affecting their production of PGE(2) and PGF(2alpha) but had no effect on the PGD(2) production by H-PGDS-expressing human megakaryocytes. Orally administered AT-56 (<30 mg/kg body weight) decreased the PGD(2) production to 40% in the brain of H-PGDS-deficient mice after a stab wound injury in a dose-dependent manner without affecting the production of PGE(2) and PGF(2alpha) and also suppressed the accumulation of eosinophils and monocytes in the bronco-alveolar lavage fluid from the antigen-induced lung inflammation model of human L-PGDS-transgenic mice.

Topics: Administration, Oral; Animals; Calcimycin; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprost; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Enzyme Inhibitors; Eosinophils; Humans; Intramolecular Oxidoreductases; Ionophores; Lipocalins; Male; Megakaryocytes; Membrane Proteins; Mice; Mice, Knockout; Monocytes; Pneumonia; Prostaglandin D2; Wound Healing; Wounds, Stab

To study whether patients with chronic obstructive pulmonary disease (COPD) at the same level of flow limitation but with different clinical phenotypes present different degrees of systemic and/or pulmonary inflammation.. We studied 15 male smokers without COPD (control group) and 39 males with COPD in stable clinical condition. The COPD patients were assigned to 2 groups based on the ratio of carbon monoxide diffusing capacity (DLCO) to alveolar volume (DLCO/VA) expressed as a percentage as follows: a) mainly emphysema (n = 15) and b) mainly chronic bronchitis (n = 24). Classification was determined by comparing both clinical features and diagnostic images.. Mean (SD) concentrations of interleukin 8 (IL-8) and 8-isoprostane in exhaled breath condensate (EBC) were significantly lower in patients with mainly emphysema (IL-8, 0.34 [0.70] pg/mL; 8-isoprostane, 0.07 [0.26] pg/mL) than in patients with chronic bronchitis (IL-8, 2.32 [3.10] pg/mL; 8-isoprostane, 1.77 [2.98] pg/mL) or in the controls (IL-8, 3.14 [4.59] pg/mL; 8-isoprostane, 1.92 [2.84] pg/mL); P < .05 for IL-8 comparisons and P < .01 for 8-isoprostane. IL-8, leukotriene B4, and 8-isoprostano in EBC correlated significantly with DLCO/VA (% of predicted) (r = 0.30, P < .05; r = 0.29, P < or = .05; and r = 0.46, P < .01, respectively) but not with forced expiratory volume in 1 second. There was a negative correlation between EBC and serum levels of both IL-8 (r = -0.31; P < .05) and 8-isoprostane (r = -0.51; P < .001). The correlation between leukotriene B4 concentrations in EBC and serum was not significant, however. No significant differences were found between smokers' and ex-smokers' serum levels of IL-8, leukotriene B4, 8-isoprostane in serum or EBC.. The results indicate that COPD patients with an emphysematous phenotype have a less intense inflammatory response and less oxidative stress in the lung.

Topics: Carbon Monoxide; Diffusion; Dinoprost; Emphysema; Humans; Hydrogen-Ion Concentration; Interleukin-8; Leukotriene B4; Male; Middle Aged; Oxidative Stress; Phenotype; Pneumonia; Pulmonary Disease, Chronic Obstructive; Smoking

Cardiac surgery using cardiopulmonary by-pass and, to a greater extent, lung resection, causes acute lung injury that is usually subclinical. Analysis of mediators in exhaled breath condensate is a promising means of monitoring inflammation in a variety of airway diseases but the contribution of the airway lining fluid from the lower respiratory tract is uncertain. We compared the analysis of markers of lung injury in exhaled breath condensate and bronchoalveolar lavage in endotracheally intubated patients before and after coronary artery bypass graft surgery with cardiopulmonary bypass and lobectomy. The neutrophil count and leukotriene B4 concentration in bronchoalveolar lavage fluid rose after coronary artery bypass graft surgery (p < 0.05), but there was no significant change in leukotriene B4, hydrogen peroxide, or hydrogen ion concentrations in exhaled breath condensate. By contrast, after lobectomy, the concentration in exhaled breath condensate of leukotriene B4, hydrogen peroxide and hydrogen ions rose significantly (p < 0.05). Exhaled breath condensate is a safe, noninvasive method of sampling the milieu of the distal lung and is sufficiently sensitive to detect markers of inflammation and oxidative stress in patients after lobectomy, but not after the milder insult associated with cardiac surgery.

Topics: Aged; Breath Tests; Bronchoalveolar Lavage Fluid; Cohort Studies; Coronary Artery Bypass; Dinoprost; F2-Isoprostanes; Female; Humans; Inflammation Mediators; Leukotriene B4; Male; Mass Spectrometry; Middle Aged; Pneumonia; Postoperative Complications; Probability; Prognosis; Risk Assessment; Sensitivity and Specificity; Severity of Illness Index; Statistics, Nonparametric

Exacerbations are an important feature of chronic obstructive pulmonary disease (COPD), accounting for a large proportion of health care costs. They are associated with increased airway inflammation and oxidative stress.. Concentrations of leukotriene B4 (LTB4), a marker of inflammation, and 8-isoprostane, a marker of oxidative stress, were measured in the exhaled breath condensate of 21 patients (11 M) with COPD during an exacerbation and 2 weeks after treatment with antibiotics. In 12 patients who had no further exacerbations these markers were also measured after 2 months.. LTB4 concentrations were raised during the COPD exacerbation (mean (SE) 15.8 (1.1) pg/ml and fell after treatment with antibiotics to 9.9 (0.9) pg/ml (p<0.0001). In 12 patients the level of LTB4 fell further from 10.6 (1.1) pg/ml to 8.5 (0.8) pg/ml (p<0.005) after 2 months. In 12 normal age matched subjects the LTB4 levels were 7.7 (0.5) pg/ml. Concentrations of 8-isoprostane were also increased during the exacerbation (13.0 (0.9) pg/ml) and fell after antibiotic treatment to 9.0 (0.6) pg/ml (p<0.0001). In 12 patients there was a further fall from 9.3 (0.7) pg/ml to 6.0 (0.7) pg/ml (p<0.001) after 2 months compared with normal subjects (6.2 (0.4) pg/ml).. Non-invasive markers of inflammation and oxidative stress are increased during an infective exacerbation of COPD and only slowly recover after treatment with antibiotics.

Topics: Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Antagonists; Adrenergic beta-Agonists; Aged; Anti-Bacterial Agents; Biomarkers; Breath Tests; Dinoprost; F2-Isoprostanes; Female; Forced Expiratory Volume; Humans; Leukotriene B4; Male; Oxidative Stress; Pneumonia; Pulmonary Disease, Chronic Obstructive; Vital Capacity

In the pathogenesis of bovine pneumonic pasteurellosis, immunodepression induced by stress or respiratory viral infection permits superinfection of the lungs with Pasteurella hemolytica, which results in exudative fibrinous pneumonia. Therefore, bovine pneumonic pasteurellosis was induced by sequential inoculations of calves with bovine herpes virus-1 (BHV-1, 3 X 10(7) tissue culture infectious dose 50 (TCID50)/nostril), followed 3 days later by challenge with P. hemolytica (15 X 10(9) colony-forming units (cfu) intratracheally). To study the pathogenic mechanisms of the disease, we examined the alterations in plasma prostaglandins (PG), thromboxane B2 (TxB2), histamine, serotonin and long-chain fatty acids (LCFA) during BHV-1 infection alone and after challenge exposure to P. hemolytica (i.e. during BHV-1-pneumonic pasteurellosis). BHV-1 infection alone markedly increased plasma PGE but modestly elevated PGF2 alpha, TxB2 and arachidonic, oleic and palmitic acids. After challenge with P. hemolytica, the levels of plasma arachidonic, oleic, and palmitic acids, together with PGE and 6-keto-PGF1 alpha, were elevated markedly, in association with clinical signs of bovine pneumonic pasteurellosis. However, PGF2 alpha and stearic acid increased only transiently whereas TxB2 was unchanged from the control. On the other hand, plasma linoleic acid, histamine and serotonin remained unaltered. These results indicate enhanced eicosanoid biosynthesis and disproportionate rises in LCFA during BHV-1 pneumonic pasteurellosis. While LCFA are needed for energy metabolism, eicosanoids may mediate the immunologic, inflammatory and pulmonary vascular reactions leading to the clinico-pathologic features of BHV-1 pneumonic pasteurellosis.

Topics: Animals; Body Temperature; Cattle; Cattle Diseases; Dinoprost; Eicosanoic Acids; Fatty Acids; Herpesvirus 1, Bovine; Oxygen Consumption; Pasteurella; Pneumonia; Prostaglandins E; Prostaglandins F; Thromboxane B2