8-hydroxy-2--deoxyguanosine and Pneumonia

Previous studies have demonstrated that 8-hydroxydeoxyguanosine (8-OHdG) exerted key roles in various pulmonary diseases, but the evidence for its role in community-acquired pneumonia (CAP) was lacking. The goal of this research was to evaluate the correlations of serum 8-OHdG with the severity and prognosis among patients with CAP through a prospective cohort study. A total of 239 patients with CAP and 239 healthy participants were enrolled. Fasting blood samples were collected. 8-OHdG and inflammatory cytokines were measured by ELISA. On admission, serum 8-OHdG was significantly increased in patients with CAP compared with control subjects. Besides, serum 8-OHdG was incrementally increased in line with CAP severity scores. Pearson correlative analysis found that serum 8-OHdG was correlated with clinical characteristics and inflammatory cytokines in patients with CAP. Linear and logistic regression analysis showed that serum 8-OHdG was positively associated with CAP severity scores. Furthermore, the prognostic outcomes were tracked. Higher serum 8-OHdG on admission increased the risks for intensive care unit admission, mechanical ventilation, vasoactive agent usage, death, and longer hospital stay among patients with CAP. Serum 8-OHdG combination with confusion, respiratory rate, blood pressure, and age ≥65 y or pneumonia severity index had stronger predictive powers for death than single 8-OHdG, CAP severity scores, or several inflammatory cytokines in patients with CAP. These results indicated that serum 8-OHdG is positively associated with the severity and poor prognosis in patients with CAP, demonstrating that 8-OHdG may be involved in the pathophysiology process of CAP.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Biomarkers; Community-Acquired Infections; Critical Care; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Humans; Length of Stay; Male; Middle Aged; Oxidative Stress; Pneumonia; Prognosis; Prospective Studies; Respiration, Artificial; Severity of Illness Index

We investigated the effects of nickel oxide nanoparticles (NiONPs) on the pulmonary inflammopathology. NiONPs were intratracheally installed into mice, and lung injury and inflammation were evaluated between 1 and 28 days. NiONPs caused significant increases in LDH, total protein, and IL-6 and a decrease in IL-10 in the BALF and increases in 8-OHdG and caspase-3 in lung tissues at 24 h. Airway inflammation was present in a dose-dependent manner from the upper to lower airways at 24 h of exposure as analyzed by SPECT. Lung parenchyma inflammation and small airway inflammation were observed by CT after NiONP exposure. 8-OHdG in lung tissues had increased with formation of fibrosis at 28 days. Focal adhesion was the most important pathways identified at 24 h as determined by protemics, whereas glutathione metabolism was the most important identified at 28 days. Our results demonstrated the pulmonary inflammopathology caused by NiONPs based on image-to-biochemical approaches.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Bronchoalveolar Lavage Fluid; Deoxyguanosine; Female; Lung Injury; Metal Nanoparticles; Mice; Mice, Inbred BALB C; Nickel; Pneumonia; Proteome

Pulmonary fibrosis, a progressive and lethal lung disease characterized by inflammation and accumulation of extracellular matrix components, is a major therapeutic challenge for which new therapeutic strategies are warranted. Cyclooxygenase (COX) inhibitors have been previously utilized to reduce inflammation. Histamine H4 receptor (H4R), largely expressed in hematopoietic cells, has been identified as a novel target for inflammatory and immune disorders. The aim of this study was to evaluate the effect of JNJ7777120 (1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine), a selective H4R antagonist, and naproxen, a well known nonsteroidal anti-inflammatory drug, and their combination in a murine model of bleomycin-induced fibrosis. Bleomycin (0.05 IU) was instilled intratracheally to C57BL/6 mice, which were then treated by micro-osmotic pump with vehicle, JNJ7777120 (40 mg/kg b.wt.), naproxen (21 mg/kg b.wt.), or a combination of both. Airway resistance to inflation, an index of lung stiffness, was assessed, and lung specimens were processed for inflammation, oxidative stress, and fibrosis markers. Both drugs alone were able to reduce the airway resistance to inflation induced by bleomycin and the inflammatory response by decreasing COX-2 and myeloperoxidase expression and activity and thiobarbituric acid-reactive substance and 8-hydroxy-2'-deoxyguanosine production. Lung fibrosis was inhibited, as demonstrated by the reduction of tissue levels of transforming growth factor-β, collagen deposition, relative goblet cell number, and smooth muscle layer thickness. Our results demonstrate that both JNJ7777120 and naproxen exert an anti-inflammatory and antifibrotic effect that is increased by their combination, which could be an effective therapeutic strategy in the treatment of pulmonary fibrosis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Anti-Inflammatory Agents; Bleomycin; Collagen; Cyclooxygenase 2; Deoxyguanosine; Disease Models, Animal; Goblet Cells; Indoles; Lung; Mice; Muscle, Smooth; Naproxen; Oxidative Stress; Peroxidase; Piperazines; Pneumonia; Pulmonary Fibrosis; Thiobarbituric Acid Reactive Substances; Transforming Growth Factor beta

Silver nanoparticles (AgNP) have been associated with the exacerbation of airway hyperresponsiveness. However, the allergenicity and toxicology of AgNP in healthy and allergic individuals are unclear. We investigated the pathophysiological responses to AgNP inhalation in a murine model of asthma. Continuous and stable levels of 33 nm AgNP were maintained at 3.3 mg/m(3) during the experimental period. AgNP exposure concomitant with ovalbumin challenge increased the enhanced pause (Penh) in the control and allergic groups. AgNP evoked neutrophil, lymphocyte and eosinophil infiltration into the airways and elevated the levels of allergic markers (immunoglobulin E [IgE] and leukotriene E4 [LTE4]), the type 2 T helper (Th2) cytokine interleukin-13 (IL-13), and oxidative stress (8-hydroxy-2'-deoxyguanosine [8-OHdG]) in healthy and allergic mice. Bronchocentric interstitial inflammation was observed after AgNP inhalation. After inhalation, the AgNP accumulated predominantly in the lungs, and trivial amounts of AgNP were excreted in the urine and feces. Furthermore, the AgNP induced inflammatory responses in the peritoneum. The inhalation of AgNP may present safety concerns in healthy and susceptible individuals.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Inhalation; Animals; Deoxyguanosine; Female; Metal Nanoparticles; Mice; Mice, Inbred BALB C; Organ Specificity; Ovalbumin; Oxidative Stress; Pneumonia; Respiratory Hypersensitivity; Silver

The total surface area is known to be an effective exposure metric for predicting the lung toxicity of low solubility nanoparticles (NPs). However, if NPs are dissolved quickly enough in the lungs, the mass may be correlated with the toxicity. Recent studies have found that the toxicity of zinc oxide (ZnO) NPs was caused by the release of zinc ions. Thus, we hypothesized that mass could be used as an exposure metric for the toxicity of ZnO NPs. Healthy Sprague-Dawley rats were exposed to a low, moderate, or high dose of 35 and 250 nm ZnO particles or filtered air. Bronchoalveolar lavage fluid was collected to determine lung inflammation, injury and oxidative stress. The lung inflammation induced by ZnO particles according to different concentration metrics, including number, mass and surface area, was compared. The mass concentration was significantly correlated with the percentage of neutrophils (R(2) = 0.84), number of neutrophils (R(2) = 0.84) and total cells (R(2) = 0.73). Similarly, surface area concentration was significantly correlated with the percentage of neutrophils (R(2) = 0.94), number of neutrophils (R(2) = 0.81) and total cells (R(2) = 0.76). There was no correlation between the number and lung inflammation. We found that both mass and surface area were effective as metrics for the toxicity of ZnO NPs, although only surface area was previously indicated to be an effective metric. Our results are also consistent with recent study results that ZnO NPs and released zinc ions may play a role mediating the toxicity of NPs.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Bronchoalveolar Lavage Fluid; Chromatography, Liquid; Deoxyguanosine; Inhalation Exposure; L-Lactate Dehydrogenase; Leukocyte Count; Male; Metal Nanoparticles; Microscopy, Electron, Transmission; Neutrophils; Particle Size; Pneumonia; Proteins; Rats; Rats, Sprague-Dawley; Surface Properties; Tandem Mass Spectrometry; X-Ray Diffraction; Zinc Oxide

Cigarette smoke (CS) induces recruitment of inflammatory cells in the lungs leading to the generation of reactive oxygen species (ROS), which are involved in lung inflammation and injury. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a multimeric system that is responsible for ROS production in mammalian cells. We hypothesized that NADPH oxidase-derived ROS play an important role in lung inflammation and injury and that targeted ablation of components of NADPH oxidase (p47(phox) and gp91(phox)) would protect lungs against the detrimental effects of CS. To test this hypothesis, we exposed p47(phox-/-) and gp91(phox-/-) mice to CS and examined inflammatory response and injury in the lung. Surprisingly, although CS-induced ROS production was decreased in the lungs of p47(phox-/-) and gp91(phox-/-) mice compared with wild-type mice, the inflammatory response was significantly increased and was accompanied by development of distal airspace enlargement and alveolar destruction. This pathological abnormality was associated with enhanced activation of the TLR4-nuclear factor-kappaB pathway in response to CS exposure in p47(phox-/-) and gp91(phox-/-) mice. This phenomenon was confirmed by in vitro studies in which treatment of peritoneal macrophages with a nuclear factor-kappaB inhibitor reversed the CS-induced release of proinflammatory mediators. Thus, these data suggest that genetic ablation of components of NADPH oxidase enhances susceptibility to the proinflammatory effects of CS leading to airspace enlargement and alveolar damage.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Cells, Cultured; Deoxyguanosine; Lipid Peroxidation; Lung; Macrophages, Peritoneal; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Mice, Knockout; NADPH Oxidase 2; NADPH Oxidases; NF-kappa B; Nicotiana; Pneumonia; Pulmonary Emphysema; Reactive Oxygen Species; Smoke; Toll-Like Receptor 4

Ozone (O3) is a well-known oxidant pollutant present in photochemical smog. Although ozone is suspected to be a respiratory carcinogen it is not regulated as a carcinogen in most countries. The genotoxic and inflammatory effects of ozone were investigated in female mice exposed to ozone for 90 min. The tail moment in bronchoalveolar lavage (BAL) cells from BALB/c mice was determined by the comet assay as a measure of DNA strand breaks. Within the first 200 min after exposure, the BAL cells from the mice exposed to 1 or 2 ppm ozone had 1.6- and 2.6-fold greater tail moments than unexposed mice. After 200 min there was no effect. It could be ruled out that the effect during the first 200 min was due to major infiltration of lymphocytes or neutrophils. Unexpectedly, ozone had no effect on the content of 8-oxo-deoxyguanosine (8-oxo-dG) in nuclear DNA or on oxidised amino acids in the lung tissue. The mRNA level of the repair enzyme ERCC1 was not increased in the lung tissue. Inflammation was measured by the cytokine mRNA level in lung homogenates. An up to 150-fold induction of interleukin-6 (IL-6) mRNA was detected in the animals exposed to 2 ppm ozone compared to the air-exposed control mice. Also at 1 ppm ozone, the IL-6 mRNA was induced. The large induction of IL-6 mRNA in the lung took place after DNA strand breaks were induced in BAL. This does not support the notion that inflammatory reactions are the cause of DNA damage. To determine whether these exposures were mutagenic, Muta Mice were exposed to 2 ppm ozone, 90 min per day for 5 days. No treatment-related mutations could be detected in the cII transgene. These results indicate that a short episode of ozone exposure at five times the threshold limit value (TLV) in US induces lung inflammatory mediators and DNA damage in the cells in the lumen of the lung. This was not reflected by an induction of mutations in the lung of Muta Mice.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Administration, Inhalation; Animals; Anti-Bacterial Agents; Bacterial Proteins; Bacteriocins; Bronchi; Bronchoalveolar Lavage Fluid; Cell Survival; Comet Assay; Deoxyguanosine; DNA Damage; DNA-Binding Proteins; DNA, Single-Stranded; Endonucleases; Female; Interleukin-6; Lung; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Ozone; Peptides; Pneumonia; Proteins; RNA, Messenger; Transcription Factors; Viral Proteins