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Russell P Bowler

Publications and source records attributed to Russell P Bowler.

34 records · Page 2Linked to original sources
PubMed2004

Proteomic analysis of pulmonary edema fluid and plasma in patients with acute lung injury.

Proteomics is the large-scale analysis of protein profiles. This approach has not yet been reported in the study of acute lung injury (ALI). This study details protein profiles in plasma and pulmonary edema fluid (EF) from 16 ALI patients and plasma and bronchoalveolar lavage fluid (BALF) from 12 normal subjects. More than 300 distinct protein spots were evident in the EF and BALF of both normal subjects and ALI patients. Of these, 158 were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. In the plasma and EF protein profile of ALI patients, there were multiple qualitative changes. For instance, in all normal subjects, but in only one of the ALI patients, seven distinct surfactant protein A isoforms were evident. Nearly all ALI patients also had protein spots that indicate truncation or other posttranslational modifications. Several of these novel changes could serve as new biomarkers of lung injury.

Adult↗
PubMed2004

Extracellular superoxide dismutase (EC-SOD) binds to type i collagen and protects against oxidative fragmentation.

The antioxidant enzyme extracellular superoxide dismutase (EC-SOD) is mainly found in the extracellular matrix of tissues. EC-SOD participates in the detoxification of reactive oxygen species by catalyzing the dismutation of superoxide radicals. The tissue distribution of the enzyme is particularly important because of the reactive nature of its substrate, and it is likely essential that EC-SOD is positioned at the site of superoxide production to prevent adventitious oxidation. EC-SOD contains a C-terminal heparin-binding region thought to be important for modulating its distribution in the extracellular matrix. This paper demonstrates that, in addition to binding heparin, EC-SOD specifically binds to type I collagen with a dissociation constant (K(d)) of 200 nm. The heparin-binding region was found to mediate the interaction with collagen. Notably, the bound EC-SOD significantly protects type I collagen from oxidative fragmentation. This expands the known repertoire of EC-SOD binding partners and may play an important physiological role in preventing oxidative fragmentation of collagen during oxidative stress.

Animals↗
PubMed2004

Oxidative stress in the pathogenesis of asthma.

Asthma affects 5% to 10% of the population of the United States. In asthmatics, oxidative stress occurs not only as a result of inflammation but also from environmental exposure to air pollution. The specific localization of antioxidants in the lung and the adaptive changes during asthma underscore the importance of oxidative stress, and therapeutic interventions that decrease exposure to environmental reactive oxygen species or augment endogenous antioxidant defenses might be beneficial as adjunctive therapies in asthmatic patients.

Antioxidants↗
PubMed2004

Physiologic correlates of distal lung inflammation in asthma.

BACKGROUND: The distal lung is an important site of inflammation in asthma. Maximal midexpiratory flows and the ratio of maximal:partial flows are purported to reflect distal lung function. OBJECTIVE: We obtained contemporaneous transbronchial biopsy, spirometry, and plethysmography to describe more accurately the relationship between physiology and distal lung inflammation in asthma. METHODS: Ten patients with severe, persistent asthma with mean +/- SE FEV(1) of 2.8 +/- 0.2 L and overnight fall in FEV(1) of 22.8% +/- 3.8% underwent transbronchial biopsy, spirometry, maximal midexpiratory flows, maximal:partial ratio, and lung volumes, all at 4 am. Morphometric analysis was performed after immunohistochemistry for eosinophils, lymphocytes, macrophages, mast cells, and neutrophils. RESULTS: Maximal midexpiratory flows, maximal:partial ratio, FEV(1), and forced vital capacity were not significantly correlated with alveolar tissue inflammation. However, the degree of eosinophilic alveolar inflammation was significantly and positively correlated with both total lung capacity (Spearman rho=0.70; P=.03) and thoracic gas volume (rho=0.62; P=.05). Correlation between eosinophils and other lung volumes was not observed. Other inflammatory cell types did not correlate with lung volumes. CONCLUSION: Purported physiologic measures of distal lung function are poorly correlated with histopathologic evidence of distal lung inflammation. Measurement of lung volumes more accurately reflects eosinophilic distal lung inflammation.

Adult↗
PubMed2004

Lung inflation with direct injection of agarose: a technique for simultaneous molecular and morphometric measurements.

The usual methods for preparing lungs for morphologic study involve the instillation of fixatives that modifyproteins and RNA such that the tissue is unsuitable for molecular studies. To develop a technique suitable for molecular studies, pieces of adult rat lungs were infiltrated with agarose, glutaraldehyde, or paraformaldehyde and the consistency of alveolar inflation was compared to lungs inflated with 10% formalin. Only direct injection with 1% agarose resulted in comparable inflation of lung tissue and preserved RNA and protein. Thus, this technique enables simultaneous molecular and morphometric analysis of the lung on small pieces of lung tissue in heterogeneous lung diseases.

Animals↗
PubMed2004

The role of oxidative stress in chronic obstructive pulmonary disease.

Tobacco smoke is the number one risk factor for chronic obstructive pulmonary disease (COPD) and contains a high concentration of oxidants. The lung has a high concentration of antioxidants and antioxidant enzymes; however, COPD patients show evidence of increased oxidative stress suggesting that endogenous antioxidants may be insufficient to prevent oxidative damage from cigarette smoke. The consequences of increased oxidative stress in the lung include increased transcription of inflammatory genes, increased protease activity, and increased mucus secretion. Oxidative stress is often associated with impaired skeletal muscle function and may be one of the causes of glucocorticoid resistance. While current pharmacologic approaches to the treatment of chronic obstructive pulmonary disease do not commonly include antioxidants, preclinical studies involving animal models suggest that antioxidant superoxide dismutase mimetics offer a potential new therapeutic approach to the prevention and treatment of chronic obstructive pulmonary disease.

Antioxidants↗
PubMed2004

Colocalization of eNOS and the catalytic subunit of PKA in endothelial cell junctions: a clue for regulated NO production.

Localization and coordinate phosphorylation/dephosphorylation of endothelial nitric oxide synthase (eNOS) are critical determinants for the basal and stimulated production of nitric oxide. Several phosphorylation sites in eNOS have been identified as targets of the cAMP-dependent protein kinase A (PKA). Basal eNOS activity is also regulated by interaction with caveolin-1, the major coat protein of caveolae. In the present study we have examined in rat aorta endothelium the subcellular steady-state distribution of eNOS, the catalytic subunit of PKA (PKA-c), and caveolin-1. Basal eNOS expression was found in two distinct locations, the endothelial cell surface and the Golgi complex. Cell surface eNOS was equally distributed over caveolar and non-caveolar membranes but was 2.5-fold enriched on luminal lamellipodia located at endothelial cell contacts. PKA-c colocalized with eNOS in the lamellipodia, whereas caveolin-1 was absent from these membrane domains. PKA-c was also found associated with cell surface caveolae and with tubulovesicular membranes of Golgi complex and endosomes. The topological proximity of eNOS with the catalytic subunit of PKA in restricted intracellular locations may provide mechanisms for differential PKA-mediated eNOS regulation.

Animals↗
PubMed2003

Evidence for extracellular superoxide dismutase as a mediator of hemorrhage-induced lung injury.

Hemorrhage results in excessive production of superoxide that is associated with severe lung injury. We examined whether the superoxide dismutase (SOD) mimetic manganese(III) mesotetrakis (di-N-ethylimidazole) porphyrin (AEOL 10150) could attenuate this lung injury and whether extracellular (EC)-SOD-deficient mice would have increased hemorrhage-induced lung injury. Compared with wild-type mice, EC-SOD-deficient mice had increased lung neutrophil accumulation, a 3.9-fold increase in myeloperoxidase activity, a 1.5-fold increase in nuclear factor (NF)-kappaB activation, and a 1.5-fold increase in lipid peroxidation 1 h after hemorrhage. Pretreatment with AEOL 10150 did not attenuate neutrophil accumulation but significantly reduced NF-kappaB activation and lipid peroxidation in both wild-type and EC-SOD-deficient mice. The increase in hemorrhage-induced neutrophil accumulation in the lungs of EC-SOD-deficient mice suggests that EC-SOD might play a role in mediating neutrophil recruitment to the lung.

Aconitate Hydratase↗
PubMed2003

Pulmonary edema fluid antioxidants are depressed in acute lung injury.

OBJECTIVE: To test the hypothesis that low concentrations of distal airspace water-soluble antioxidants are associated with acute lung injury. DESIGN: Prospective, cohort study. SETTING: Medical intensive care unit of two tertiary care hospitals. SUBJECTS: Subjects were 29 patients with acute lung injury and 23 normal, healthy, volunteers. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Pulmonary edema fluid from subjects with acute lung injury was aspirated immediately after intubation. Compared with the bronchoalveolar lavage from normal subjects (corrected for dilution using urea concentrations), undiluted edema fluid from acute lung injury subjects had significantly lower concentrations of the antioxidants urate (757 +/- 232 microM vs. 328 +/- 75 microM), glutathione (138 +/- 25 microM vs. 7 +/- 4 microM), and ascorbate (85 +/- 21 microM vs. 27 +/- 10 microM). CONCLUSIONS: Acute lung injury is associated with decreased concentrations of water-soluble antioxidants in the distal airspaces. In acute lung injury, the distal airspace antioxidants ascorbate, urate, and glutathione may play a role in attenuating lung injury.

Adult↗
PubMed2003

Interaction among nitric oxide, reactive oxygen species, and antioxidants during endotoxemia-related acute renal failure.

Acute renal failure (ARF) during sepsis is associated with increased nitric oxide (NO) and oxygen radicals, including superoxide (O(2)(-)). Because O(2)(-) reacts with NO in a rapid manner, it plays an important role in modulating NO levels. Therefore, scavenging of O(2)(-) by superoxide dismutase (SOD) may be critical for preserving NO bioavailability. In mice, substantial renal extracellular SOD (EC-SOD) expression implies its important role in scavenging O(2)(-) in the kidney. We hypothesized that during endotoxemic ARF, EC-SOD is decreased in the kidney, resulting in increased O(2)(-) and thus decreased vascular NO bioavailability with resultant renal vasoconstriction and ARF. In the present study, normotensive endotoxemic ARF was induced in mice using lipopolysaccharide (LPS; 5 mg/kg ip). Sixteen hours after LPS, glomerular filtration rate (GFR; 50 +/- 16 vs. 229 +/- 21 microl/min, n = 8, P < 0.01) and renal blood flow (RBF; 0.61 +/- 0.10 vs. 0.86 +/- 0.05 ml/min, n = 8, P < 0.05) were subsequently decreased. EC-SOD mRNA and protein expression in endotoxemic kidneys were decreased at 16 h compared with controls. A catalytic antioxidant, metalloporphyrin, reversed the deleterious effects of endotoxemia on renal function as GFR (182 +/- 40 vs. 50 +/- 16 microl/min, n = 6, P < 0.01) and RBF (1.08 +/- 0.10 vs. 0.61 +/- 0.10 ml/min, n = 6, P < 0.05) were preserved. Similar results were obtained with tempol, a chemically dissimilar antioxidant. Specific inhibition of inducible nitric oxide synthase (iNOS), l-N(6)-(1-iminoethyl)-lysine, reversed the renal protective effect on GFR and RBF observed with antioxidant treatment during endotoxemia. In summary, renal EC-SOD expression is decreased during endotoxemia. Antioxidant therapy preserved GFR and RBF during endotoxemia. The reversal of this protective effect by inhibition of iNOS suggests the importance of the bioavailability of NO for preservation of renal function during early endotoxemia.

Acute Kidney Injury↗
PubMed2002

Oxidative stress in airways: is there a role for extracellular superoxide dismutase?

Airways are exposed to high levels of environmental oxidants, yet they also have enriched extracellular antioxidants. Airways disease such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease have evidence of increased oxidative stress, suggesting that reactive oxygen and nitrogen species may overwhelm antioxidant defenses in airway diseases. Extracellular superoxide dismutase is abundant in pulmonary tissues and protects the lung from increased oxidative stress; however, its role in asthma and other airway diseases has not been fully elucidated. Proteolytic processing of extracellular superoxide dismutase decreases its affinity for the extracellular matrix and may be a mechanism to regulate its distribution during conditions of inflammation or oxidative stress.

Animals↗
PubMed2002

A catalytic antioxidant (AEOL 10150) attenuates expression of inflammatory genes in stroke.

Oxidative stress is a major source of injury from cerebral ischemia and reperfusion. We hypothesized that a catalytic antioxidant AEOL 10150 [manganese (III) meso-tetrakis (di-N-ethylimidazole) porphyrin] would attenuate changes in brain gene expression in a mouse model of transient middle cerebral artery occlusion (MCAO). C57BL/6J mice were subjected to either sham surgery or 60 min of right MCAO. AEOL 10150 or phosphate-buffered saline was given intravenously 5 min after onset of reperfusion (n = 6 per group). Six hours later, parenchyma within the MCA distribution was harvested. RNA from the six brains in each group was pooled and mRNA expression determined using an Affymetrix murine MG_U74A v. 2.0 expression microarray. Each experiment was performed three times. The largest changes in expression occurred in stress response and inflammatory genes such as heat shock protein, interleukin-6, and macrophage inflammatory protein-2. Treatment with AEOL 10150 attenuated only the increase in expression of inflammatory genes. This suggests that AEOL 10150 protects brain by attenuating the immune response to ischemia and reperfusion.

Animals↗
PubMed2002

Furin proteolytically processes the heparin-binding region of extracellular superoxide dismutase.

Extracellular superoxide dismutase (EC-SOD) is an antioxidant enzyme that attenuates brain and lung injury from oxidative stress. A polybasic region in the carboxyl terminus distinguishes EC-SOD from other superoxide dismutases and determines EC-SOD's tissue half-life and affinity for heparin. There are two types of EC-SOD that differ based on the presence or absence of this heparin-binding region. It has recently been shown that proteolytic removal of the heparin-binding region is an intracellular event (Enghild, J. J., Thogersen, I. B., Oury, T. D., Valnickova, Z., Hojrup, P., and Crapo, J. D. (1999) J. Biol. Chem. 274, 14818-14822). By using mammalian cell lines, we have now determined that removal of the heparin-binding region occurs after passage through the Golgi network but before being secreted into the extracellular space. Specific protease inhibitors and overexpression of intracellular proteases implicate furin as a processing protease. In vitro experiments using furin and purified EC-SOD suggest that furin proteolytically cleaves EC-SOD in the middle of the polybasic region and then requires an additional carboxypeptidase to remove the remaining lysines and arginines. A mutation in Arg(213) renders EC-SOD resistant to furin processing. These results indicate that furin-dependent processing of EC-SOD is important for determining the tissue distribution and half-life of EC-SOD.

Amino Acid Sequence↗
PubMed2002

Oxidative stress in allergic respiratory diseases.

There is ample evidence that allergic disorders, such as asthma, rhinitis, and atopic dermatitis, are mediated by oxidative stress. Excessive exposure to reactive oxygen and nitrogen species is the hallmark of oxidative stress and leads to damage of proteins, lipids, and DNA. Oxidative stress occurs not only as a result of inflammation but also from environmental exposure to air pollution and cigarette smoke. The specific localization of antioxidant enzymes in the lung and the rapid reaction of nitric oxide with reactive oxygen species, such as superoxide, suggest that antioxidant enzymes might also function as cell-signaling agents or regulators of cell signaling. Therapeutic interventions that decrease exposure to environmental reactive oxygen species or augment endogenous antioxidant defenses might be beneficial as adjunctive therapies for allergic respiratory disorders.

Antioxidants↗
PubMed2002

Role of extracellular superoxide dismutase in bleomycin-induced pulmonary fibrosis.

Bleomycin administration results in well-described intracellular oxidative stress that can lead to pulmonary fibrosis. The role of alveolar interstitial antioxidants in this model is unknown. Extracellular superoxide dismutase (EC-SOD) is the primary endogenous extracellular antioxidant enzyme and is abundant in the lung. We hypothesized that EC-SOD plays an important role in attenuating bleomycin-induced lung injury. Two weeks after intratracheal bleomycin administration, we found that wild-type mice induced a 106 +/- 25% increase in lung EC-SOD. Immunohistochemical staining revealed that a large increase in EC-SOD occurred in injured lung. Using mice that overexpress EC-SOD specifically in the lung, we found a 53 +/- 14% reduction in bleomycin-induced lung injury assessed histologically and a 17 +/- 6% reduction in lung collagen content 2 wk after bleomycin administration. We conclude that EC-SOD plays an important role in reducing the magnitude of lung injury from extracellular free radicals after bleomycin administration.

Animals↗