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Biomedical subjects

A J Ghio

Publications and source records attributed to A J Ghio.

At least 91 records · Page 5Linked to original sources
PubMed1994

Synthetic surfactant scavenges oxidants and protects against hyperoxic lung injury.

Injury and mortality after exposure to 100% oxygen can be diminished by surfactants that may operate by mechanisms other than those responsible for surface tension effects. We tested the hypotheses that 1) synthetic surfactant and its components function as antioxidants in vitro and 2) decrements in hyperoxic injury after treatment with a surfactant and its components are associated with decreases in oxidative stress to the lung. A synthetic surfactant (Exosurf) and its non-surface-active components tyloxapol and cetyl alcohol were incubated in an iron-containing hydroxyl radical-generating system to determine their abilities to prevent oxidation of deoxyribose. Doses of tyloxapol, cetyl alcohol, and artificial surfactant diminished the absorbance of thiobarbituric acid-reactive products of deoxyribose. Similarly, tyloxapol, cetyl alcohol, and the surfactant decreased hydroxylated products of salicylate in the same system. Rats were instilled intratracheally with saline, tyloxapol, tyloxapol plus cetyl alcohol, or artificial surfactant and immediately exposed to air or 100% oxygen. After 61 h of oxygen exposure, pleural fluid volume and wet-to-dry lung weight ratios were decreased in animals treated with surfactant and/or its components. There were also decrements in thiobarbituric acid-reactive products of lung tissue. In separate experiments, mean survival of saline-treated rats exposed to 100% oxygen was 67.3 +/- 8.1 h and > 96 h for rats given the surfactant or its components. We conclude that tyloxapol, cetyl alcohol, and Exosurf can function as antioxidants in vitro and their in vivo instillation is associated with reduction in measures of hyperoxic injury, oxidized tissue products, and mortality.

Animals↗
PubMed1994

Hydroxyl radicals are formed in the rat lung after asbestos instillation in vivo.

The hydroxyl radical (.OH) has been implicated as a cause of lung injury following asbestos exposure. However, despite in vitro evidence associating asbestos with .OH production, there has been no demonstration of such generation in vivo. We tested the hypothesis that .OH is formed in the lungs of rats exposed to asbestos in vivo by using salicylate as a free radical trap. Asbestos was instilled intratracheally, and control rats were sham-exposed. Six to seven days after exposure, the rats were given salicylate, the lungs were isolated, and salicylate hydroxylation products (2,3- and 2,5-dihydroxybenzoic acid), reflecting .OH production, were measured. There was significantly more 2,3-dihydroxybenzoic acid in asbestos-exposed lungs compared with control lungs (2.32 +/- 0.360 nmol/lung versus 0.292 +/- 0.125, respectively, P < 0.001) and 2,5-dihydroxybenzoic acid (9.69 +/- 1.65 nmol/lung versus 2.63 +/- 0.274, respectively, P < 0.001). To demonstrate that the dihydroxybenzoic acid was actually formed in the lungs, the lungs from asbestos-exposed and control rats were isolated and perfused with either salicylate or 2,3-dihydroxybenzoic acid. In the lungs perfused with salicylate, 2,3- and 2,5-dihydroxybenzoic acids were detectable only in asbestos-exposed lungs. In the isolated lungs perfused with 2,3-dihydroxybenzoic acid, there was no significant difference in 2,3-dihydroxybenzoic acid between asbestos-exposed and control lungs. We conclude that asbestos stimulates .OH production in lungs in vivo.

Animals↗
PubMed1993

Lavage phospholipid concentration after silica instillation in the rat is associated with complexed [Fe3+] on the dust surface.

The basis for surfactant accumulation after silica exposure is not known. As a result of an association between elevations in extracellular surfactant and oxidant exposures, we tested the hypothesis that (1) surfactant-enriched material can function as an in vitro target for oxidants catalyzed by Fe3+ complexed to the surface of silica, and (2) in vivo alveolar accumulation of surfactant after exposure of the lower respiratory tract to silica is associated with the concentration of Fe3+ complexed to the dust surface. Surfactant-enriched material was incubated in both chemical and cellular systems with either Gey's balanced salt solution, acid-washed silica, deferoxamine-treated silica, wetted silica, or iron-loaded silica. The absorbance of oxidized products was associated with concentrations of complexed iron on the surface of the silica dust. Rats (n = 10/group) were intratracheally instilled with either normal saline, 6.0 mg acid-washed silica, 6.0 mg deferoxamine-treated silica, 6.0 mg wetted silica, or 6.0 mg iron-loaded silica. Ninety-six hours after tracheal instillation, silica significantly increased extracellular surfactant as reflected by lipid phosphorous in the total lavage fluid. Lipid accumulation was associated with concentrations of surface complexed iron on the surface of the silica.

Animals↗
PubMed1992

Generation of hydroxyl radical by crocidolite asbestos is proportional to surface [Fe3+].

Differences among fibrous silicates to effect injury in biological systems have been postulated to reflect oxidant generation by structural iron within the crystal lattice of amphiboles. Iron is also coordinated to the surface of all silicates in concentrations which depend on the density of acidic functional groups. We tested the hypothesis that oxidant generation by crocidolite is proportional to surface-complexed iron rather than variance in the lattice concentrations of this transition metal. Surface iron was quantified after its reduction to Fe2+ and chelation by citrate. Thiobarbituric acid (TBA) reactive products and dihydroxybenzoic acid products of salicylate were employed as indices of nonspecific oxidant and hydroxyl radical generation, respectively. Surface iron, TBA reactive products, and dihydroxybenzoic acid products all diminished after pretreatment of crocidolite with the metal chelator deferoxamine in concentrations varying from 0 to 250 mM. Inclusion of deferoxamine in the reaction mixture provided similar results of diminishing both TBA reactive products and dihydroxybenzoic acid generation. We conclude that oxidant generation by crocidolite is proportional to surface concentrations of iron which can be chelated using deferoxamine. The design of synthetic fibers without health effects after exposure will likely necessitate decreasing the number of surface acidic functional groups to diminish the capacity to complex iron (i.e., minimize the percentage SiO2).

Asbestos↗
PubMed1992

Role of surface complexed iron in oxidant generation and lung inflammation induced by silicates.

Inhalation of silicates induces a variety of lung diseases in humans. The molecular mechanism(s) by which these dusts cause disease is not known. Because several naturally occurring mineral oxides have large amounts of transition metal ions on their surfaces, we tested the hypothesis that surface complexation of iron may be an important determinant of their ability to induce disease. Silica, crocidolite, kaolinite, and talc complexed considerable concentrations of Fe3+ onto their surfaces from both in vitro and in vivo sources. The potential biological importance of iron complexation was assessed by examining the relationship between surface [Fe3+] and the ability of silicates to mediate oxidative degradation of deoxyribose in vitro, induce a respiratory burst and elicit leukotriene B4 (LTB4) release by alveolar macrophages (AM) in vitro, and cause acute alveolitis after intratracheal insufflation. For these studies, three varieties of silicate dusts were used: iron-loaded, wetted (unmodified), and deferoxamine-treated to remove Fe3+. The ability of silicates to catalyze oxidant generation in an ascorbate/H2O2 system in vitro, to trigger respiratory burst activity and LTB4 release by AM, and to induce acute lung inflammation in the rat all increased with surface complexed Fe3+. The results of these studies suggest that surface complexation of iron may be an important determinant in the pathogenesis of disease after silicate exposure.

Adsorption↗
PubMed1992

Pulmonary oxalate deposition associated with Aspergillus niger infection. An oxidant hypothesis of toxicity.

Tissue injury by Aspergillus niger infection is associated with the deposition of calcium oxalate crystals. Oxalate is recognized to function as a ligand for numerous metal cations and will react with ferric ion to form a coordination complex. We describe oxalate deposition in the lung of a patient with A. niger infection and quantify surface-complexed Fe3+. Crystals collected from lung tissue demonstrated considerable concentrations of surface iron. In addition, we tested the hypothesis that this surface coordination of Fe3+ by oxalate is associated with increased in vitro oxidant generation. Calcium oxalate crystals (1.0 mg/ml) complexed all available Fe3+ from solutions of ferric chloride to concentrations of as much as 1.0 mM. Oxidant generation in both a chemical and a cellular system, measured as thiobarbituric-acid-reactive products of deoxyribose and chemiluminescence, respectively, increased with coordination of higher concentrations of inorganic iron. We conclude that calcium oxalate associated with A. niger infection complexes iron cations onto the crystalline surfaces and may generate oxidants at the solid-solution interface, which could result in tissue injury.

Aspergillosis↗
PubMed1991

Reduction of neutrophil influx diminishes lung injury and mortality following phosgene inhalation.

Phosgene inhalation causes a severe noncardiogenic pulmonary edema characterized by an influx of neutrophils into the lung. To study the role of neutrophils in lung injury and mortality after phosgene, we investigated the effects of leukocyte depletion with cyclophosphamide, inhibiting the generation of the chemotaxin leukotriene B4 with the 5-lipoxygenase inhibitor AA861 and impairing neutrophil migration with the microtubular poison colchicine. Cyclophosphamide, AA861, and colchicine injected before exposure significantly reduced percent neutrophils, protein, and thiobarbituric acid-reactive products in bronchoalveolar lavage fluid of rats exposed to phosgene (0.5 ppm X 60 min). Cyclophosphamide, AA861, and colchicine also significantly decreased mortality from phosgene (2.0 ppm X 90 min) in mice. Colchicine significantly reduced neutrophil influx, lung injury, and mortality even when given 30 min after phosgene exposure. We conclude that lung injury and mortality after phosgene exposure are associated with an influx of neutrophils into the lung. Prevention of neutrophil migration with colchicine may hold therapeutic potential in phosgene poisoning.

Administration, Inhalation↗
PubMed1991

Changes in forced expiratory volume in one second and peak expiratory flow rate across a work shift among unexposed blue collar workers.

Pre- and postshift spirometry was obtained on 1,113 blue collar workers employed at 35 work sites judged to have no hazardous occupational respiratory exposures on the basis of inspection visits and environmental sampling. In addition to spirometry, a standardized questionnaire was administered by trained personnel. A study population of 944 remained after exclusion of workers for incomplete demographic data and/or spirometry with poor within-session reproducibility, i.e., greater than or equal to 10% variability in the two largest values of either FVC and/or FEV1. Overall mean values of changes across the work shift in FEV1 and peak expiratory flow rate (PEFR) were -0.8% (-0.04 L) and +2.1% (+0.13 L/s), respectively. Standard deviations for these across-shift changes were 5.8% (0.19 L) and 13.2% (1.19 L/s) for FEV1 and PEFR, respectively. In univariate analyses, mean values of across-shift changes were not statistically related to age, race, sex, smoking status, work shift, or FEV1/FVC ratio. However, variability (i.e., standard deviation) of across-shift changes were significantly related to some of these factors. These observations provide a basis for interpreting results of occupational respiratory morbidity surveys involving measurement of changes in FEV1 and/or PEFR across a work shift.

Adolescent↗
PubMed1990

Hypothesis: is lung disease after silicate inhalation caused by oxidant generation?

Inhaled silicate dusts may cause lung disease through their surface coordination of iron with subsequent oxidant generation via the Fenton reaction. Pneumoconiosis, irritant bronchitis, focal emphysema, and carcinoma may be produced by oxidants either directly through lipid peroxidation and protein inactivation, or indirectly by oxidant-mediated release of cytokines such as platelet-derived growth factor. The increased incidence of tuberculosis observed among silicate workers could be explained by accumulation of iron complexed by dust particles in the lung and made available to dormant mycobacteria as a virulence factor.

Dust↗
PubMed1990

Mechanism of phosgene-induced lung toxicity: role of arachidonate mediators.

We have previously shown that phosgene markedly increases lung weight gain and pulmonary vascular permeability in rabbits. The current experiments were designed to determine whether cyclooxygenase- and lipoxygenase-derived mediators contribute to the phosgene induced lung injury. We exposed rabbits to phosgene (1,500 ppm/min), killed the animals 30 min later, and then perfused the lungs with a saline buffer for 90 min. Phosgene markedly increased lung weight gain, did not appear to increase the synthesis of cyclooxygenase metabolites, but increased 10-fold the synthesis of lipoxygenase products. Pre- or posttreatment with indomethacin decreased thromboxane and prostacyclin levels without affecting leukotriene synthesis and partially reduced the lung weight gain caused by phosgene. Methylprednisolone pretreatment completely blocked the increase in leukotriene synthesis and lung weight gain. Posttreatment with 5,8,11,14-eicosatetraynoic acid (ETYA), a nonmetabolized competitive inhibitor of arachidonic acid metabolism, or the leukotriene receptor blockers, FPL 55712 and LY 171883, also dramatically reduced the lung weight gain caused by phosgene. These results suggest that lipoxygenase products contribute to the phosgene-induced lung damage. Because phosgene exposure did not increase cyclooxygenase synthesis or pulmonary arterial pressure, we tested whether phosgene affects the lung's ability to generate or to react to thromboxane. Infusing arachidonic acid increased thromboxane synthesis to the same extent in phosgene-exposed lungs as in control lungs; however, phosgene exposure significantly reduced pulmonary vascular reactivity to thromboxane but not to angiotension II and KCl.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1990

Reference equations used to predict pulmonary function. Survey at institutions with respiratory disease training programs in the United States and Canada.

Adult respiratory disease training programs in the United States and Canada were surveyed to determine which reference equations were used to predict normal pulmonary function and how ethnic differences were approached. Replies from 139 of the 180 (77.2 percent) institutions surveyed were received and evaluated. Surprisingly few studies account for most of the equations in use: three studies account for 85 percent of the spirometric equations, two for 83 percent of the lung volume equations and five for 84 percent of the diffusing capacity equations. Although there are no definite data, the form of many of the replies suggests that equipment default settings may influence the selection process. Of those responding to the ethnic difference question, 53 percent of institutions applied no correction for ethnic differences. There was no consistent pattern to the method of correction among those who did.

Canada↗
PubMed1989

Impairment after adult respiratory distress syndrome. An evaluation based on American Thoracic Society recommendations.

To test the hypothesis that impairment after the adult respiratory distress syndrome (ARDS) is uncommon, we evaluated 41 ARDS survivors using ATS standards for determination of impairment. A total of 101 trials of pulmonary function tests were obtained between 1 and 388 wk after the onset of ARDS. It was possible to evaluate impairment at 1 yr or more after ARDS in 27 subjects. Eighteen of the 27 were impaired. The percentage of ARDS survivors who were impaired on the basis of FVC, FEV1, FEV1/FVC, and DLCOsb was 50.0, 61.1, 33.3, and 82.4%, respectively. Impairment was mild in 13 (72.2%), moderate in four (22.2%), and severe in one (5.6%). Smoking status had no predictive value in determining impairment. Physiologic indices of ARDS severity (maximal pulmonary artery pressure, lowest static thoracic compliance, and maximal level of PEEP) were found to be significantly different when those impaired 1 yr or more after ARDS were compared with those not impaired. Symptoms were found to have no association with impairment. We conclude that, using ATS criteria, impairment 1 yr or more after ARDS onset is common. Patient characteristics and symptoms after ARDS have no association with impairment 1 yr or more after ARDS onset, whereas physiologic indices of severity during ARDS do.

Adult↗
PubMed1989

Heritability estimates of pulmonary function.

To test the hypothesis that there is genetic control of pulmonary function parameters independent of that influencing height, we evaluated 74 pairs of asymptomatic, nonsmoking twins. FVC, FEV1, FEF25-75%, TLCsb, RVsb, Dsb, and D/VA were measured. Pulmonary function indices were adjusted for height using simple linear regression. Mean intrapair differences (unadjusted and adjusted for height) were compared using t tests of independent samples. Within pair, Holzinger's, and Falconer's heritability estimates were calculated using height-adjusted residual values. When total variances of a function parameter were statistically different between monozygotes and dizygotes, the among component heritability estimate was calculated and used as the best indicator of heritability. Following adjustment for height, no measure of pulmonary function which satisfied the requirements of the analysis was found to be significantly heritable.

Adult↗
PubMedDate not supplied

Increased expression of cyclooxygenase 2 mediates oil fly ash-induced lung injury.

We have previously shown that in vitro exposure to the combustion-derived ambient air pollutant residual oil fly ash (ROFA) induces the expression of prostaglandin H synthase 2 (COX2) in human airway epithelial cells. To determine the role of prostaglandins and COX2 expression in ROFA-induced lung injury in vivo, we have examined the effect of intratracheal ROFA instillation on COX2 expression, prostaglandin synthesis, and indices of pulmonary injury and inflammation in adult Sprague-Dawley rats. ROFA treatment induced a marked increase in the level of prostagladin E2 (PGE2) recovered in the bronchoalveolar lavage fluid (BALF), which was effectively decreased by pretreating the animals with the specific COX2 inhibitor NS398. Immunohistochemical analyses of rat airways showed concomitant expression of COX2 in the proximal airway epithelium of rats treated with ROFA. Increases in BALF protein, but not interleukin 6 (IL-6) increases or ROFA-induced polymorphonuclear neutrophils (PMN) influx into the airway, were blunted by administration of NS398 prior to ROFA instillation. These data demonstrate that prostaglandins mediate lung injury induced by exposure to ROFA and implicate increased expression of COX2 as a mechanism that contributes to the toxicity of metal-laden ambient particulate matter.

Air Pollutants↗