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Biomedical subjects

A J Ghio

Publications and source records attributed to A J Ghio.

At least 73 records · Page 4Linked to original sources
PubMed1997

Iron accumulation in lung allografts after transplantation.

Lung transplantation has become a therapeutic option for end-stage pulmonary diseases, but after transplantation, infections and obliterative bronchiolitis (OB) are major causes of long-term morbidity and mortality. OB is a fibroproliferative disease, of poorly understood etiology, characterized by an irreversible decline in allograft function. Because diseases with tissue iron overload are characterized by fibrosis and end-organ failure, we studied the iron concentrations in BAL fluid and lung tissue in 10 lung allograft patients. BAL fluid revealed significantly elevated iron concentrations in allograft patients compared with five normal volunteers (135+/-16.54 micromol/L vs 33.65+/-7.48 micromol/L, respectively). Prussian blue staining of biopsy specimens of lung allograft tissue revealed an accumulation of iron primarily in alveolar macrophages. Immunohistochemical stains for ferritin revealed accumulation of the protein in macrophages, interstitium, vascular walls, and bronchiolar epithelium. Iron studies of the blood (serum ferritin and iron concentrations) revealed no evidence for systemic iron overload. In conclusion, patients with pulmonary allografts appear to have elevated concentrations of iron in lung tissue. This iron overload may place the allografts at increased risk of metal-mediated injury and fibrosis.

Adult↗
PubMed1996

Induction of prostaglandin H synthase 2 in human airway epithelial cells exposed to residual oil fly ash.

Exposure to ambient air containing respirable particulate matter at concentrations below the current National Ambient Air Quality Standard has been associated with increased rates of pulmonary-related morbidity and mortality. To identify mechanisms involved in pulmonary responses to such exposure, we studied the effects of the emission source particulate air pollutant residual oil fly ash (ROFA) on prostaglandin metabolism in cultured human airway epithelial cells. Epithelial cells exposed to ROFA for 24 hr secreted substantially increased amounts of the prostaglandin H synthase (PHS) products prostaglandins E2 and F2 alpha. The ROFA-induced increase in prostaglandin synthesis was correlated with a marked increase in PHS activity. Western blots showed that ROFA exposure induced dose-dependent increases in PHS2 protein levels. Reverse transcriptase-PCR analyses demonstrated accompanying increases in PHS2 mRNA which were evident by 2 hr of continuous exposure. In contrast, expression of PHS1 was not affected by ROFA treatment of airway epithelial cells. There were no alterations in arachidonic acid release, incorporation, or availability in ROFA-exposed cells. These data show that exposure to ROFA induces PHS2 expression, leading to increased prostaglandin synthesis in cultured airway epithelial cells. These findings suggest that prostaglandins may play a role in the toxicology of air pollution particle inhalation.

Air Pollutants↗
PubMed1996

Lung inflammation after exposure to nonfibrous silicates increases with chelatable [Fe3+].

Lung exposures to complexes of coordinated iron can be associated with a neutrophilic alveolitis. We tested the hypothesis that lung inflammation after intratracheal instillation of mineral oxides in rats increases with surface-complexed [Fe3+]. The 10 mineral oxides employed had measurable [Fe3+] complexed to the dust surface. The metal was incompletely coordinated, as demonstrated by the ability of the particles to catalyze electron transfer and generate thiobarbituric acid (TBA) reactive products of deoxyribose. After exclusion of those silicates containing structural iron within the crystal lattice, there was a significant correlation between the concentration of chelatable metal and TBA-reactive products (r = 0.82; p = .04). Four days after intratracheal instillation of the 10 mineral oxide particles into rats, lavage neutrophils and protein were significantly increased for all dusts compared to injected saline. Among those dusts with no structural iron, the correlation between chelatable iron concentrations and percentage neutrophils did not reach significance (r = 0.73; p = .10), but that between metal and lavage protein did (r = 0.80; p = .05). We conclude that (1) mineral oxides complex iron cations at the surface, (2) in vitro measures of oxidant generation increase with the concentration of surface iron among those dusts with no structural iron, and (3) acute inflammation following introduction of these particles into the lower respiratory tract also increases with surface iron concentrations among those mineral oxides with no structural iron.

Animals↗
PubMed1996

Association of pulmonary artery size on chest radiograph with residence at elevated altitudes.

Mean pulmonary artery pressure (PAP) has been demonstrated to correlate with measures of pulmonary artery size. We tested the hypothesis that residence at elevated altitudes, a determinant of mean PAP, can be associated with increases in pulmonary artery size on chest radiographs from healthy adults. The study population consisted of three groups of asymptomatic, nonsmoking adults without hazardous respiratory exposures living at altitudes approximating 0 m (group 1, n = 197), 1,400 m (group 2, n = 145), and 2,600 m above sea level (group 3, n = 196). The width of the right descending pulmonary artery (RDPA) was measured at its widest diameter before bifurcation. In a multivariate regression model, significant associations were detected between RDPA width and residence at elevated altitudes (F = 13.84, p = 0.0002), age (F = 32.49, p < 0.0001), and gender (F = 56.10, p < 0.0001), with 36% of the variability of the measure determined by these three variables (r2 = 0.36). Mean RDPA width increased as altitude at residence increased. Larger mean values were noted among older individuals and males. We conclude that residence at altitudes of 1,400 and 2,600 m above sea level is associated with increases in pulmonary artery size on chest radiograph.

Adolescent↗
PubMed1996

Composition of lung lavage in pulmonary alveolar microlithiasis.

A case of pulmonary alveolar microlithiasis (PAM) is reported wherein total lung lavage was performed for relief of dyspnea. Characterization of the lavage material and examination of the microliths isolated from the lavage fluid confirmed previous reports of their spherical-ovoid shape and a 2:1 calcium to phosphate composition. The microliths contained considerable amounts of ionizable iron and generated oxidants in an in vitro system. A detailed biochemical analysis of the lavage fluid reflected elevations in total protein, phosphatidylserine, phosphatidylglycerol and the ratio of phosphatidylglycerol to phosphatidylinositol. Surfactant apoprotein-A levels approximated that of normal patients. The potential roles of oxidant generation and alterations in surfactant metabolism are discussed in the context of the pathogenesis of PAM.

Adult↗
PubMed1996

Tolerance to phosgene is associated with a neutrophilic influx into the rat lung.

Exposures to 100% oxygen, ozone, nitrogen oxides, and phosgene increase both lung lavage protein concentrations and neutrophils. The inhibition of the neutrophil influx can diminish lavage protein concentrations after exposures to these oxidant gases. Similarly, this injury can be reduced by pre-exposure to either the same (tolerance) or a different (cross-tolerance) oxidant gas. We tested the hypothesis that diminished injury after the development of tolerance of phosgene (COCl2) is associated with a decreased incursion of neutrophils. Sixty-day-old rats (n=12/group) were exposed to varying concentrations of COCl2. Lung lavage (n = 6/group) 24 h after a first phosgene exposure demonstrated an increase in both protein concentrations and percentage neutrophils. The remaining animals (n = 6/group) were exposed to COCl2 2 ppm x 60 min 1 wk later. Lavage confirmed the development of tolerance with protein concentrations diminished after the second exposure in those rats that had inhaled higher doses of COCl2 during the first exposure. However, the neutrophilic influx was not diminished but rather was increased. The association of the neutrophil incursion with a protective effect was further established in studies employing colchicine and dextran. Colchicine decreased neutrophil influx occurring after the first exposure and subsequently diminished the development of tolerance after a second exposure. Intratracheal instillation of dextran produced a neutrophil incursion and subsequently decreased injury after a phosgene exposure. In investigations using both colchicine and dextran, neutrophil influx increased with the development of adaptation. Thus, lung injury after the development of tolerance to phosgene provides a unique animal model of a respiratory distress syndrome in which neutrophils are not associated with injury but rather with a protective effect.

Adaptation, Physiological↗
PubMed1996

Tyloxapol inhibits NF-kappa B and cytokine release, scavenges HOCI, and reduces viscosity of cystic fibrosis sputum.

Cystic fibrosis (CF) patients develop progressive cytokine-mediated inflammatory lung disease, with abundant production of thick, tenacious, protease- and oxidant-rich purulent airway secretions that are difficult to clear even with physiotherapy. In the search for a potential treatment, we have tested tyloxapol, an alkylaryl polyether alcohol polymer detergent previously used as a mucolytic agent in adult chronic bronchitis. Tyloxapol inhibits activation of the transcription factor nuclear factor-kappa B (NK-kappa B), reduces resting secretion of the cytokine interleukin-8 (IL-8) in cultured human monocytes, and inhibits lipopolysaccharide (LPS)-stimulated release of tumor necrosis factor-alpha (TNF-alpha), IL-1 beta, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), and the eiconsanoids thromboxane A2 and leukotriene B4 (LTB4). We have previously shown that tyloxapol is a potent antioxidant for hydroxyl radicals ( OH). Tyloxapol (0.05 to 0.1% wt/vol) effectively scavenges the oxidant hypochlorous acid (HOCl; 1 to 7.5 mM) in vitro, and protects from HOCl-mediated lung injury in rats. Tyloxapol also reduces the viscosity of CF sputum (from 463 +/- 133 to 128 +/- 52 centipoise). We conclude that tyloxapol is potentially useful as a new antiinflammatory therapy for CF lung disease, and could possibly promote clearance of secretions in the CF airway.

Adult↗
PubMed1995

Reactive oxygen species produced by liver mitochondria of rats in sepsis.

Reactive oxygen species (ROS) can be generated in experimental shock states through several different mechanisms. We measured ROS production in metabolically active liver mitochondria from rats rendered septic by cecal ligation and puncture. By polarography, the State 4 and State 3 respiration rates of liver mitochondria isolated from septic animals were no different from control organelles. During oxidation of succinate, however, nonenzymatic hydroxylation of salicylic acid to 2,3-dihydroxybenzoic acid by mitochondria from septic rats was increased, indicating generation of hydroxyl radical (OH.). Inhibition of electron transport at Complex I with rotenone had no effect on this pattern of OH. production, but rotenone and cyanide abolished the differences in OH. formation between control and septic liver mitochondria. Measurements of H2O2 release suggested that septic mitochondria will increase rates of H2O2 production in the presence of succinate. Additional investigations revealed no difference in the release of iron between septic and control mitochondria. When referenced to respiration rate, both OH. and H2O2 production were greater in septic liver mitochondria. The reproducible effect of sepsis on generation of reactive oxygen species by liver mitochondria utilizing FAD-linked but not NAD-linked substrates suggests that enhanced mitochondrial oxidative stress in sepsis is related to alterations in the activity of Complex II of the electron transport chain.

Animals↗
PubMed1995

Hydroxyl radical production and lung injury in the rat following silica or titanium dioxide instillation in vivo.

The hydroxyl radical (.OH) is a highly reactive oxygen free radical that has been implicated as a cause of lung injury following exposure to silica and silicates. Despite evidence that silica generates .OH in vitro, there has been no previous demonstration of in vivo production of .OH after exposure to nonfibrous mineral oxide dusts. We tested the hypothesis that instillation of silica into rat lungs is associated with greater .OH production and acute lung inflammation in vivo relative to the instillation of a less toxic nonsilicate particle, titanium dioxide. The production of .OH in the lungs following dust instillation was measured using sodium salicylate as an .OH trap. Seven days after dust exposure, the rats were given intraperitoneal salicylate, the lungs isolated, and salicylate hydroxylation products (2,3- and 2,5-dihydroxybenzoic acid), reflecting .OH, were measured. There was significantly more 2,3-dihydroxybenzoic acid in silica-exposed lungs compared with lungs instilled with titanium dioxide. In addition, the instillation of silica into rat lungs in vivo was associated with a greater acute inflammatory response. We conclude that following in vivo exposure, silica stimulates greater .OH production relative to the less toxic particle, titanium dioxide. These differences in .OH generation correspond to disparities in acute lung inflammation.

Animals↗
PubMed1995

Nitration of tyrosine by hydrogen peroxide and nitrite.

Peroxynitrite anion is a powerful oxidant which can initiate nitration and hydroxylation of aromatic rings. Peroxynitrite can be formed in several ways, e.g. from the reaction of nitric oxide with superoxide or from hydrogen peroxide and nitrite at acidic pH. We investigated pH dependent nitration and hydroxylation resulting from the reaction of hydrogen peroxide and nitrite to determine if this reaction proceeds at pH values which are known to occur in vivo. Nitration and hydroxylation products of tyrosine and salicyclic acid were separated with an HPLC column and measured using ultraviolet and electrochemical detectors. These studies revealed that this reaction favored hydroxylation between pH 2 and pH 4, while nitration was predominant between pH 5 and pH 6. Peroxynitrite is presumed to be an intermediate in this reaction as the hydroxylation and nitration profiles of authentic peroxynitrite showed similar pH dependence. These findings indicate that hydrogen peroxide and nitrite interact at hydrogen ion concentrations present under some physiologic conditions. This interaction can initiate nitration and hydroxylation of aromatic molecules such as tyrosine residues and may thereby contribute to the biochemical and toxic effects of the molecules.

Hydrogen Peroxide↗
PubMed1995

Rare earth (cerium oxide) pneumoconiosis: analytical scanning electron microscopy and literature review.

Rare earth pneumoconiosis is an uncommonly reported disease caused by the inhalation of dust containing lanthanides, also known as rare earth metals, which are common industrial materials. The pathologic manifestations and natural history of this disorder are incompletely understood. We describe a male patient with a 35-year history of optical lens grinding, an occupation associated with exposure to cerium oxide, a rare earth metal-containing compound. The patient presented with progressive dyspnea and an interstitial pattern on chest X-ray; open lung biopsy showed interstitial fibrosis histologically indistinguishable from usual interstitial pneumonitis. However, scanning electron microscopy with energy-dispersive X-ray analysis demonstrated numerous particulate deposits in the lung, of which the majority contained the rare earth metal cerium alone or in combination with other elements. Our case is one of the first to describe rare earth pneumoconiosis associated with pulmonary fibrosis in the occupational setting of optical lens manufacture. Besides reinforcing the contention that rare earth metals are potentially harmful, our case suggests that such agents may be causally related to the development of pulmonary fibrosis.

Aged↗
PubMed1994

DNA strand breaks following in vitro exposure to asbestos increase with surface-complexed [Fe3+].

Surface functional groups on silicate dusts complex iron cations which can cycle through reduction and oxidation states to generate free radicals. These oxidants have a capacity to produce DNA strand breaks and mutations which are primary events in cancer induction. A differential in the capacity of fibrous silicates to produce carcinoma is recognized with the amphiboles demonstrating a greater biologic effect than the serpentine fiber chrysotile. We tested the hypothesis that the differences in genotoxicity of these fibrous silicates correspond to varying concentrations of iron complexed to the surface. Relative to chrysotile, the amphibole fibers complexed greater amounts of iron cations from both inorganic and in vivo sources. Increased concentrations of surface-complexed iron were associated with greater oxidant generation, measured as thiobarbituric acid-reactive products of deoxyribose, and more covalently closed, circular DNA strand scission. These results indicate that genotoxic effects of these fibers may correspond to their capacity to complex iron at the surface.

Asbestos↗
PubMed1994

Complexation of iron cation by sodium urate crystals and gouty inflammation.

Gouty inflammation can be suppressed by an iron chelator. We therefore hypothesized that arthritis associated with sodium urate crystal deposition could follow the incomplete complexation of iron cation with subsequent oxidant generation as the metal cycles through reduced and oxidized states. Urate crystals adsorbed Fe3+ in vitro and crystals collected from a human tophus had significant concentrations of ionizable iron. Urate crystals oxidized deoxyribose to a thiobarbituric acid (TBA)-reactive product, augmented luminol chemiluminescence by neutrophils, released leukotriene B4 from neutrophils, activated complement, and promoted neutrophil chemotaxis. All of these events increased with the concentration of complexed iron and were suppressed by the iron chelator deferoxamine or the .OH scavenger dimethylthiourea. These results suggest that some portion of gouty inflammation after urate crystal deposition could result from the incomplete complexation of iron with subsequent catalytic generation of reactive oxygen species.

Chemotaxis, Leukocyte↗
PubMed1994

Phagocyte-generated superoxide reduces Fe3+ to displace it from the surface of asbestos.

Injury after exposure to mineral oxide dusts is considered to be mediated by free radical generation. In vitro production of hydroxyl radical by a fibrous silicate increases with the [Fe3+] complexed to the dust surface. The study hypothesis tested was that extracellular fluids and phagocytic cells can decrease concentrations of iron complexed to the surface of a fibrous silicate by employing host chelators and reductants. Such a depletion of surface [Fe3+] would predict decrements in both oxidant generation and the resultant injury after inhalation and instillation of these mineral oxides. Crocidolite (2.0 mg) which was exposed to either 5.0 ml rat plasma or 10.0 ml rat lavage fluid for 1 h had diminished surface [Fe3+]. Similarly, incubations of crocidolite (2.0 mg) with either 10.0 ml rat alveolar macrophages (1.0 x 10(6) cells/ml) or 10.0 ml rat neutrophils (1.0 x 10(7) cells/ml) decreased concentrations of surface iron. In vivo exposures of asbestos contained in chambers allowing or precluding inflammatory cell entry revealed that the influx of phagocytes was associated with greater decreases in surface [Fe3+]. The body chelators transferrin and lactoferrin were unable to extract the metal from fiber surface in vitro. However, superoxide generated by phagocytes did displace the iron from the crocidolite surface. We conclude that extracellular fluids and phagocytic cells have a capacity to diminish [Fe3+] complexed to the surface of asbestos and therefore decrease the potential for oxidative stress and injury to a living system after exposure to these dusts.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Humic-like substances in cigarette smoke condensate and lung tissue of smokers.

Deposition of pigmented matter in the lower respiratory tract correlates with the extent of emphysema in smokers as well as with free radical generation and iron accumulation. Pulmonary emphysema is postulated to be mediated by free radical generation which is either directly or indirectly associated with cigarette smoke exposure. The hypothesis was tested that 1) incomplete combustion of tobacco yields humic-like substances (HLS) which 2) deposit in the lung as pigmented particulates, 3) complex iron cations in vitro and in vivo, and 4) have a capacity to catalyze oxidant formation. HLS, isolated by alkali extraction of cigarette smoke condensate (CSC) (Tobacco Health Research Institute, University of Kentucky), demonstrated a high carbon and low carboxylate content on elemental and functional group analyses, respectively, compared with values for HLS sequestered from soils. The HLS isolated from CSC had a capacity to complex iron in vitro and accumulated the metal in vivo after intratracheal instillation in an animal model. Both HLS and its iron complex generated free radicals, and some portion of this oxidant generation was metal dependent. Lung tissue collected at autopsy from smokers contained HLS with an infrared spectrum almost identical to that of the material isolated from CSC. Associations between particulate deposition, metal accumulation, and free radical generation suggest a possible role of HLS in the induction of lung disease following cigarette exposure.

Animals↗
PubMed1994

Complexation of iron by humic-like substances in lung tissue: role in coal workers' pneumoconiosis.

Deposition of coal dust in the lungs during the mining of this energy resource can cause an inappropriate fibrosis. Those characteristics of the coal responsible for lung injury are not known. The hypothesis was tested that 1) humic-like substances (HLS) in coal complex iron cations, which subsequently catalyze oxidant generation; and 2) the accumulation of this metal in the lungs of coal miners is associated with collagen deposition. In vitro measurements of ionizable ferric ion concentration ([Fe3+]) and oxidant generation by 10 standard coal dusts increased with the concentration of HLS. Dust mass, nonheme [Fe3+], and hydroxyproline concentrations in lung tissue were significantly higher in the lungs of coal miners, relative to matched controls. Although hydroxyproline concentrations increased with both dust mass and tissue nonheme [Fe3+], the association with the latter appeared greater. HLS in coal dusts sequestered in human lungs may be associated with injury as a result of their capacity to complex metals, which catalyze oxidant generation.

Coal↗
PubMed1994

Lung injury after silica instillation is associated with an accumulation of iron in rats.

It has been postulated that the incomplete complexation of host iron by the surface of mineral oxides is essential in in vivo lung injury after exposure to these dusts. We investigated the associations between in vivo iron accumulation after intratracheal instillation of silica dust in rats and 1) concentrations of antioxidants and oxidized products in the lung and 2) an index of chronic fibrotic injury. Fifty milligrams of minusil were intratracheally instilled into 60-day-old, male Sprague-Dawley rats. Ionizable Fe3+ complexed to the surface of silica increased from 12.7 +/- 1.4 mumol/g to values as high as 42.5 +/- 9.1 mumol/g dust after instillation. Corresponding to this elevation of surface-adsorbed metal, concentrations of iron in bronchoalveolar lavage fluid, lung tissue, plasma, and liver tissue all increased. Antioxidant molecules in lung tissue, including ascorbate, urate, and glutathione, all decreased, whereas superoxide dismutase increased. Oxidized products in the lung tissue, measured as thiobarbituric acid-reactive products, similarly increased, reflecting an oxidant stress. Dietary depletion of iron stores before instillation of silica dust resulted in low iron stores (hematocrit values of 21.8 +/- 1.9) and low iron concentrations in lavage fluid, lung tissue, and liver tissue. Rats on iron-depleted diets demonstrated a diminished fibrotic injury after dust instillation. Complexation of iron by the dust surface may be central in collagen deposition after silica exposure.

Animals↗