The eosinophil and acute lung injury.
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Animals↗
Biomedical subjects
J R Hoidal
Publications and source records attributed to J R Hoidal.
Clearance of neutrophil-derived myeloperoxidase by the macrophage mannose receptor.
Uptake of neutrophil-derived myeloperoxidase by the macrophage mannose receptor was studied. Rat bone marrow-derived macrophages internalized 75% of [125I]myeloperoxidase through a mannose-specific process. Uptake via the mannose receptor is highly sensitive to treatment with oxidants. Treatment of rat macrophages with 1 mM H2O2 for 30 min resulted in a 94% reduction in uptake of myeloperoxidase. By Percoll gradient fractionation studies, 38% of internalized myeloperoxidase was delivered to the lysosomal compartment during a 15-min chase period, similar to findings for delivery of other ligands for this receptor. Once in the lysosome, the myeloperoxidase remained enzymatically active for several hours, with 50% activity remaining at 8 h. Finally, myeloperoxidase-containing macrophages had an increased capacity to down-regulate their own mannose receptors or receptors on neighboring macrophages, possibly through the myeloperoxidase-mediated production of oxidized halogens. Thus, the macrophage mannose receptor plays a potentially physiologic role in regulating extracellular myeloperoxidase levels. The receptor-mediated uptake may either arm the macrophage to contribute to oxidant-mediated tissue damage or may function to clear extracellular myeloperoxidase during the resolution phase of the inflammatory process.
Animals↗
Role of cytochrome P-450 in reperfusion injury of the rabbit lung.
Reactive oxygen species are a major cause of damage occurring in ischemic tissue after reperfusion. During reperfusion transitional metals such as iron are required for reactive oxygen species to mediate their major toxic effects. Xanthine oxidase is an important source of reactive oxygen species during ischemia-reperfusion injury, but not in all organs or species. Because cytochrome P-450 enzymes are an important pulmonary source of superoxide anion (O2-.) generation under basal conditions and during hyperoxia, and provide iron catalysts necessary for hydroxyl radical (.OH) formation and propagation of lipid peroxidation, we postulated that cytochrome P-450 might have a potential role in mediating ischemia-reperfusion injury. In this report, we explored the role of cytochrome P-450 enzymes in a rabbit model of reperfusion lung injury. The P-450 inhibitors 8-methoxypsoralen, piperonyl butoxide, and cimetidine markedly decreased lung edema from transvascular fluid flux. Cimetidine prevented the reperfusion-related increase in lung microvascular permeability, as measured by movement of 125I-albumin from the vascular space into lung water and alveolar fluid. P-450 inhibitors also prevented the increase in lung tissue levels of thiobarbituric acid reactive products in the model. P-450 inhibitors did not block enhanced O2-. generation by ischemic reperfused lungs, measured by in vivo reduction of succinylated ferricytochrome c in lung perfusate, but did prevent the increase in non-protein-bound low molecular weight chelates of iron after reperfusion. Thus, cytochrome P-450 enzymes are not likely a major source of enhanced O2-. generation, but serve as an important source of iron in mediating oxidant injury to the rabbit lung during reperfusion. These results suggest an important role of cytochrome P-450 in reperfusion injury to the lung and suggest potential new therapies for the disorder.
Animals↗
Ibuprofen prevents oxidant lung injury and in vitro lipid peroxidation by chelating iron.
Because ibuprofen protects from septic lung injury, we studied the effect of ibuprofen in oxidant lung injury from phosgene. Lungs from rabbits exposed to 2,000 ppm-min phosgene were perfused with Krebs-Henseleit buffer at 50 ml/min for 60 min. Phosgene caused no increase in lung generation of cyclooxygenase metabolites and no elevation in pulmonary arterial pressure, but markedly increased transvascular fluid flux (delta W = 31 +/- 5 phosgene vs. 8 +/- 1 g unexposed, P less than 0.001), permeability to albumin (125I-HSA) lung leak index 0.274 +/- 0.035 phosgene vs. 0.019 +/- 0.001 unexposed, P less than 0.01; 125I-HSA lavage leak index 0.352 +/- 0.073 phosgene vs. 0.008 +/- 0.001 unexposed, P less than 0.01), and lung malondialdehyde (50 +/- 7 phosgene vs. 24 +/- 0.7 mumol/g dry lung unexposed, P less than 0.01). Ibuprofen protected lungs from phosgene (delta W = 10 +/- 2 g; lung leak index 0.095 +/- 0.013; lavage leak index 0.052 +/- 0.013; and malondialdehyde 16 +/- 3 mumol/g dry lung, P less than 0.01). Because iron-treated ibuprofen failed to protect, we studied the effect of ibuprofen in several iron-mediated reactions in vitro. Ibuprofen attenuated generation of .OH by a Fenton reaction and peroxidation of arachidonic acid by FeCl3 and ascorbate. Ibuprofen also formed iron chelates that lack the free coordination site required for iron to be reactive. Thus, ibuprofen may prevent iron-mediated generation of oxidants or iron-mediated lipid peroxidation after phosgene exposure. This suggests a new mechanism for ibuprofen's action.
Animals↗
Dusts causing pneumoconiosis generate .OH and produce hemolysis by acting as Fenton catalysts.
Silicates causing pneumoconiosis function as Fenton catalysts to generate hydroxyl radicals (.OH) when incubated with hydrogen peroxide and a reducing substance. In contrast, silicates which do not cause pneumoconiosis demonstrate no Fenton activity. Catalytic activity is decreased by pretreatment of silicates with the iron chelators deferoxamine or transferrin. Hemolysis from silicates is decreased by interventions which remove superoxide anion or hydrogen peroxide from the medium, or by pretreatment of dusts with iron chelators. Thus, asbestos and nonfibrous silicates may cause pneumoconiosis through a common oxidant mechanism by catalyzing production of toxic .OH radicals in the lung.
Catalysis↗
Differences in lung function and prevalence of pneumoconiosis between two kaolin plants.
To investigate the origin of differences in previously published pulmonary function studies of workers in kaolin plants in Georgia, spirometric and radiographic data collected in a cross sectional survey of two large plants were analysed. As compared with workers in plant 2, workers in plant 1 had a 2.7-fold greater prevalence of pneumoconiosis and a mean 0.361 decrement in adjusted forced vital capacity. Our previous finding that exposure to kaolin was not associated with a decrement in lung function may have resulted from failure to consider differences between the plants.
Adolescent↗
Dibutyryl cAMP, aminophylline, and beta-adrenergic agonists protect against pulmonary edema caused by phosgene.
Phosgene is a toxic oxidant gas that causes the adult respiratory distress syndrome in exposed workers. Phosgene exposure markedly increased lung weight gain in buffer-perfused isolated rabbit lungs (31 +/- 5 g over 60 min after phosgene vs. 7.7 +/- 1.2 in control lungs, P less than 0.01) and markedly increased the lung leak index for 125I-albumin (0.28 +/- 0.03 after phosgene vs. 0.02 +/- 0.01 in control lungs, P less than 0.01). Pretreatment with dibutyryl adenosine 3',5' -cyclic monophosphate (DBcAMP), aminophylline, or terbutaline plus isoproterenol prevented the increase in lung weight caused by phosgene (31 +/- 5 g phosgene, 11.7 +/- 2.8 DBcAMP, 7.5 +/- 2.5 aminophylline, 6.1 +/- 1 terbutaline and isoproterenol, 6.1 +/- 1.2 control + aminophylline, and 7.7 +/- 1.2 control; all treatments were P less than 0.01 vs. the untreated phosgene group and not significantly different from control lungs). Pretreatment with aminophylline prevented the increase in lung leak index for 125I-albumin (0.28 +/- 0.03 after phosgene vs. 0.06 +/- 0.02 in aminophylline-treated lungs, P less than 0.01). Posttreatment with aminophylline and terbutaline also prevented the increase in lung weight caused by phosgene. These results indicate that phosgene dramatically increases the movement of fluid and protein across the pulmonary vasculature and that treatment with DBcAMP, aminophylline, terbutaline, or isoproterenol markedly reduces the pulmonary edema caused by phosgene.
Aminophylline↗
Long-term pulmonary sequelae after Legionella pneumophila infection in the hamster.
It has been reported that infections with Legionella pneumophila can lead to chronic inflammatory and fibrotic reactions in the human lung. To better characterize the nature of the residual abnormalities caused by this bacterium, we inoculated Syrian hamsters intratracheally with 10(8) serotype 1 L. pneumophila organisms and assessed histologic, functional, and biochemical changes at intervals up to 180 days. Acutely, L. pneumophila caused an intense alveolar macrophage (AM) and polymorphonuclear leukocyte (PMN) response within the lower air spaces, air-filled lungs were noncompliant, and there was an associated 25 to 50% increase in the lung content of collagen and elastin after 10 days. An inflammatory response, consisting principally of AM and centered around the terminal bronchioles, was still prominent in some infected lungs after 90 and 180 days, and the severity of the inflammation was correlated with a persistent restrictive defect in the elastic behavior of the lung. However, by histologic examination, fibrosis was not prominent, and the more representative abnormality was one of mild, diffuse air-space enlargement. Frank emphysematous changes were present focally in some lungs. In addition, an irregularly distributed lymphocytic infiltrate and goblet cell metaplasia were present in the larger bronchi of infected animals. We conclude that a single infection with L. pneumophila is capable of causing long-term inflammatory reactions in the lung, with morphologic features of both fibrosis and emphysema.
Animals↗
Role of reactive oxygen species in reperfusion injury of the rabbit lung.
We have developed a model of reperfusion injury in Krebs buffer-perfused rabbit lungs, characterized by pulmonary vasoconstriction, microvascular injury, and marked lung edema formation. During reperfusion there was a threefold increase in lung superoxide anion (O2-) production, as measured by in vivo reduction of nitroblue tetrazolium, and a twofold increase in the release of O2- into lung perfusate, as measured by reduction of succinylated ferricytochrome c. Injury could be prevented by the xanthine oxidase inhibitor allopurinol, the O2- scavenger SOD, the hydrogen peroxide scavenger catalase, the iron chelator deferoxamine, or the thiols dimethylthiourea or N-acetylcysteine. The protective effect of SOD could be abolished by the anion channel blocker 4,4'-diisothiocyano-2,2'-stilbene disulfonic acid, indicating that SOD consumes O2- in the extracellular medium, thereby creating a concentration gradient favorable for rapid diffusion of O2- out of cells. Our results extend information about the mechanisms of reperfusion lung injury that have been assembled by studies in other organs, and offer potential strategies for improved organ preservation, for treatment of reperfusion injury after pulmonary thromboembolectomy, and for explanation and therapy of many complications of pulmonary embolism.
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
Oxidant-mediated inhibition of ligand uptake by the macrophage mannose receptor.
We have investigated the effect of oxidants on ligand recognition and internalization by the macrophage mannose receptor. Rat bone marrow macrophages were treated with increasing concentrations of H2O2 for 30 min at 37 degrees C. Fifty percent inhibition of ligand uptake was observed at 250 microM, with only 10% of control uptake remaining following exposure to 1 mM H2O2 for 30 min. Electron micrographic analysis of macrophages following H2O2 treatment showed no morphological alterations compared to untreated cells. Ligand uptake was also inhibited by the following H2O2 generating systems: menadione, xanthine/xanthine oxidase, glucose/glucose oxidase, and phorbol 12-myristate 13-acetate-stimulated polymorphonuclear leukocytes. Inhibition could be blocked by catalase plus or minus superoxide dismutase. Treatment of macrophages at 4 degrees C with H2O2 had no effect on ligand binding, whereas treatment with H2O2 at 37 degrees C reduced binding to 15% of control levels and decreased the number of surface receptors to one-third of control cells. H2O2 treatment inhibited ligand degradation by macrophages, but did not prevent ligand movement from the surface to the interior of the cell. In addition, ligand delivery to lysosomes was blocked by oxidant treatment. These results suggest that treatment of macrophages with reagent H2O2 or H2O2-generating systems inhibits the normal ligand delivery and receptor recycling process involving the mannose receptor. Potential mechanisms might include receptor oxidation, alterations in ATP levels, or membrane lipid peroxidation.
Animals↗
Proteinase 3. A distinct human polymorphonuclear leukocyte proteinase that produces emphysema in hamsters.
Studies were designed to explore the possibility that human polymorphonuclear leukocyte granule constituents in addition to elastase (HLE) had the potential to cause emphysema. A two-step purification of three serine proteinases was developed. Granule extract proteins were initially separated by dye-ligand affinity chromatography. Fractions eluted were divided into four pools. Hamsters were given a single intratracheal instillation of saline +/- 0.1 mg protein of each pool. While pool 2 contained HLE and cathepsin G, the most dramatic bullous emphysema developed in animals treated with pool 4. The esterase from pool 4, designated proteinase 3 (PR-3) was purified, characterized in vitro, and tested for its ability to cause emphysema. PR-3 is a neutral serine proteinase with isoenzyme forms. Its ability to degrade elastin at pH 6.5 is slightly greater than that of HLE, but it is less active than HLE at pH 7.4 or 8.9. PR-3 has weak activity against azocasein. Its ability to degrade hemoglobin is intermediate to that of HLE and cathepsin G at pH 7.4. PR-3 has no activity against chromogenic substrates specific for HLE or cathepsin G. Its pI is substantially less than HLE or cathepsin G. It is also immunologically distinct from HLE. It induces emphysema in hamsters commensurate with that of HLE. We conclude that PR-3 may be important in the pathogenesis of human emphysema.
Animals↗
Therapy with red blood cells decreases hyperoxic pulmonary injury.
Results of attempts to ameliorate hyperoxic pulmonary injury using novel systems for delivery of antioxidant enzymes are reviewed. Intratracheal insufflation of either liposome encapsulated superoxide dismutase or encapsulated catalase increased levels of enzyme activities in rat lung homogenates and prevented lethal effects of an atmosphere of oxygen. Intact erythrocytes placed in the tracheobronchial tree of rats also dramatically improved survival in hyperoxia. Recyclable glutathione appeared to be the constituent of erythrocytes, which was responsible for the protection. In rabbits, erythrocytes also protected from oxidant-mediated ischemic-reoxygenation lung injury. These studies suggest a possible role for erythrocytes as biologic packets of antioxidant enzymes.
Animals↗
Changes in the cell surface protein composition of human alveolar macrophages induced by smoking.
The cell surface proteins of human alveolar macrophages obtained from nonsmokers have been compared to those of alveolar macrophages obtained from smokers. Proteins of nonsmokers' alveolar macrophages surface labeled with 125I differed from those of smokers' alveolar macrophages, as shown by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Three major radiolabeled proteins with molecular weights of 183,000, 80,000, and 30,000 were identified in fresh smokers' cells. The major radiolabeled protein of nonsmokers' macrophages had an apparent molecular weight of approximately 183,000. Affinity chromatography suggested the Mr 183,000 protein is a mannose receptor. In contrast, the molecular weight of the major radiolabeled protein of smokers' alveolar macrophages was approximately 30,000; the Mr 183,000 protein was less prominent. When nonsmokers' alveolar macrophages were cultured in vitro before 125I labeling, the cell surface protein pattern changed to resemble that of smokers' alveolar macrophages; the Mr 183,000 protein could no longer be detected on the cell surface, whereas a Mr 80,000 protein was increased in quantity and a new Mr 30,000 protein was detected. Nonadherent macrophages showed similar changes in their surface-labeled proteins but also contained a new prominently labeled Mr 70,000 protein. Limited proteolysis peptide mapping with five different enzymes did not reveal any evidence of homology among the Mr 183,000, 80,000, 70,000, and 30,000 proteins. The differences in cell surface protein composition between alveolar macrophages of smokers and nonsmokers may reflect their functional capabilities or their state of "activation" and may be mechanistically important in the development of various pulmonary diseases seen in smokers including cancer. These results also demonstrate that major changes in the surface proteins of the human alveolar macrophage plasma membrane can occur rapidly following manipulation.
Affinity Labels↗
Expression of a metalloproteinase that degrades native type V collagen and denatured collagens by cultured human alveolar macrophages.
Human pulmonary alveolar macrophages obtained by bronchoalveolar lavage from both normal controls and smokers secreted in vitro a neutral proteinase that degraded denatured collagens. Optimal expression of the proteinase was detected after 3-5 d of culture. The proteinase could not be detected in the media of cultures that had been treated with 0.5 micrograms/ml of cycloheximide. The gelatinase had an Mr of 90,000 and was immunologically cross-reactive with human neutrophil gelatinase. When newly synthesized 35S-methionine-labeled proteins were analyzed, the proteinase appeared to be a major secretion product of alveolar macrophages. Chromatography on gelatin-Sepharose gave a single peak of activity that was predominantly composed of the 90,000-mol-wt proteinase. The proteolytic activity in the gelatin-Sepharose-purified material was inhibited by EDTA and 1,10-phenanthroline, but not by N-ethylmaleimide or phenylmethanesulfonyl fluoride, indicating that the proteinase was a metalloproteinase. The partially purified material was also capable of degrading native type V collagen and this degradation was inhibited in the presence of an antibody to neutrophil gelatinase. The data suggest that human alveolar macrophages in culture elaborate a metalloproteinase that degrades both native type V collagen and denatured collagens.
Collagen↗
A quantitative in vitro assay of polymorphonuclear leukocyte migration through human amnion membrane utilizing 111in-oxine.
A modified amnion chemotaxis assay is described for measurement of polymorphonuclear leukocyte(s) (PMNL) migration (random and directed) into a viable membrane. The primary modifications are the use of 111In-oxine-labelled PMNL and replacement of the nitrocellulose 'trap' filter with a type I collagen sponge. The modifications resulted in four important benefits: the quantification of PMNL migration was simplified; reader subjectivity was eliminated; the information gained of the migration process was enhanced; and the assay time was decreased. The amnion chemotaxis assay with the modifications reported should provide the means of evaluating several aspects of the inflammatory response of PMNL.
Amnion↗
Cigarette smoking causes accumulation of polymorphonuclear leukocytes in alveolar septum.
The polymorphonuclear leukocyte (PMN) may play an important role in the pathogenesis of emphysema. Cigarette smoking is associated with the accumulation of PMN in the lung as determined by bronchoalveolar lavage. We enumerated alveolar wall PMN on histologic sections from lungs of humans and hamsters with and without cigarette smoke exposure. In human nonsmokers, there were 0.9 +/- 0.2 PMN/mm alveolar wall. In cigarette smokers without emphysema, there were 2.1 +/- 0.3 PMN/mm alveolar wall (p less than 0.01), and in cigarette smokers with emphysema, there were 2.4 +/- 0.7 PMN/alveolar wall (p less than 0.05). There were 1.7 +/- 0.3 PMN/mm alveolar wall in the lungs of hamsters unexposed to cigarette smoke compared with 3.1 +/- 0.3 PMN/mm alveolar wall in smoke-exposed hamsters (p less than 0.005). Although cigarette smoking causes PMN to accumulate within alveolar septa, the accumulation does not seem to be closely related to the development of emphysema. This suggests that additional or other factors are important in the pathogenesis of emphysema.
Aged↗
The prevention of elastase-induced emphysema in hamsters by the intratracheal administration of a synthetic elastase inhibitor bound to albumin microspheres.
The peptide, succinyl-alanyl-alanyl-prolyl-valine chloromethylketone (SPCK), a synthetic inhibitor of elastase, was covalently attached to human albumin microspheres (HAM) and administered intratracheally to hamsters 15 min and 8 h prior to the instillation of porcine pancreatic elastase. Pressure-volume relationships and histologic examination of excised lungs after 4 wk showed complete protection from emphysema when SPCK-HAM was administered either 15 min or 8 h before elastase exposure. Concurrent experiments with free SPCK showed that protection was achieved only if elastase was administered within 15 min after the instillation of SPCK. Extending this period to 8 h not only led to a failure of free SPCK to prevent emphysema but actually resulted in more extensive air-space enlargement. The prolonged effectiveness conferred by the attachment of SPCK to a biodegradable carrier should reduce the frequency with which it would have to be administered for the therapeutic intervention of emphysema and should minimize any toxic side reactions.
Albumins↗
Protection against pulmonary oxygen toxicity in rats by the intratracheal administration of liposome-encapsulated superoxide dismutase or catalase.
To test the feasibility of using liposomes to deliver therapeutic agents to the lungs, the effect of liposome-encapsulated superoxide dismutase (SOD) or catalase on pulmonary oxygen toxicity was studied in rats. The SOD or catalase was encapsulated in negatively changed multilamellar liposomes and administered directly into the trachea of adult rats, which were subsequently exposed to hyperoxia (greater than 95% O2). Response to hyperoxia was examined by studying lung SOD and catalase activities, survival rates, and lung morphology. Rats receiving liposome-encapsulated SOD or catalase showed increased levels of enzyme activities in the lung homogenates compared with those in the control groups after 24 to 72 h of hyperoxic exposure. Elevated enzyme levels in the lungs of rats treated with liposome-encapsulated SOD or catalase were accompanied by a significant improvement in survival rates after 72 h of hyperoxic exposure and less lung injury than in the other control groups.
Animals↗