Oxygen radicals in cell injury and cell death.
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Biomedical subjects
Publications and source records attributed to J S Warren.
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In the rat, both IgG and IgA immune complexes induce oxygen radical mediated lung injury that is partially complement-dependent. In vivo studies have suggested that the chief sources of oxygen radicals in IgG and IgA immune complex-induced lung injury are neutrophils and tissue macrophages, respectively. The current studies have been designed to provide additional insights into these two models of tissue injury. Preformed monoclonal IgG and IgA immune complexes stimulated dose-dependent O2-. and H2O2 production by alveolar macrophages. In contrast, neutrophils exhibited O2-. production and lysosomal enzyme secretion in response to IgG immune complexes, but not in response to IgA complexes. There is evidence that C5a significantly amplifies these responses. Purified human C5a enhanced the O2-. responses of neutrophils activated with IgG immune complexes and alveolar macrophages activated with either IgG or IgA immune complexes. Addition of C5a alone to neutrophils or alveolar macrophages had no direct stimulatory effect as measured by O2-. production. The observation that O2-. responses of immune complex-activated alveolar macrophages can be significantly enhanced by the presence of C5a and that C5a can also enhance O-2. responses of IgG immune complex-stimulated neutrophils suggests a potential amplification mechanism through which complement may participate in both IgG and IgA immune complex-induced lung injury. The present data corroborate in vivo studies which suggest that IgG immune complex lung injury is primarily neutrophil-mediated, whereas IgA complex lung injury is predominantly macrophage-mediated.
Considerable attention has been focused on the role of electrostatic charge in the pathogenesis of immune complex-mediated tissue injury. The authors have examined the ability of cationic (histone, polyhistidine, polyarginine) and anionic (polyanetholsulfonate) polyelectrolytes to modulate acute immune complex-mediated tissue injury. Tissue injury elicited in rats by the reversed dermal Arthus reaction was increased 26-43% by addition of polyelectrolytes to antibody prior to its intradermal injection. Kinetic studies using 111In-labeled neutrophils indicated that the enhanced tissue injury was not the result of increased influx of neutrophils. Infusion of polyethylene glycol-conjugated superoxide dismutase prior to induction of the Arthus reaction resulted in 40-68% suppression of tissue injury. Concomitant in vitro functional studies (enzyme secretion, O-2 and H2O2 generation, and chemiluminescence) of rat neutrophils demonstrated that addition of polyelectrolytes to preformed immune complexes (IgG-bovine serum albumin) resulted in marked increases in O-2, H2O2, and chemiluminescence, but no increases in enzyme secretion, compared with neutrophils stimulated with immune complexes alone. The cationic polyelectrolytes did not alter the capacity of preformed immune complexes to activate complement in vitro. These studies suggest that both cationic and anionic polyelectrolytes can increase the pathogenic potential of immune complexes and that this modulation is, at least in part, mediated by enhanced generation of toxic oxygen-derived metabolites by neutrophils.
IgA immune complex-induced lung injury in the rat is oxygen radical mediated and partially complement-dependent but develops fully after neutrophil depletion. The extent to which monocytes, lung interstitial macrophages, and alveolar macrophages may be involved in the development of lung injury in this model is unclear. To further understand the pathogenesis of IgA lung injury, we have examined the capacity of phagocytic cells isolated from different anatomic compartments of the lung to produce toxic oxygen-derived metabolites. [3H]Thymidine pulse labeling and autoradiography as well as in vivo phagocytosis studies were used to distinguish macrophages isolated from the alveolar and interstitial compartments. Lung interstitial macrophages were characterized ultrastructurally, cytochemically, and functionally. Interstitial macrophages were relatively uniform in size, had blunt pseudopodia, and contained almost no intracytoplasmic lamellar inclusions compared to alveolar macrophages. Similar to monocytes and alveolar macrophages, interstitial macrophages contained nonspecific esterase activity and exhibited the capacity to phagocytize latex and opsonized zymosan particles. Lung interstitial and alveolar macrophages incubated with IgA immune complexes, IgG immune complexes, or phorbol ester (PMA) produced similar amounts of O2-. in a dose-dependent manner. In contrast, peripheral blood neutrophils responded to IgG immune complexes and PMA but not to IgA immune complexes. Monocytes produced a small amount of O2-. in response to PMA but almost no O2-. in response to IgA or IgG immune complexes. These data are consistent with recent in vivo studies which indicate that IgA immune complex lung injury is neutrophil independent. The data provide direct in vitro evidence that lung interstitial and alveolar macrophages produce O2-. following incubation with PMA, IgA, or IgG immune complexes and may therefore contribute to the development of oxygen radical mediated lung injury.
Granulocytopenia and oral mucosal defects have been reported to be important predisposing factors to recently recognized cases of Capnocytophaga septicemia. The authors call attention to an apparent preponderance of these cases in the pediatric age group and emphasize laboratory features which they have found helpful in the diagnosis of Capnocytophaga infections. Thirteen patients with Capnocytophaga infections were seen during a seven-year period. Seven of these patients had Capnocytophaga bacteremia. Six of seven bacteremic patients were granulocytopenic, six had oral mucosal defects, and three died. Five of the seven bacteremic patients were younger than 20 years of age. This represents a disproportionate distribution of cases in the pediatric age group within the author's institution, because 43% of blood culture specimens submitted to their microbiology laboratory are obtained from pediatric patients. This observation is supported by a review of the reported cases of Capnocytophaga septicemia in which 7 of 12 patients were younger than 20 years of age. Because Capnocytophaga may superficially resemble the more commonly isolated Fusobacterium nucleatum, distinguishing features for laboratory identification are discussed.
In recent years, increasing clinical and experimental data have provided compelling evidence that neutrophil-derived oxygen radicals and their metabolites are important mediators of vascular endothelial injury. In this review, attention is directed toward in vitro, ex vivo, and in vivo experimental studies contributing to current understanding of mechanisms of oxyradical mediated endothelial damage. Although these studies may have broad significance, they appear to have particular relevance to the pathogenesis of the adult respiratory distress syndrome and other types of acute pulmonary dysfunction.
A 75-year-old man developed synchronous multicentric cutaneous sarcomas and basal cell carcinoma of the face 57 years after receiving irradiation for acne. During the previous 30 years he had been treated many times for actinic keratoses and basal cell carcinomas. Surgical treatment had included total nasectomy, excision, and replacement of the skin of the upper and lower lips and the chin. Due to the multiplicity of morphologic patterns, it was difficult to subtype the sarcomas. Ultrastructural studies showed histiocyte-like, fibroblast-like and vasoformative cells suggesting an origin from a pluripotential mesenchymal stem cells.
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An unusual congenital tumorous malformation of mesenchymal tissue caused severe respiratory distress in a premature infant. The solid mass, which replaced almost the entire left lung, was composed of interlacing fascicles of spindle cells that percolated through otherwise well-developed fetal lung tissue. The normal anatomic arrangement of bronchial components was altered, but bronchial cartilages were present. Ultrastructural study of the lesion showed mesenchymal cells with fibroblastic differentation.
Most Pasteurella multocida infections in humans have been associated with animal bites or scratches. While a variety of infections involving P multocida, unassociated with animal trauma, have been described, infections of the urinary tract are rare. We studied a case in which P multocida was isolated from the urine of a woman with advanced uterine cervical cancer. In most of the cases in which P multocida has been isolated from urine, the patients have had anatomic defects of the urinary tract, as well as an underlying chronic illness. These host-related characteristics appear to be important in the pathogenesis of P multocida urinary tract infection.
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We examined the ability of human lysozyme (HLZM) to enhance the immunogenicity of a methylcholanthrene-induced murine fibrosarcoma of C57BL/10 mice. Following s.c. injection of 10(4) live tumor cells, 100% of mice developed palpable tumors within 16 +/- 3 (S.D.) days. Prechallenge immunization with 10(6) irradiated tumor cells with or without complete Freund's adjuvant resulted in protection from tumor development in 14 and 22% of mice, respectively. Incubation of tumor cells with HLZM prior to immunization approximately doubled the degree of protection, with 42 to 44% of mice remaining free of tumor. This enhanced protection was dependent on the enzymatic activity of HLZM. These data suggest that HLZM enhances tumor cell immunogenicity in this model.
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To examine the relation between social support and appraisal of life events in predicting adaptive, externalizing, and internalizing behavior in 265 school-age children, child-report on both a global and a significant other measure of social support was used. Life event scores were separated into events endorsed as negative and events endorsed as positive by the child. Using hierarchical regression analyses, the present study tested two models: main effects and moderator models of the relation between life events, social support, and behavioral outcome. Support was found for global social support and positive life events in predicting adaptive, externalizing, and internalizing behavior. Gender differences were also found. Support was found for both the main effects and moderator models of the association between life events and global social support. Appraisal of life events as positive appears to compensate for lower levels of global social support. Appraisal is discussed as a possible protective factor from maladjustment after exposure to major life events.
We have analyzed leukocyte to lung adhesive interactions and neutrophil-mediated lung injury using a rat lung organ culture system. Rat lung slices were maintained in tissue culture on gelatin sponges floating at the gas-liquid interface. Maintenance of three-dimensional alveolar structure, critical to the viability of lung tissue, was achieved by instilling 0.5% agarose (in 37 degrees C RPMI 1640) into the lungs during tissue explanation. Quantitative neutrophil to lung adhesive interactions were examined using an adaptation of the Woodruff-Stamper frozen section binding assay. Pretreatment of organ cultures with recombinant human tumor necrosis factor (rhTNF) resulted in a protein synthesis-dependent three- to fourfold increase in adhesiveness for neutrophils. Time course and mononuclear leukocyte binding experiments revealed that TNF-induced rat lung adhesiveness peaks at 4 h and is largely neutrophil-specific. Agonist-induced activation of neutrophils in the presence of [3H]leucine-labeled organ cultures resulted in lung injury as assessed by radioisotope release. These observations are consistent with endothelial cell culture data that indicate that TNF-induced endothelium exhibits a protein synthesis-dependent increase in adhesiveness for neutrophils. These data validate rat lung organ cultures as a model system that can be used to assess mechanisms of neutrophil adhesion and leukocyte-mediated tissue injury.
Among 123 older African Americans recruited into a church-based exercise program, 43% had dropped out within four months. Compared to those who did not drop out, drop outs had lower levels of education, energy to do activities, energy to exercise, and self-ratings of health, all based on measures taken before the class. Over half of those who dropped out cited non-exercise related health problems, and 17% caregiver responsibilities. Of those who dropped out, half said they would continue to exercise and 32% said they intended to start within the next six months.
BACKGROUND: The study objective was to compare the accuracy of radiograph interpretation by emergency and family physicians with radiologists' overreadings. METHODS: We undertook a historical chart review of patients seen consecutively during a 1-year period at an inner-city emergency department of a medium-volume community hospital. The participants were a racially mixed group of 22,141 patients for whom 12,083 radiographs had been ordered. We compared interpretations by emergency and family physicians with those of radiologists who performed overreadings within 24 hours. This intervention was performed retrospectively. Measurements consisted of descriptive statistics, such as percentages and chi-square analysis. RESULTS: The main result was an overall discrepancy rate (ODR) of 1.1 percent. This figure is significantly different (P < 0.0001) from the lowest reported overall discrepancy rate to date (2.8 percent). CONCLUSIONS: Consistently low overall discrepancy rates have specific implications for the medical practice and reimbursement of primary care physicians for radiograph interpretation.