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Query: UMLS:C0032285 (pneumonia)
 54,520 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A mouse model of pulmonary tuberculosis induced by the intratracheal instillation of live and virulent mycobacteria strain H37-Rv was used to examine the relationship of the histopathological findings with the local kinetics production and cellular distribution of tumour necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha) and transforming growth factor-beta (TGF-beta). The histopathological and immunological studies showed two phases of the disease: acute or early and chronic or advanced. The acute phase was characterized by inflammatory infiltrate in the alveolar-capillary interstitium, blood vessels and bronchial wall with formation of granulomas. During this acute phase, which lasted from 1 to 28 days, high percentages of TNF-alpha and IL-1 alpha immunostained activated macrophages were observed principally in the interstium-intralveolar inflammatory infiltrate and in granulomas. Electron microscopy studies of these cells, showed extensive rough endoplasmic reticulum, numerous lysosomes and occasional mycobacteria. Double labelling with colloid gold showed that TNF-alpha and IL-1 alpha were present in the same cells, but were confined to separate vacuoles near the Golgi area, and mixed in larger vacuoles near to cell membrane. The concentration of TNF-alpha and IL-1 alpha as well as their respective mRNAs were elevated in the early phase, particularly at day 3 when the bacillary count decreased. A second peak was seen at days 14 and 21-28 when granulomas appeared and evolved to full maturation. In contrast, TGF-beta production and numbers of immunoreactive cells were low in comparison with the advanced phase of the disease. The chronic phase was characterized by histopathological changes indicative of more severity (i.e. pneumonia, focal necrosis and extensive interstitial fibrosis) with a decrease in the TNF-alpha and IL-1 alpha production that coincided with the highest level of TGF-beta. The bacillary counts were highest as the macrophages became large, vacuolated foamy cells, and containing numerous bacilli with immunoreactivity to mycobacterial lipids and lipoarabinomannan (LAM). These macrophages displayed poor and scarce TNF-alpha and IL-1 alpha immunostaining but still strong immunoreactivity to TGF-beta. These cytokine production kinetics and the spatial relationship between immunostained cells and lung lesions corroborate the important role of TNF-alpha and IL-1 alpha in the constitution of granulomas and immune protection during the early phase of the infection, and also suggest an important if not primary role for TGF-beta in the immunopathogenesis of the advanced forms of pulmonary tuberculosis.
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PMID:Analysis of the local kinetics and localization of interleukin-1 alpha, tumour necrosis factor-alpha and transforming growth factor-beta, during the course of experimental pulmonary tuberculosis. 917 16

The generation of a vigorous inflammatory response is essential for rapid clearance of microbes from the alveolar space. The magnitude of the inflammatory response is tightly controlled by host-derived cytokines, which mediate lung inflammation by serving as leukocyte chemoattractants, leukocyte activating factors, or afferent signals in the induction or regulation of other effector molecules. In this chapter, the role of specific cytokines in lung innate and adaptive immunity against bacterial, mycobacterial, fungal, and parasitic pathogens is reviewed. Future directions regarding the use of specific forms of immunotherapy, including compartmentalized cytokine delivery using gene therapy, as adjuvant therapy in the treatment of pneumonia are explored.
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PMID:Cytokines and pulmonary host defenses. 919 51

A murine model of pneumonia due to the mouse pneumonitis agent (MoPn [murine Chlamydia trachomatis]) in mice deficient in CD4+ T-cell function (major histocompatibility complex [MHC] class II function [class II-/-], CD8+ T-cell function (beta2-microglobulin deficient, MHC class I deficient [Beta2m-/-]), B-cell function (C57BL/10J-Igh(tm1Cgn) [Igh-/-]), and gamma interferon (IFN-gamma) (C57BL/6-Ifg(tm1) [Ifg-/-]) or interleukin-4 (C57BL/6J(tm1Cgn29) [IL4-/-]) production was employed to determine if each of these mechanisms was critical to resistance against reinfection by C. trachomatis or if alternate compensatory mechanisms existed in their absence which could potentially be exploited in vaccine development. Resistance to reinfection with MoPn was heavily dependent on CD4+ T cells. CD4 T-cell-deficient MHC class II-/- mice were very susceptible to reinfection with MoPn, showing the critical importance of this cell to resistance. These mice lacked antibody production but did produce IFN-gamma, apparently by mechanisms involving NK and CD8+ T cells. Neutralization of IFN-gamma in these mice led to a borderline increase in susceptibility, showing a possible role (albeit small) of this cytokine in this setting. Tumor necrosis factor alpha (TNF-alpha) was also present at increased levels in these mice. Igh-/- B-cell-deficient mice which produce no antibody to MoPn were only modestly more susceptible to reinfection than immunized B-cell-intact controls, showing that antibody, including lung immunoglobulin A, is not an absolute requirement for relatively successful host defense in this setting. Levels of lung IFN-gamma and TNF-alpha were elevated in Igh-/- mice compared to those in controls. IL-4-/- mice (deficient in Th2 function) could develop normal resistance to reinfection with MoPn. Conversely, normal mice rendered partially IFN-gamma deficient by antibody depletion were somewhat impaired in their ability to develop acquired immunity to MoPn, again indicating a role for this cytokine in host defense against rechallenge. Of most importance, however, congenitally IFN-gamma-deficient Ifg-/- mice (which have elevated levels of other cytokines, including TNF-alpha and granulocyte-macrophage colony-stimulating factor) are paradoxically more resistant to MoPn rechallenge than controls, showing that IFN-gamma is not an absolute requirement for acquired resistance and implying the presence of very effective compensatory host defense mechanism(s). In vivo depletion of TNF-alpha significantly increased MoPn levels in the lungs in these mice. Thus, resistance to reinfection in this model is flexible and multifactorial and is heavily dependent on CD4+ T cells, with a probable role for IFN-gamma and TNF-alpha and a possible modest role for Th1-dependent antibody. Since IFN-gamma was dispensable in host defense, the highly effective mechanism or mechanisms which can compensate for its absence (which include TNF-alpha) deserve further study.
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PMID:Humoral and cellular immunity in secondary infection due to murine Chlamydia trachomatis. 919 62

Mycobacteria are ubiquitous in the environment, but they are not part of the normal human microbial flora. It has been suggested that variable contact with mycobacteria can influence susceptibility to mycobacterial pathogens and the efficacy of subsequent Mycobacterium bovis BCG vaccination. To test this, mice were immunized with high or low doses of an environmental saprophyte, M. vaccae, that is intensely immunogenic as an autoclaved preparation. Two months later, they received an intratracheal challenge with M. tuberculosis H37Rv. Recipients of a low Th1-inducing dose (10(7) organisms) were partially protected and maintained a high ratio of interleukin 2 (IL-2)-positive to IL-4-positive cells in the perivascular, peribronchial, and granulomatous areas of the lung, whereas in unimmunized controls the IL-4-positive cells increased markedly between days 21 and 28. In contrast, recipients of the high dose (10(9) organisms), which primes Th2 as well as Th1 cytokine production, died more rapidly than unimmunized controls and showed massive pneumonia from day 7. The ratio of IL-2-positive to IL-4-positive cells in all compartments of the lung rapidly fell to 1 by day 14 for these animals. These events correlated with cytokine mRNA profiles and with increases in the local toxicity of tumor necrosis factor alpha (TNF-alpha), demonstrable only when a major Th2 component was present. These data indicate that cross-reactive epitopes present in an environmental saprophyte can evoke either protective responses or responses that increase susceptibility to M. tuberculosis. The latter are associated with the presence of a Th2 component and increased sensitivity to TNF-alpha.
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PMID:Pathogenesis of tuberculosis in mice exposed to low and high doses of an environmental mycobacterial saprophyte before infection. 923 93

Induction of pneumonia in C57Bl/6 mice by intranasal inoculation with 10(6) cfu of Streptococcus pneumoniae resulted in sustained expression of interleukin (IL)-6 mRNA in lungs and increases in lung and plasma IL-6 concentrations. In IL-6-deficient (IL-6-/-) mice, pneumonia was associated with higher lung levels of the proinflammatory cytokines tumor necrosis factor-alpha, IL-1beta, and interferon-gamma and of the antiinflammatory cytokine IL-10 than in wild type (IL-6+/+) mice (all P < .05). Also, the plasma concentrations of soluble tumor necrosis factor receptors were higher in IL-6-/- mice (P < .05), while the acute-phase protein response was strongly attenuated (P < .01). Lungs harvested from IL-6-/- mice 40 h after inoculation contained more S. pneumoniae colonies (P < .05). IL-6-/- mice died significantly earlier from pneumococcal pneumonia than did IL-6+/+ mice (P < .05). During pneumococcal pneumonia, IL-6 down-regulates the activation of the cytokine network in the lung and contributes to host defense.
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PMID:Interleukin-6 gene-deficient mice show impaired defense against pneumococcal pneumonia. 923 10

Pseudomonas aeruginosa is the most frequent Gram-negative pathogen causing nosocomial pneumonia. Four different strains of P. aeruginosa (including three isogenic transposon mutants) were utilized in experiments in mice to characterize the specific patterns of cytokine generation in response to bacterial products and cytotoxicity. Intratracheal instillation of any of the strains led to the up-regulation of IL-1beta, IL-6, and TNF-alpha mRNA. Instillation of the cytotoxic strains (PA103, PA103tox::omega) led to IL-10 mRNA up-regulation in the lungs and increased concentrations of IL-10 in the blood. In contrast, the instillation of the noncytotoxic strains (PA01, PA103exsA::omega) did not lead to an increase in IL-10 mRNA in the lungs or to an increase of IL-10 concentration in blood. IL-10 production appears to be a response to either cellular injury or to specific cytotoxic exoproducts produced by the bacteria. The systemic administration of rIL-10 significantly decreased the lung injury and the mortality in mice who had received the cytotoxic strains. The improvement in survival induced by administration of rIL-10 required the concomitant presence of IFN-gamma, as blockade of IFN-gamma with a neutralizing Ab led to 100% mortality, despite the administration of rIL-10. These results suggest that IL-10 is produced in response to specific bacterial products and that there is a potential role for IL-10 in the treatment of cytotoxic P. aeruginosa pneumonia.
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PMID:IL-10 improves lung injury and survival in Pseudomonas aeruginosa pneumonia. 930 Jul 9

4 wk after intraperitoneal inoculation of 0.2 LD50 (50% lethal dose) of murine cytomegalovirus (MCMV) in adult BALB/c mice, MCMV remained detectable in the salivary glands, but not in the lungs or other organs. When the T cells of these mice were activated in vivo by a single injection of anti-CD3 monoclonal antibody, interstitial pneumonitis was induced in the lungs that were free of the virus with an excessive production of the cytokines. In the lungs of such mice persistently infected with MCMV, the mRNA of the cytokines such as IL-2, IL-6, TNF-alpha, and IFN-gamma were abundantly expressed 3 h after the anti-CD3 injection, and the elevated levels continued thereafter. A marked expression of inducible nitric oxide synthetase (iNOS) was then noted in the lungs, suggesting that such cytokines as TNF-alpha and IFN-gamma may have induced iNOS. Although the increase in NO formation was demonstrated by the significant elevation of the serum levels of nitrite and nitrate, the interstitial pneumonitis was not associated with either increased superoxide formation or peroxynitrite-induced tyrosine nitration. Nevertheless, the administration of an NO antagonist also alleviated the interstitial pneumonitis provoked by anti-CD3 mAb. Based on these findings, it was concluded that MCMV-associated pneumonitis is mediated by a molecule of cytokine-induced NO other than peroxynitrite.
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PMID:Nitric oxide mediates murine cytomegalovirus-associated pneumonitis in lungs that are free of the virus. 931 83

The current study examined the proliferative capacity and cytokine secretion pattern of peripheral blood mononuclear cells (PBMC) from human immunodeficiency virus type 1 (HIV-1)-infected patients in response to the major surface glycoprotein (MSG) of Pneumocystis carinii. PBMC from AIDS patients with <200 CD4 cells/mL had significantly less proliferative responses to MSG than did healthy controls. Cytokine analysis indicated that interferon-gamma secreted in response to MSG was also significantly less. There was no significant difference in interleukin-4 levels following incubation with MSG between any of the groups; however, all the HIV-infected persons had slightly elevated levels. When the CDC class C3 patients who had a previous episode of P. carinii pneumonia were compared with those who had not had a previous episode, there was a significant increase in the proliferative response to MSG and in interleukin-4 secretion. CDC class C3 patients who had a previous episode of P. carinii pneumonia showed a predominately Th2 response to MSG.
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PMID:Proliferative and cytokine responses of human T lymphocytes isolated from human immunodeficiency virus-infected patients to the major surface glycoprotein of Pneumocystis carinii. 941 98

The aim of this study was to determine the lung levels of metallothionein (MT), a free radical scavenger, because oxygen-derivated free radicals (ODFRs) have been involved both in reperfusion injury of transplanted lungs and in cardiac or renal allograft destruction. First, MT localization was evaluated in 14 normal human lung biopsy specimens. Then, in lung transplant recipients, MT content in BAL fluid (BALF) and its transcription rate in alveolar macrophages (AMs) were determined. The BALFs of 69 patients were separated into six groups: lung transplant recipients in clinically stable condition (CSR), those with acute rejection (AR), asymptomatic cytomegalovirus infection (ACMV), cytomegalovirus pneumonitis (CMVP), bronchiolitis obliterans syndrome (BOS), and patients without transplants who served as control subjects (NTCs). In normal lungs, 83% of AMs were positively stained. MT staining was also observed in pleural endothelial cells and basal cells from bronchial epithelium. In lung transplant recipients, MT levels in BALF were significantly higher in patients with CSR, AR, ACMV, and CMVP compared with NTCs, while during BOS, MT had a significantly lower level compared with other lung transplant groups. However, no difference among groups was found concerning MT-II messenger RNA expression in AMs, showing that, as in normal lung, AMs are not the only cells that produce MT. These data report for the first time to our knowledge MT cell distribution in human lung with specific emphasis on its enhanced levels after lung transplantation, even in the absence of complication. Possible correlation among MT levels, ODFRs, cytokine levels, and corticosteroid treatment during complications of lung transplantation are discussed.
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PMID:Metallothionein expression in human lung and its varying levels after lung transplantation. Toulouse Lung Transplantation Group. 949 54

Besides its well-established effects on granulocytopoiesis, granulocyte colony-stimulating factor (G-CSF) has been shown to have direct effects on the recruitment and bactericidal ability of neutrophils, resulting in improved survival of experimentally infected animals. We studied the effect of G-CSF on the course of experimental pneumonia induced by Klebsiella pneumoniae, an important gram-negative bacillary pulmonary pathogen. Using a highly reproducible murine model, we here show the paradoxical finding that mortality from infection was significantly increased when animals received G-CSF before induction of pneumonia. Administration of G-CSF promoted replication of bacteria in the liver and spleen, thus indicating an impairment rather than an enhancement of antibacterial mechanisms. By contrast, a monoclonal antibody against Klebsiella K2 capsule significantly reduced bacterial multiplication in the lung, liver, and spleen, and abrogated the increased mortality caused by G-CSF. In vitro studies showed a direct effect of G-CSF on K pneumoniae resulting in increased capsular polysaccharide (CPS) production. When bacteria were coincubated with therapeutically achievable concentrations of G-CSF, phagocytic uptake and killing by neutrophils was impaired. Western blot analysis showed three binding sites of G-CSF to K pneumoniae. Binding of 125I-G-CSF to K pneumoniae was displaced by an excess of unlabeled G-CSF, whereas an unrelated cytokine, interleukin-1alpha, did not compete with G-CSF binding to the bacteria. Thus, in this model, the direct effect of G-CSF on a bacterial virulence factor, CPS production, outweighed any beneficial effect of G-CSF on recruitment and stimulation of leukocytes.
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PMID:Granulocyte colony-stimulating factor worsens the outcome of experimental Klebsiella pneumoniae pneumonia through direct interaction with the bacteria. 951 54


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