Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

Untreated infections with Chlamydia trachomatis commonly result in ascending infection to fallopian tubes and subsequent immune-mediated tubal pathology in females. The proposed immune-mediated injury may be associated with the increased recruitment of CD4 cells to the upper genital tract (GT) (oviducts) in comparison to the lower GT (cervix) during infection, as shown in animal models. To understand the mechanisms responsible for this biased recruitment of CD4 cells within the GT, we characterized chemokine expression patterns in the upper and lower GTs in mice during infection with the murine pneumonitis biovar of Chlamydia trachomatis. Enzyme-linked immunosorbent assays of supernatants from GT homogenates revealed that the levels of the Th1-associated chemokines CXCL9 (monokine induced by gamma interferon), CXCL10 (interferon-inducible protein 10), and CCL5 (RANTES) were significantly higher in the upper GT than in the lower GT after infection, while the CCL3 (macrophage inflammatory protein 1 alpha) level was not increased. In contrast, the level of chemokine CCL11 (eotaxin) was significantly elevated in the lower GT later in the course of infection. Increased levels of mRNA confirmed the selective differences in chemokine expression within the upper and lower GTs. The increased levels of Th1-inducible chemokines in the upper GT were not due to differences in the magnitude of infection or progesterone pretreatment. These data demonstrate that the upper and lower regions of the GT respond differently to Chlamydia infection.
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PMID:Chemokine expression patterns differ within anatomically distinct regions of the genital tract during Chlamydia trachomatis infection. 1185 42

Pneumonia virus of mice (PVM; Paramyxoviridae, subfamily Pneumovirinae) is an important pathogen for the study of physiologically relevant acute inflammatory responses in rodent hosts. In contrast to the severe symptomatology observed in response to infection with PVM strain J3666, infection with strain 15 resulted in few clinical symptoms, limited cellular inflammatory response, and no production of macrophage inflammatory protein-1alpha or monocyte chemoattractant peptide (MCP)-1. Microarray analysis of transcripts from lung tissue indicates that PVM J3666 infection promotes up-regulation of specific proinflammatory genes, most notably interferon (IFN)-1beta, IFN response genes, and chemokines MCP-1, MCP-3, RANTES (regulated on activation, normally T cell-expressed and secreted), and eotaxin. Of these, only RANTES expression increased in response to infection with strain 15, with no increased expression of IFN or IFN response genes, despite ongoing viral replication. These results suggest that pneumovirus replication alone is insufficient to promote antiviral inflammation and that evaluation of the more divergent strain-specific pneumovirus proteins may provide some intriguing leads toward the molecular basis of this differential response.
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PMID:Differential expression of proinflammatory cytokine genes in vivo in response to pathogenic and nonpathogenic pneumovirus infections. 1208 56

Recruitment of neutrophils into alveolar air spaces is an early event in the pathogenesis of pneumonia due to Streptococcus pneumoniae. This results from chemokines released by activated endothelial and epithelial cells and alveolar macrophages. Culture supernatants of 6 wild-type strains of S. pneumoniae, shown to contain choline-binding protein A (CbpA; clades A and B), induced release of chemokine CXCL8 from the human alveolar epithelial cell line A549, whereas a CbpA deletion mutant elicited significantly reduced CXCL8 release, compared with that of its isogenic parent (P<.01). Recombinant CbpA up-regulated expression of messenger RNA of CXCL8 and CCL2 but not of XCL1, CXCL10, CCL1, CCL3, CCL4, or CCL5 in A549 cells and induced increased secretion of CXCL8, CCL2, CXCL1, and CXCL5 in a dose- and time-dependent manner. CbpA also increased the expression of intercellular adhesion molecule 1 (CD54) by A549 cells. Thus, CbpA of S. pneumoniae induces the transcription and release of proinflammatory molecules by human alveolar epithelial cells.
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PMID:Choline-binding protein A of Streptococcus pneumoniae elicits chemokine production and expression of intercellular adhesion molecule 1 (CD54) by human alveolar epithelial cells. 1240 94

The gram-negative bacterium Pseudomonas aeruginosa is an opportunistic human pathogen associated with both an acute lung disease in patients with hospital-acquired pneumonia and a chronic, progressive lung disease in individuals with cystic fibrosis. A unique characteristic of this bacterium in its natural environment is the secretion of a wide variety of factors designed to ensure its growth and survival. Evidence suggests, however, that when present in the human host, these same factors may contribute to disease. In the course of studying the effect of P. aeruginosa secretory factors on airway epithelial cells, we observed that metalloproteases in bacterial-conditioned medium, as well as purified alkaline protease and elastase, degraded human RANTES, monocyte chemotactic protein-1 (MCP-1), and epithelial neutrophil-activating protein-78 (ENA-78). Under identical conditions, interleukin-8 (IL-8) was significantly more resistant to proteolysis. Degradation was accompanied by a loss of chemotactic activity. These data suggest that metalloproteases from P. aeruginosa could alter the relative amounts of critical immunomodulatory cytokines in the airway and, thus, could contribute to the pathophysiology observed in P. aeruginosa-associated lung disease.
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PMID:Metalloproteases from Pseudomonas aeruginosa degrade human RANTES, MCP-1, and ENA-78. 1285 57

Chemokines are increased and may exert effects on both inflammatory and remodeling events in idiopathic pulmonary pneumonia (IIP). Accordingly, we examined the concomitant expression of inflammatory CC chemotactic cytokines or chemokines and their corresponding receptors in surgical lung biopsies obtained at the time of disease diagnosis and pulmonary fibroblasts grown from these biopsies. By gene array analysis, upper and lower lobe biopsies and primary fibroblast lines from patients with usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia, and respiratory bronchiolitis-interstitial lung disease, but not patients without IIP, exhibited CCL7 gene expression. TAQMAN, immunohistochemical, and ELISA analyses confirmed that CCL7 was expressed at significantly higher levels in UIP lung biopsies compared with biopsies from patients with nonspecific interstitial pneumonia, respiratory bronchiolitis-interstitial lung disease, and from patients without IIP. Higher levels of CCL7 were present in cultures of IIP fibroblasts compared with non-IIP fibroblasts, and CCL5, a CCR5 agonist, significantly increased the synthesis of CCL7 by UIP fibroblasts. Together, these data suggest that CCL7 is highly expressed in biopsies and pulmonary fibroblast lines obtained from patients with UIP relative to patients with other IIP and patients without IIP, and that this CC chemokine may have a major role in the progression of fibrosis in this IIP patient group.
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PMID:Enhanced monocyte chemoattractant protein-3/CC chemokine ligand-7 in usual interstitial pneumonia. 1533 89

We present an antiviral-immunomodulatory therapeutic strategy involving the chemokine receptor antagonist Met-RANTES, which yields significant survival in the setting of an otherwise fatal respiratory virus infection. In previous work, we demonstrated that infection with the natural rodent pathogen pneumonia virus of mice involves robust virus replication accompanied by cellular inflammation modulated by the CC chemokine macrophage inflammatory protein 1alpha (MIP-1alpha). We found that the antiviral agent ribavirin limited virus replication in vivo but had no impact on morbidity and mortality associated with this disease in the absence of immunomodulatory control. We show here that ribavirin reduces mortality, from 100% to 10 and 30%, respectively, in gene-deleted CCR1(-/-) mice and in wild-type mice treated with the small-molecule chemokine receptor antagonist, Met-RANTES. As MIP-1alpha-mediated inflammation is a common response to several distantly related respiratory virus pathogens, specific antiviral therapy in conjunction with blockade of the MIP-1alpha/CCR1 inflammatory cascade may ultimately prove to be a useful, generalized approach to severe respiratory virus infection and its pathological sequelae in human subjects.
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PMID:Functional antagonism of chemokine receptor CCR1 reduces mortality in acute pneumovirus infection in vivo. 1525 70

Pneumonia virus of mice (PVM) is the first infection model that replicates features of severe human respiratory syncytial virus (hRSV) disease in the mouse. The PVM model has highlighted the importance of inflammation to the pathogenesis of severe disease, demonstrating that the inflammatory response remains active and acute even when virus replication ceases in response to appropriate antiviral therapy. The fact that the inflammatory response continues and is not completely linked to ongoing virus replication indicates the need for concurrent anti-inflammatory or, ideally, specific immunomodulatory therapy. The chemokine macrophage inflammatory protein-1alpha (MIP-1alpha) and its receptor, CC chemokine receptor 1 (CCR1), have been identified as crucial to the inflammatory response to PVM and hRSV and thus as elements to exploit for potential immunomodulatory control. Biochemical blockade of MIP-1alpha signaling with the CCR1 antagonist met-RANTES prevents the inflammatory response to PVM and results in reduced morbidity and mortality when administered in conjunction with the antiviral agent ribavirin. Ongoing exploration into the biology of PVM infection will identify other pathways and targets to be exploited for immunomodulatory control of hRSV and related severe respiratory virus infections.
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PMID:The pneumonia virus of mice infection model for severe respiratory syncytial virus infection: identifying novel targets for therapeutic intervention. 1562 52

Understanding the requirements for protection against pneumococcal carriage and pneumonia will greatly benefit efforts in controlling these diseases. Recently, it has been shown that genetic polymorphisms can result in diminished expression of CCL5, which results in increased susceptibility to and progression of infectious diseases. We show that CCL5, together with Th cytokine mRNA expression, is temporally up-regulated during pneumococcal carriage. To determine the contribution of CCL5 to pneumococcal surface antigen A-specific humoral and cellular pneumococcal immunity, mice were treated with anti-CCL5 or control Abs before and during Streptococcus pneumoniae strain EF3030-challenge for the initiation of carriage. CCL5 blockade resulted in a decrease of CD4(+) and CD8(+) T cells as well as CD11b(+) cells in the spleen, cervical lymph node, lung, and nasopharyngeal associated lymphoid tissue during the recognition phase of the pneumococcal adaptive immune response. CCL5 blockade significantly reduced the Ag-specific IgG2a and IgG1 Abs in serum and IgA Ab levels in nasal washes. These decreases also corresponded to reductions in Ag-specific T cell (mucosal and systemic) responses. CCL5 inhibition resulted in decreasing the quantity of IL-4- and IFN-gamma-secreting CD4(+) T cells and increasing the number of Ag-specific IL-10-producing CD4(+) T cells; these changes combined also corresponded with the transition from pneumococcal carriage to lethal pneumonia. These data suggest that CCL5 is an essential factor for the induction and maintenance of protective pneumococcal immunity.
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PMID:CCL5 modulates pneumococcal immunity and carriage. 1645 92

Influenza A virus pneumonia is characterized by severe lung injury and high mortality. Early infection elicits a strong recruitment of monocytes from the peripheral blood across the endo-/epithelial barrier into the alveolar air space. However, it is currently unclear which of the infected resident lung cell populations, alveolar epithelial cells or alveolar macrophages, elicit monocyte recruitment during influenza A virus infection. In the current study, we investigated whether influenza A virus infection of primary alveolar epithelial cells and resident alveolar macrophages would elicit a basal-to-apical monocyte transepithelial migration in vitro. We found that infection of alveolar epithelial cells with the mouse-adapted influenza A virus strain PR/8 strongly induced the release of monocyte chemoattractants CCL2 and CCL5 followed by a strong monocyte transepithelial migration, and this monocytic response was strictly dependent on monocyte CCR2 but not CCR5 chemokine receptor expression. Analysis of the adhesion molecule pathways demonstrated a role of ICAM-1, VCAM-1, integrin-associated protein (CD47), and junctional adhesion molecule-c on the epithelial cell surface interacting with monocyte beta(1) and beta(2) integrins and integrin-associated protein in the monocyte transmigration process. Importantly, addition of influenza A virus-infected alveolar macrophages further enhanced monocyte transmigration across virus-infected epithelium in a TNF-alpha-dependent manner. Collectively, the data show an active role for virus-infected alveolar epithelium in the regulation of CCL2/CCR2-dependent monocyte transepithelial migration during influenza infection that is essentially dependent on both classical beta(1) and beta(2) integrins but also junctional adhesion molecule pathways.
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PMID:Alveolar epithelial cells direct monocyte transepithelial migration upon influenza virus infection: impact of chemokines and adhesion molecules. 1684 92

Community-acquired pneumonia (CAP) is associated with high morbidity and mortality, and Streptococcus pneumoniae is the most prevalent causal pathogen identified in CAP. Impaired pulmonary host defense increases susceptibility to pneumococcal pneumonia. S. pneumoniae may up-regulate Toll-like receptor (TLR)-2 expression and activate TLR-2, contributing to pneumococcus-induced immune responses. In the current study, the course of severe murine pneumococcal pneumonia after pulmonary TLR-2-mediated immunostimulation with synthetic macrophage-activating lipopeptide-2 (MALP-2) was examined. Intratracheal MALP-2 application evoked enhanced proinflammatory cytokine and chemokine release, resulting in recruitment of polymorphonuclear neutrophils (PMN), macrophages, and lymphocytes into the alveolar space in WT, but not in TLR-2-deficient mice. In murine lungs as well as in human alveolar epithelial cells (A549), MALP-2 increased TLR-2 expression at both mRNA and protein level. Blood leukocyte numbers and populations remained unchanged. MALP-2 application 24 hours before intranasal pneumococcal infection resulted in increased levels of CCL5 associated with augmented leukocyte recruitment, and decreased levels of anti-inflammatory IL-10 in bronchoalveolar lavage fluid. Clinically, MALP-2-treated as compared with untreated mice showed increased survival, reduced hypothermia, and increased body weight. MALP-2 also reduced bacteremia and improved bacterial clearance in lung parenchyma, as examined by immunohistochemistry. In conclusion, pulmonary immunostimulation with MALP-2 before infection with S. pneumoniae improved local host defense and increased survival in murine pneumococcal pneumonia.
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PMID:Immunostimulation with macrophage-activating lipopeptide-2 increased survival in murine pneumonia. 1893 26


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