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)

Fibrosis, characterized by the accumulation of collagen, is a consequence of a chronic inflammatory response. The purpose of this study was to determine if the mRNA expression of the chemokines, lymphotactin (Ltn), RANTES, eotaxin, macrophage inflammatory protein (MIP)-1 alpha, -1 beta, and -2, interferon-inducible protein 10 (IP-10), and monocyte chemotactic protein-1 (MCP-1), are altered during the development of radiation-induced pneumonitis and fibrosis. Further, we wished to determine if these changes differ between two strains of mice that vary in their sensitivity to radiation fibrosis. Fibrosis-sensitive (C57BL/6) and fibrosis-resistant (C3H/HeJ) mice were irradiated with a single dose of 12.5 Gy to the thorax. Total lung RNA was prepared and hybridized utilizing RNase protection assays. Data were quantified by phosphorimaging and results normalized to a constituitively expressed mRNA L32. 8 weeks post-irradiation most chemokines measured were elevated to varying degrees. The degree of elevation of each chemokine was identical in both strains. This suggested that chemotactic activity for neutrophils, macrophages, and lymphocytes were occurring during pneumonitis. By 26 weeks post-irradiation, messages encoding Ltn, RANTES, IP-10, and MCP-1 were elevated only in fibrosis sensitive (C57BL/6) mice. In situ hybridization demonstrated that MCP-1 and RANTES transcripts were produced predominantly from macrophages and lymphocytes. These studies suggest that lymphocytic recruitment and activation are key components of radiation-induced fibrosis.
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PMID:Alterations in the expression of chemokine mRNA levels in fibrosis-resistant and -sensitive mice after thoracic irradiation. 963 54

Protection against infections with the intracellular bacterium Chlamydia spp. requires Th1-polarized CD4+ T cell immunity. In BALB/c mouse lung infections, immediate innate and nascent Chlamydia-specific immune responses following intranasal inoculation of Chlamydia psittaci strain B577 were modulated by 7-day i.p. administration of murine rIL-12, the initiation cytokine for Th1 immunity. Treatment with IL-12 reduced the severity of chlamydial pneumonia, abolished mortality (37.5% in untreated mice), and significantly reduced numbers of chlamydial organisms in lungs. On day 4 after inoculation, the neutrophil:macrophage ratio in bronchointerstitial pneumonias was 1.96 in untreated mice and 0.51 in IL-12-treated mice. This immediate, IL-12-mediated shift in innate inflammatory phenotype was correlated with a significant reduction of lung concentrations of the neutrophil chemoattractant macrophage inflammatory protein (MIP)-2 (putative murine homologue of human IL-8), monocyte chemotactic protein-1, and TNF-alpha; and a reduction in MIP-1alpha and IFN-gamma, at high-dose infection only, and IL-12-independent IL-10 levels. Chlamydia-specific Ab titers and Ig isotype ratios indicated an IL-12-dependent Th1 shift. Recall responses of IL-12-primed mice to secondary chlamydial lung infection eliminated chlamydiae more effectively and generated a lung cytokine profile conducive to perpetuation of the Th1 memory population. These data support the hypothesis that genetic differences in endogenous IL-12 production and response pathways could determine disease outcomes characterized by poor chlamydial clearance and a purulent inflammatory infiltrate vs effective elimination of chlamydiae in a macrophage-dominated response.
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PMID:IL-12 administered during Chlamydia psittaci lung infection in mice confers immediate and long-term protection and reduces macrophage inflammatory protein-2 level and neutrophil infiltration in lung tissue. 997 97

Epidemiology studies associate increased pulmonary morbidity with episodes of high particulate air pollution (size range 0.1-10 microm diameter, PM10). Pneumonia, often viral in origin, is increased following episodes of high PM10 pollution. Therefore, this study was undertaken to investigate how PM10 alters airway inflammatory responses to respiratory syncytial virus (RSV), a frequent cause of viral pneumonia in infants and the elderly. Supernatants of unexposed and PM10-exposed alveolar macrophage (AM) cultured with uninfected or RSV-infected airway epithelial cells were assessed for a number of chemokines responsible for inflammatory responses in the lung. AM exposure to PM10 in the absence of infection resulted in a significant increase in interleukin (IL)-8 and macrophage inflammatory protein (MIP)-1alpha production but not in MIP-1beta or monocyte chemotactic protein (MCP)-1. AM responded to RSV infection by the production of IL-8, MIP-1alpha, MIP-1beta, and MCP-1, while RANTES was derived solely from the RSV-infected bronchial epithelial cell line BEAS-2B. In the presence of PM10, the AM response to RSV was blunted. RSV-induced MCP-1 was significantly decreased, and the levels of MIP-1 and IL-8 were lower than expected from a combined response to PM10 and RSV. Furthermore, AM analyzed for uptake of virus showed a 50% decrease in viral antigen when exposed to PM10 RSV-induced production of RANTES by epithelial cells was decreased in the presence of AM but not affected by PM10 exposure. Taken together, these results suggest that AM-regulated inflammatory responses to viral infection are altered by exposure to PM10 in a manner that may result in increased spread of infection and thus may increase viral pneumonia-related hospital admissions.
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PMID:Exposure to urban air particulates alters the macrophage-mediated inflammatory response to respiratory viral infection. 1049 14

Streptococcus pneumoniae pneumonia frequently occurs in leukopenic hosts, and most patients subsequently develop lung injury and septicemia. However, few correlations have been made so far between microbial growth, inflammation, and histopathology of pneumonia in specific leukopenic states. In the present study, the pathogenesis of pneumococcal pneumonia was investigated in mice rendered leukopenic by the immunosuppressor antineoplastic drug cyclophosphamide. Compared to the immunocompetent state, cyclophosphamide-induced leukopenia did not hamper interleukin-1 (IL-1), IL-6, macrophage inflammatory protein-1 (MIP-1), MIP-2, and monocyte chemotactic protein-1 secretion in infected lungs. Leukopenia did not facilitate bacterial dissemination into the bloodstream despite enhanced bacterial proliferation into lung tissues. Pulmonary capillary permeability and edema as well as lung injury were enhanced in leukopenic mice despite the absence of neutrophilic and monocytic infiltration into their lungs, suggesting an important role for bacterial virulence factors and making obvious the fact that neutrophils are ultimately not required for lung injury in this model. Scanning and transmission electron microscopy revealed extensive disruption of alveolar epithelium and a defect in surfactant production, which were associated with alveolar collapse, hemorrhage, and fibrin deposits in alveoli. These results contrast with those observed in immunocompetent animals and indicate that leukopenic hosts suffering from pneumococcal pneumonia are at a higher risk of developing diffuse alveolar damage.
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PMID:Pathogenesis of pneumococcal pneumonia in cyclophosphamide-induced leukopenia in mice. 1211 31

Idiopathic pneumonia syndrome is characterized by noninfectious diffuse lung injury after myeloablative chemotherapy and bone marrow transplant. Because little is known about its pathogenesis after autologous-based regimens, we have developed a murine model that closely mimics the human lung disease process. Using an autologous regimen similar to that used for patients with metastatic breast cancer, mice developed pulmonary injury as early as 1 day posttransplant. This lung injury was most dramatically characterized by decreased lung compliance that was associated with an intense monocytic cellular infiltrate of activated macrophages. This influx was preceded by an acute elevation in monocyte chemotactic protein-1 and macrophage inflammatory protein-1alpha. The conditioning regimen caused substantial oxidative stress as manifest by elevations in lung lipid peroxidation and oxidized glutathione. To test the hypothesis that oxidation is directly responsible for the lung toxicity, we administered the antioxidant, n-acetylcysteine. These mice showed substantially less lung injury, thus providing direct evidence that oxidative stress plays a distinct role in the development of lung injury in the early periautologous bone marrow transplant period. Attenuation of lung oxidative stress and/or inflammation in patients undergoing autologous bone marrow transplant may reduce the subsequent development of idiopathic pneumonia syndrome.
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PMID:Idiopathic pneumonia syndrome after syngeneic bone marrow transplant in mice. 1247 Oct 68

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

Invasive aspergillosis is a severe pneumonia that is usually fatal despite currently available therapy. The disease disproportionately afflicts immunocompromised patients, indicating the critical importance of the immune status of the host in this infection, but the defense mechanisms against this pathogen remain incompletely understood. In the current study, we hypothesized that the chemokine ligand monocyte chemotactic protein-1, also designated CC chemokine ligand-2 (MCP-1/CCL2) is necessary for effective host defense against invasive aspergillosis in immunocompromised hosts. We found a rapid and marked induction of MCP-1/CCL2 in the lungs of neutropenic mice with invasive aspergillosis. Neutralizing MCP-1/CCL2 resulted in twofold greater mortality and greater than threefold increase in pathogen burden in the lungs. Neutralization of MCP-1/CCL2 also resulted in reduced recruitment of NK cells to the lungs at early time points, but did not affect the number of other leukocyte effector cells in the lungs. Ab-mediated depletion of NK cells similarly resulted in impaired defenses against the infection, resulting in a greater than twofold increase in mortality and impaired clearance of the pathogen from the lungs. These data establish MCP-1/CCL2-mediated recruitment of NK cells to the lungs as a critical early host defense mechanism in invasive aspergillosis and demonstrate NK cells to be an important and previously unrecognized effector cell in this infection.
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PMID:Chemokine-mediated recruitment of NK cells is a critical host defense mechanism in invasive aspergillosis. 1467 81

Pneumonia virus of mice (PVM; family Paramyxoviridae) is a natural pathogen of rodents that reproduces important clinical features of severe respiratory syncytial virus infection in humans. As anticipated, PVM infection induces transcription of IFN antiviral response genes preferentially in wild-type over IFN-alphabetaR gene-deleted (IFN-alphabetaR-/-) mice. However, we demonstrate that PVM infection results in enhanced expression of eotaxin-2 (CCL24), thymus and activation-regulated chemokine (CCL17), and the proinflammatory RNase mouse eosinophil-associated RNase (mEar) 11, and decreased expression of monocyte chemotactic protein-5, IFN-gamma-inducible protein-10, and TLR-3 in lung tissue of IFN-alphabetaR-/- mice when compared with wild type. No differential expression of chemokines MIP-1alpha or MIP-2 or Th2 cytokines IL-4 or IL-5 was observed. Differential expression of proinflammatory mediators was associated with distinct patterns of lung pathology. The widespread granulocytic infiltration and intra-alveolar edema observed in PVM-infected, wild-type mice are replaced with patchy, dense inflammatory foci localized to the periphery of the larger blood vessels. Bronchoalveolar lavage fluid from IFN-alphabetaR-/- mice yielded 7- to 8-fold fewer leukocytes overall, with increased percentages of eosinophils, monocytes, and CD4+ T cells, and decreased percentage of CD8+ T cells. Differential pathology is associated with prolonged survival of the IFN-alphabetaR-/- mice (50% survival at 10.8 +/- 0.6 days vs the wild type at 9.0 +/- 0.3 days; p < 0.02) despite increased virus titers. Overall, our findings serve to identify novel transcripts that are differentially expressed in the presence or absence of IFN-alphabetaR-mediated signaling, further elucidating interactions between the IFN and antiviral inflammatory responses in vivo.
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PMID:Inflammatory responses to pneumovirus infection in IFN-alpha beta R gene-deleted mice. 1617 21

Pneumonia is a major complication of human immunodeficiency virus (HIV) pathogenesis but it develops only after prolonged infection. We used the macaque model to explore a hypothesis that the disease is a two-stage process, the first stage being establishment of the viral infection in the lung and the second being amplification of virus replication by host factors induced by chemical agents or opportunistic pathogens in the lung. Bleomycin, a chemical known to induce diffuse alveolar damage and pulmonary fibrosis with accumulation of macrophages and a rich T helper type 2 (Th2) cytokine environment, was inoculated intratracheally into five of eight SHIV 89.6P-infected macaques and into one uninfected macaque. Three additional simian HIV (SHIV)-infected macaques without bleomycin treatment served as untreated virus controls. Although none of the animals became clinically ill, bleomycin induced classical host responses in the lungs of all the treated, virus-infected macaques. There was enhanced production of the chemokine, monocyte chemotactic protein-1 (MCP-1), that had previously been shown to cause enhanced replication of the virus. Four of the five treated animals developed more productive SHIV infection in the lungs compared with the infected untreated animals. Enhanced virus replication was found primarily in infiltrating macrophages. Enhanced replication of the virus in the lungs was associated with host factors induced by the drug and supported the hypothesis for a two-stage process of pulmonary pathogenesis.
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PMID:Bleomycin treatment causes enhancement of virus replication in the lungs of SHIV-infected macaques. 1722 Mar 71

Mononuclear phagocytes are critical components of the innate host defense of the lung to inhaled bacterial pathogens. The monocyte chemotactic protein CCL2 plays a pivotal role in inflammatory mononuclear phagocyte recruitment. In this study, we tested the hypothesis that increased CCL2-dependent mononuclear phagocyte recruitment would improve lung innate host defense to infection with Streptococcus pneumoniae. CCL2 transgenic mice that overexpress human CCL2 protein in type II alveolar epithelial cells and secrete it into the alveolar air space showed a similar proinflammatory mediator response and neutrophilic alveolitis to challenge with S. pneumoniae as wild-type mice. However, CCL2 overexpressing mice showed an improved pneumococcal clearance and survival compared with wild-type mice that was associated with substantially increased lung mononuclear phagocyte subset accumulations upon pneumococcal challenge. Surprisingly, CCL2 overexpressing mice developed bronchiolitis obliterans upon pneumococcal challenge. Application of anti-CCR2 Ab MC21 to block the CCL2-CCR2 axis in CCL2 overexpressing mice, though completely abrogating bronchiolitis obliterans, led to progressive pneumococcal pneumonia. Collectively, these findings demonstrate the importance of the CCL2-CCR2 axis in the regulation of both the resolution/repair and remodelling processes after bacterial challenge and suggest that overwhelming innate immune responses may trigger bronchiolitis obliterans formation in bacterial lung infections.
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PMID:Lung-specific overexpression of CC chemokine ligand (CCL) 2 enhances the host defense to Streptococcus pneumoniae infection in mice: role of the CCL2-CCR2 axis. 1744 67


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