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)

Cyclosporin A (CsA) blocks T cell activation by interfering with the Ca2+-dependent phosphatase, calcineurin. Proinflammatory responses to bacteria that are activated by Ca2+-fluxes in airway cells are a potential target for CsA. Although local immunosuppression may be advantageous to control airway inflammation, it could also increase susceptibility to bacterial pneumonia and invasive infection. As aerosolized CsA is currently under study in lung transplantation, we examined its direct effects on airway cells as well as in a murine model of pneumonia. Epithelial interleukin-6 production was very effectively inhibited by CsA, whereas CXCL8 production, the major PMN chemokine, was only modestly diminished. Responses to a TLR2 agonist Pam3Cys were more sensitive to CsA inhibition than those activated by Pseudomonas aeruginosa. CsA substantially blocked activation of nuclear factor of activated T cells and cAMP-responsive element-binding protein (P<0.001), inhibited CCAAT/enhancer-binding protein by 50% (P<0.05), and minimally blocked activator protein-1 and nuclear factor-kappaB responses to bacteria in epithelial cells. The in vitro effects were confirmed in a mouse model of P. aeruginosa infection with similar rates of PMN recruitment, pneumonia and mortality in CsA treated and control mice. These studies indicate that airway epithelial signaling is a potential target for CsA, and such local immunosuppression may not increase susceptibility to invasive infection.
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PMID:The effect of cyclosporin A on airway cell proinflammatory signaling and pneumonia. 1587 61

Pneumonia is frequently associated with changes in coagulation and fibrinolysis in the bronchoalveolar space. To determine the effect of lipopolysaccharide (LPS) on the hemostatic balance in the human lung, six healthy subjects inhaled nebulized LPS or saline in a randomized cross-over study and bronchoalveolar lavage fluid was obtained six hours thereafter. LPS induced soluble tissue factor and thrombin-antithrombin complexes and inhibited plasminogen activator activity in BALF. Additionally plasminogen activator inhibitor type 1 production was upregulated after LPS inhalation. LPS also elicited local activation of neutrophils (release of elastase, myeloperoxidase and bactericidal/permeability increasing protein) and secretion of interleukin (IL)-6 and IL-8. Inhalation of LPS by healthy humans reproduces major features of the procoagulant response to inflammatory and infectious lung diseases and may be used as a novel model to evaluate pathogenetic mechanisms and new interventions.
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PMID:Activation of coagulation and inhibition of fibrinolysis in the lung after inhalation of lipopolysaccharide by healthy volunteers. 1596 85

This study explored, the inflammatory response during experimental pneumonia in surfactant-depleted animals as a function of ventilation strategies and surfactant treatment. Following intratracheal instillation of Group B streptococci (GBS), surfactant-depleted piglets were treated with conventional (positive-end expiratory pressure (PEEP) of 5 cmH2O, tidal volume 7 mL x kg(-1)) or open lung ventilation. During the latter, collapsed alveoli were recruited by applying high peak inspiratory pressures for a short period of time, combined with high levels of PEEP and the smallest possible pressure amplitude. Subgroups in both ventilation arms also received exogenous surfactant. Conventionally ventilated healthy animals receiving GBS and surfactant-depleted animals receiving saline served as controls. In contrast with both control groups, surfactant-depleted animals challenged with GBS and conventional ventilation showed high levels of interleukin (IL)-8, tumour necrosis factor (TNF)-alpha and myeloperoxidase in bronchoalveolar lavage fluid after 5 h of ventilation. Open lung ventilation attenuated this inflammatory response, but exogenous surfactant did not. Systemic dissemination of the inflammatory response was minimal, as indicated by low serum levels of IL-8 and TNF-alpha. In conclusion, the current study indicates that the ventilation strategy, but not exogenous surfactant, is an important modulator of the inflammation during Group B streptococci pneumonia in mechanically ventilated surfactant-depleted animals.
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PMID:Effect of ventilation strategy and surfactant on inflammation in experimental pneumonia. 1599 97

Salmonella enterica serovar Choleraesuis is an enteric pathogen of swine, producing septicemia, enterocolitis, pneumonia, and hepatitis. The initial molecular events at the site of Salmonella infection are hypothesized to be critical in the initiation of innate and adaptive immune responses; however, the acute immune response elicited by porcine intestinal tissues is not well understood. To address this need, we employed explants of jejunal Peyer's patch (JPP) mucosa from pigs to examine Salmonella-induced immune responses under controlled conditions as well as to overcome limitations of whole animal approaches. JPP explants mounted in Ussing chambers maintained normal histological structure for 2 h and stable short-circuit current and electrical conductance for 2.5 h. After ex vivo luminal exposure to Salmonella serovar Choleraesuis, JPP responded with an increase in mRNA expression of IL-1beta and IL-8, but not TNFalpha. Increased IL-1beta and IL-8 expression were dependent on efficient Salmonella adhesion and internalization, whereas mutant Salmonella did not induce inflammatory cytokine expression. Commensal enteric bacteria, present in some experiments, also did not induce inflammatory cytokine expression. These findings indicate that Salmonella uptake by Peyer's patch is important in the induction of an innate response involving expression of IL-1beta and IL-8, and that ex vivo intestinal immune tissue explants provide an intact tissue model that will facilitate investigation of mucosal immunity in swine.
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PMID:Salmonella enterica serovar Choleraesuis infection of the porcine jejunal Peyer's patch rapidly induces IL-1beta and IL-8 expression. 1611 91

In order to define the significance of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) upon progression from sepsis or severe sepsis to septic shock a prospective study was designed with 90 enrolled patients with septic syndrome due to ventilator-associated pneumonia. Blood was sampled on seven consecutive days upon initiation of symptoms and concentrations of tumour necrosis factor-alpha (TNFalpha), interleukin-6 (IL-6), IL-8 and sTREM-1 were estimated in serum by an enzymeimmunoassay. No differences in concentrations of TNFalpha, IL-6 and IL-8 were found between patients with sepsis, severe sepsis and septic shock on the first day of presentation of symptoms. Patients presenting with septic shock had concentrations of sTREM-1 significantly higher than both patients with sepsis and severe sepsis on the first day; no difference was found between patients with sepsis and severe sepsis. A positive correlation was detected between sTREM-1 and the white blood cell count. Serum levels of sTREM-1 were significantly lower in patients where VAP resolved compared to those where VAP did not resolve; similar findings were noted between patients who eventually survived and those who died. IL-6 followed the kinetics of sTREM-1 in correlation to patients's prognosis; levels of TNFalpha and IL-8 were unrelated to prognosis. It is concluded that sTREM-1 is particularly increased upon evolution from sepsis or severe sepsis to septic shock. Its sustained increase is an indication of poor outcome. The underlined pathophysiological role of sTREM-1 for the transition from sepsis or severe sepsis to septic shock might constitute a novel target for immunomodulatory therapy.
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PMID:Does soluble triggering receptor expressed on myeloid cells-1 play any role in the pathogenesis of septic shock? 1617 57

Mycoplasma pneumoniae is a major cause of community-acquired pneumonia. We evaluated the efficacy of LBM415, a novel peptide deformylase inhibitor antimicrobial agent, for the treatment of M. pneumoniae pneumonia in a mouse model. Eight-week-old BALB/c mice were intranasally inoculated once with 10(7) CFU of M. pneumoniae. Groups of mice were treated with LBM415 (50 mg/kg of body weight) or placebo subcutaneously daily for 13 days, starting 24 h after inoculation. Groups of mice were evaluated at the baseline; at days of treatment 1, 3, 6, and 13; and at 7 days after treatment. The MIC of LBM415 against M. pneumoniae was <0.005 microg/ml. LBM415-treated mice had significantly lower bronchoalveolar lavage fluid M. pneumoniae concentrations than placebo-treated mice on days 6 and 13 of treatment. Compared with placebo treatment, therapy with LBM415 significantly decreased lung histopathology scores at days 3, 6, and 13 of treatment and at 7 days after treatment. Airway obstruction was significantly lower in LBM415-treated mice than in placebo-treated mice on days 1, 3, and 6 of treatment and after 7 days of therapy, while airway hyperresponsiveness was significantly lower only on day 3 of therapy. The bronchoalveolar lavage fluid concentrations of tumor necrosis factor alpha, gamma interferon (IFN-gamma), interleukin-6 (IL-6), IL-12, KC (functional IL-8), monocyte chemotactic protein 1, macrophage inflammatory protein 1alpha, monokine induced by IFN-gamma, and IFN-inducible protein 10 were significantly reduced in LBM415-treated mice compared with the levels in placebo-treated mice. There were no differences in the bronchoalveolar lavage fluid concentrations of granulocyte-macrophage colony-stimulating factor, IL-1beta, IL-2, IL-4, IL-5, and IL-10 between the two groups of mice. LBM415 therapy had beneficial microbiologic, histologic, respiratory, and immunologic effects on acute murine M. pneumoniae pneumonia.
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PMID:Evaluation of LBM415 (NVP PDF-713), a novel peptide deformylase inhibitor, for treatment of experimental Mycoplasma pneumoniae pneumonia. 1618 89

The phospholipids sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) act via transmembrane receptors S1P 1-5 and LPA 1-3, respectively. Both have been implicated in inflammatory responses. S1P and LPA receptor profiles on neutrophils of patients with pneumonia compared with healthy subjects were determined by PCR and Western blotting. Chemotaxis studies were performed to assess functional differences. S1P or LPA receptors were immunoprecipitated from neutrophils to assess receptor heterodimerization with CXCR1, an IL-8 receptor, by Western blotting. Receptors S1P 1, 4, and 5 and LPA 2 were expressed on neutrophils from both subject groups, but S1P 3 and LPA 1 receptor expression was mainly confined to neutrophils of patients with pneumonia. Chemotaxis of neutrophils from patients with pneumonia compared with control subjects was significantly increased in response to S1P and LPA. Pretreatment with S1P or LPA reduced IL-8-induced neutrophil chemotaxis and transcriptional expression of the CXCR1 receptor. Receptors S1P 3 and 4 and LPA 1 formed constitutive heterodimers with CXCR1. LPA treatment reduced the amount of LPA 1/CXCR1 heterodimer. Therefore, profiles of S1P and LPA receptors differ between neutrophils of patients with pneumonia and control subjects, with consequences for neutrophil function.
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PMID:Neutrophil sphingosine 1-phosphate and lysophosphatidic acid receptors in pneumonia. 1622 6

To gain further insight into the pathogenesis of porcine enzootic pneumonia (PEP), cytokine expression in different pulmonary compartments was examined. Mycoplasma hyopneumoniae (Mh) and proinflammatory and immunoregulatory cytokines (IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10 and TNF-alpha) were detected by immunohistochemical methods in porcine lungs experimentally infected with Mh. Ten pigs were inoculated intranasally with Mh and killed in pairs weekly from 1- to 5-week post-inoculation (wpi). Three Mh-free pigs were taken as controls. Mh-antigen was shown in paraffin-wax-embedded tissues by immunohistochemistry in the luminal surface of bronchial and bronchiolar epithelial cells of all Mh-infected pigs. Significant increase in cytokine expression was detected on snap-frozen tissues from the bronchoalveolar exudate of the airways, mononuclear cells of the alveolar septa and macrophages and lymphocytes of the peribronchial and peribronchiolar lymphoid tissue, from 1 wpi onwards, compared to expression in non-pneumonic lungs. The main cytokines in the BALT of Mh-infected animals that showed an increase were IL-2, IL-4, IL-8, IL-10 and TNF-alpha. In the alveolar septa and bronchoalveolar exudate IL-1 (alpha and beta), IL-2, IL-4, IL-8 and IL-10 expression also increased in infected animals.
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PMID:Cytokine expression in porcine lungs experimentally infected with Mycoplasma hyopneumoniae. 1632 64

The recruitment of polymorphonuclear leukocytes (PMN) from the vascular space to the alveolar air space is an early event in host defense against pneumococcal pneumonia. Pneumolysin is a virulence factor for Streptococcus pneumoniae, but a specific role for pneumolysin in neutrophil-endothelial cell interactions has not been investigated. Using a Transwell system, we studied in vitro migration of PMNs across a monolayer of human pulmonary microvascular endothelial cells in response to wild-type S. pneumoniae (D39) and a pneumolysin-deficient mutant (plnA(-)) incubated on the abluminal surface of the monolayer. S. pneumoniae induction of PMN migration was dose dependent and elicited by > or =10(5) D39. Mutants lacking pneumolysin had dramatically reduced potency for eliciting PMN migration compared with the parent strain (5 x 10(6) plnA(-) elicits 18.6% PMN migration vs. 55.5% for 5 x 10(6) D39). The disparity between D39 and plnA(-) persisted in ethanol-fixed bacteria, consistent with the properties of pneumolysin. Neither conditioned medium from D39 nor purified pneumolysin elicited PMN migration to the same extent as the intact D39, suggesting that the role of pneumolysin in eliciting PMN migration requires a more complex interaction between the organism, the endothelium, and the PMN. Both D39 and plnA(-) adhered to, and translocated across, the endothelium in the abluminal to luminal direction and elicited similar levels of IL-8 production. Neither strain elicited upregulation of the endothelial adhesion molecules ICAM-1, VCAM-1, or E-selectin, and they did not cause translocation of NF-kappaB to the nucleus. These findings demonstrate a novel role for pneumolysin in pneumococcus-induced PMN recruitment across the pulmonary endothelium.
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PMID:Neutrophil transendothelial migration in vitro to Streptococcus pneumoniae is pneumolysin dependent. 1633 81

Hospital-acquired pneumonia is a serious and potentially life-threatening complication, with reported pneumonia-attributable mortality rates as high as 50%. Rapid diagnosis and immediate institution of adequate empirical antimicrobial treatment are of paramount importance in patient management. Nevertheless, some patients deteriorate and develop respiratory insufficiency, septic shock and a multiorgan dysfunction syndrome. Early recognition of these patients might help in reducing morbidity and mortality. Elevated systemic levels of proinflammatory cytokines (IL-1beta, IL-6, IL-8 and IL-10) at the time of diagnosis of hospital-acquired pneumonia appear to be indicative of subsequent progression to septic shock. Should this now become a part of patient management?
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PMID:Can we predict septic shock in patients with hospital-acquired pneumonia? 1628 65


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