Helicobacter pylori infection is associated with gastric epithelial damage, including apoptosis, ulceration, and cancer. Although bacterial factors and the host response are believed to contribute to gastric disease, no receptor has been identified that explains how the bacteria attach and signal the host cell to undergo apoptosis. Using H. pylori as “bait” to capture receptor proteins in solubilized membranes of gastric epithelial cells, class II major histocompatibility complex (MHC) molecules were identified as a possible receptor. Signaling through class II MHC molecules leading to the induction of apoptosis was confirmed using cross-linking IgM antibodies to surface class II MHC molecules. Moreover, binding of H. pylori and the induction of apoptosis were inhibited by antibodies recognizing class II MHC. Since type 1 T helper cells are present during infection and produce interferon (IFN)-γ, which increases class II MHC expression, gastric epithelial cell lines were exposed to H. pylori in the presence or absence of IFN-γ. IFN-γ increased the attachment of the bacteria as well as the induction of apoptosis in gastric epithelial cells. In contrast to MHC II–negative cell lines, H. pylori induced apoptosis in cells expressing class II MHC molecules constitutively or after gene transfection. These data describe a novel receptor for H. pylori and provide a mechanism by which bacteria and the host response interact in the pathogenesis of gastric epithelial cell damage.

The transcription factor nuclear factor (NF)-kB controls the expression of numerous respiratory syncytial virus (RSV)-inducible inflammatory and immunomodulatory genes. Using a BALB/c mouse model, the present article shows that RSV potently and specifically activates NF-kB in vivo, a process that involves nuclear translocation of the subunits RelA, p50, and c-Rel in the lung. By depletion of alveolar macrophages (AMs) in BALB/c mice and use of C3H/HeJ mice lacking a functional Toll-like receptor (TLR)-4 signaling pathway, we demonstrate the existence of distinct but sequentially integrated RSV-inducible early NF-kB responses in the lung. The first response occurs early after RSV inoculation, is AM and TLR4 dependent, and is viral replication independent, whereas the second response involves epithelial cells and/or inflammatory cells, is TLR4 independent, and requires viral replication. NF-kB may be considered a central activator of not only inflammatory but also innate immune responses to RSV.Respiratory syncytial virus (RSV), the major cause of serious lower respiratory tract infections in infancy and early childhood [1], can be considered among the most potent biological stimuli inducing the expression and/or secretion of proinflammatory and immunomodulatory mediators [2-4]. These events have been extensively demonstrated in airway epithelial cells, the primary site of RSV replication, and in other cell types that are targets of abortive viral replication or viral attachment only (such as monocytes/macrophages, eosinophils, and neutrophils). In vitro, RSV has been shown to induce expression of a number of genes in epithelial cells and macrophages, including the cytokines interleukin (IL)-1 [5], tumor necrosis factor (TNF)-a, IL-6 [6], and IL-10 [7]; the CXC chemokines IL-8, growth-related oncogene (GRO)-a, epithelial-derived neutrophil-activating protein(ENA)-

Lower respiratory tract disease caused by respiratory syncytial virus (RSV) is characterized by profound airway mucosa inflammation, both in infants with naturally acquired infection and in experimentally inocuRespiratory syncytial virus (RSV) is the major cause of serious lower respiratory disease in infancy and early childhood (5). Bronchiolitis, the more severe clinical manifestation of RSV infection, is characterized by necrosis and sloughing of the respiratory epithelium and plugging of the small bronchioles with fibrin and mucus. An intense peribronchial infiltration of mononuclear cells (lymphocytes and monocytes) occurs, with considerable edema (1, 8, 10). In addition, presence of the granule-associate cytotoxic proteins histamine, eosinophil cationic protein, and major basic protein in nasopharyngeal secretions and tracheobronchial aspirates suggests that RSV infection triggers the migration to the airways and activation of basophils and eosinophils (12,17,37,46). The evidence of an inverse correlation between the levels of these cytotoxic mediators and the degree of oxygen saturation in RSV-infected infants further underscores the critical role played by mucosal inflammation in the pathogenesis of RSV airway disease (12,45,46).The mouse model shows close similarity to the pathogenesis of RSV-induced lower airway disease in humans. In BALB/c mice, RSV rapidly replicates in the lungs after intranasal inoculation, and induces mononuclear cell infiltration around peribronchial and perivascular tissues (41) and objective plethysmographic signs of pulmonary dysfunction (i.e., increased respiratory rates and airway hyperresponsiveness) (29, 44).These pathophysiologic changes correlate with the amount of viral inoculum (44), consistent with the observation that more severe disease occurs in infected children who have higher concentrations of RSV in their secretions (4, 16).The mechanisms that regulate selective recruitment of inflammatory cells to the airways and their activation following RSV infection are still largely unknown. Similarly, virus-or host-specific factors that may influence these events have not been yet identified. Much of the cellular response at sites of tissue inflammation is controlled by gradients of chemotactic factors that direct leukocyte transendothelial migration and movement through the extracellular matrix. The composition of this cellular response is dependent upon the discrete target cell selectivity of these chemotactic molecules. Chemokines, a superfamily of small chemotactic cytokines, have emerged as central regulatory molecules in inflammatory, immune, and infectious processes of the lung (28). Chemokines have been primarily divided into two main subfamilies, CXC (␣) and CC (␤), upon their sequence homology and the position of the first two cysteine residues. In general, this subdivision is mirrored by the activity of these two chemokine groups on neutrophils (CXC) or monocytes, eosinophils, and basophils (CC). However, within the CXC subfamily, chemokines such as gamma inte...

IMPORTANCE No interventions have yet been identified to reduce the risk of acute kidney injury in the setting of cardiac surgery.OBJECTIVE To determine whether remote ischemic preconditioning reduces the rate and severity of acute kidney injury in patients undergoing cardiac surgery. DESIGN, SETTING, AND PARTICIPANTSIn this multicenter trial, we enrolled 240 patients at high risk for acute kidney injury, as identified by a Cleveland Clinic Foundation score of 6 or higher, between August 2013 and June 2014 at 4 hospitals in Germany. We randomized them to receive remote ischemic preconditioning or sham remote ischemic preconditioning (control). All patients completed follow-up 30 days after surgery and were analyzed according to the intention-to-treat principle.INTERVENTIONS Patients received either remote ischemic preconditioning (3 cycles of 5-minute ischemia and 5-minute reperfusion in one upper arm after induction of anesthesia) or sham remote ischemic preconditioning (control), both via blood pressure cuff inflation. MAIN OUTCOMES AND MEASURESThe primary end point was the rate of acute kidney injury defined by Kidney Disease: Improving Global Outcomes criteria within the first 72 hours after cardiac surgery. Secondary end points included use of renal replacement therapy, duration of intensive care unit stay, occurrence of myocardial infarction and stroke, in-hospital and 30-day mortality, and change in acute kidney injury biomarkers.RESULTS Acute kidney injury was significantly reduced with remote ischemic preconditioning (45 of 120 patients [37.5%]) compared with control (63 of 120 patients [52.5%]; absolute risk reduction, 15%; 95% CI, 2.56%-27.44%; P = .02). Fewer patients receiving remote ischemic preconditioning received renal replacement therapy (7 [5.8%] vs 19 [15.8%]; absolute risk reduction, 10%; 95% CI, 2.25%-17.75%; P = .01), and remote ischemic preconditioning reduced intensive care unit stay (3 days [interquartile range, 2-5]) vs 4 days (interquartile range, 2-7) (P = .04). There was no significant effect of remote ischemic preconditioning on myocardial infarction, stroke, or mortality. Remote ischemic preconditioning significantly attenuated the release of urinary insulinlike growth factor-binding protein 7 and tissue inhibitor of metalloproteinases 2 after surgery (remote ischemic preconditioning, 0.36 vs control, 0.97 ng/mL 2 /1000; difference, 0.61; 95% CI, 0.27-0.86; P < .001). No adverse events were reported with remote ischemic preconditioning.CONCLUSIONS AND RELEVANCE Among high-risk patients undergoing cardiac surgery, remote ischemic preconditioning compared with no ischemic preconditioning significantly reduced the rate of acute kidney injury and use of renal replacement therapy. The observed reduction in the rate of acute kidney injury and the need for renal replacement warrants further investigation.TRIAL REGISTRATION German Clinical Trials Register Identifier: DRKS00005333

Respiratory syncytial virus (RSV) produces intense pulmonary inflammation, in part through its ability to induce chemokine synthesis in infected airway epithelial cells. RANTES (regulated upon activation, normally T-cell expressed and presumably secreted) is a CC chemokine which recruits and activates monocytes, lymphocytes, and eosinophils, all cell types present in the lung inflammatory infiltrate induced by RSV infection. In this study, we analyzed the mechanism of RSV-induced RANTES promoter activation in human type II alveolar epithelial cells (A549 cells). Promoter deletion and mutagenesis experiments indicate that RSV requires the presence of five different cis regulatory elements, located in the promoter fragment spanning from ؊220 to ؉55 nucleotides, corresponding to NF-B, C/EBP, Jun/CREB/ATF, and interferon regulatory factor Respiratory syncytial virus (RSV) is an enveloped, negativesense single-stranded RNA virus (18). Since its isolation, RSV has been identified as a leading cause of epidemic respiratory tract illness in children in the United States and worldwide. In fact, RSV is so ubiquitous that it will infect 100% of children before the age of 3 (15). In infants and young children, RSV is the most common etiologic agent of bronchiolitis and is also responsible for 50% of pneumonia cases in children up to 2 years of age (38). Each year approximately 100,000 children are hospitalized with RSV disease, with an estimated annual cost close to $300 million in the United States alone (15, 17).The main targets of RSV infection are respiratory epithelial cells. In bronchiolitis and pneumonia, RSV antigen can be identified in epithelial cells from throughout the lower respiratory tract, with less virus found in lungs of children with bronchiolitis than in lungs of children with pneumonia, where large amounts of viral antigen are detected. Necrosis of the airway epithelium is associated with mononuclear cell infiltration, mainly peribronchial and perivascular in bronchiolitis, and between the interalveolar walls, leading to alveolar filling, in pneumonia (reviewed in reference 38). Moreover, the presence of cell-specific inflammatory mediators in nasopharyngeal secretions and in tracheobronchial aspirates of children with bronchiolitis suggests that RSV infection triggers the migration to the airways and local activation of eosinophil and basophil leukocytes (11,13).Much of the cellular response at sites of tissue inflammation is controlled by gradients of chemotactic factors that direct leukocyte transendothelial migration and movement through the extracellular matrix. The composition of this cellular response is dependent on the discrete target cell selectivity of these chemotactic molecules. Chemokines, a family of small chemotactic cytokines, regulate the migration and activation of leukocytes and therefore play a key role in inflammatory and infectious processes of the lung (29). RANTES (regulated upon activation, normal T-cell expressed and presumably secreted) is a member of the CC branch of the che...

The presence of histamine and eosinophil cationic protein in nasopharyngeal secretions of infants with respiratory syncytial virus (RSV)-induced bronchiolitis implies the activation of basophil and eosinophil leukocytes, but the specific mechanism of their recruitment has not been elucidated. Chemokines are potent and selective leukocyte chemotactic molecules that are also expressed by airway epithelial cells. Therefore, the pattern of chemokines produced in response to RSV infection was investigated in primary cultures of human nose- and adenoid-derived epithelial cells. Interleukin-8, growth-related peptide-alpha, and monocyte chemotactic protein-1 were constitutively released by uninfected epithelial cells and were not further enhanced by infection with RSV. RANTES (regulated upon activation, normal T cell-expressed and -secreted), which was present in negligible concentrations in uninfected cultures, was strongly induced by RSV infection, in a dose- and time-dependent manner. Through the release of RANTES, epithelial cells may control the selective concentration and activation of basophils and eosinophils in RSV-infected airway mucosa.

IntroductionSepsis has been identified as a risk factor for human cytomegalovirus (CMV) reactivation in critically ill patients. However, the contribution of CMV reactivation on morbidity and mortality is still controversial. Therefore, we analyzed the incidence and impact of CMV reactivation on outcome in patients with severe sepsis.MethodsIn a prospective longitudinal double-blinded observational study, 97 adult nonimmunosuppressed CMV-seropositive patients with new onset of severe sepsis were included. Leukocytes, plasma and tracheal secretions were examined weekly for CMV-DNA by PCR. Tracheal secretions were additionally tested for HSV (Herpes Simplex Virus)-DNA. The influence of CMV-reactivation on the endpoints was analysed by Cox proportional-hazard regression analysis. Time-dependency was evaluated by landmark analysis.ResultsSix out 97 died and five were discharged from the hospital within 72 hours and were excluded of the analysis. CMV reactivation occurred in 35 of the 86 (40.69%) analysed patients. HSV infection occurred in 23 of the 35 (65.7%) CMV reactivators. In 10 patients CMV-plasma-DNAemia appeared with a DNA-content below 600 copies/ml in four cases and a peak amount of 2,830 copies/ml on average. In patients with and without CMV reactivation mortality rates were similar (37.1% vs. 35.3%, P = 0.861), respectively. However, in the multivariate COX regression analyses CMV reactivation was independently associated with increased length of stay in the ICU (30.0, interquartile range 14 to 48 vs. 12.0, interquartile range 7 to 19 days; HR (hazard ratio) 3.365; 95% CI (confidence interval) 1.233 to 9.183, P = 0.018) and in the hospital (33.0, interquartile range 24 to 62 vs. 16.0, interquartile range 10 to 24 days, HR 3.3, 95% CI 1.78 to 6.25, P < 0.001) as well as prolonged mechanical ventilation (22.0, interquartile range 6 to 36 vs. 7.5, interquartile range 5 to 15.5 days; HR 2.6,CI 95% 1.39 to 4.94; P < 0.001) and impaired pulmonary gas exchange (six days, interquartile range 1 to 17, vs. three, interquartile range 1 to 7, days in reactivators vs. non-reactivators, P = 0.038). HSV reactivation proved not to be a risk factor for these adverse effects.ConclusionsThese data indicate an independent correlation between CMV reactivation and increased morbidity in the well-defined group of nonimmunosuppressed patients with severe sepsis, but CMV reactivation had no impact on mortality in this group with low CMV-DNA plasma levels. Thus, the potential harms and benefits of antiviral treatment have to be weighed cautiously in patients with severe sepsis or septic shock.

Respiratory syncytial virus (RSV) is the major etiologic agent of severe epidemic lower respiratory tract infections in infancy. Airway mucosal inflammation plays a critical role in the pathogenesis of RSV disease in both natural and experimental infections. RSV is among the most potent biological stimuli that induce the expression of inflammatory genes, including those encoding chemokines, but the mechanism(s) that controls virus-mediated airway inflammation in vivo has not been fully elucidated. Herein we show that the inoculation of BALB/c mice with RSV results in rapid activation of the multisubunit IB kinase (IKK) in lung tissue. IKK transduces upstream activating signals into the rate-limiting phosphorylation (and proteolytic degradation) of IB␣, the inhibitory subunit that under normal conditions binds to the nuclear factor (NF)-B complex and keeps it in an inactive cytoplasmic form. Mice treated intranasally with interleukin-10 or with a specific cell-permeable peptide that blocks the association of the catalytic subunit IKK␤ with the regulatory protein NEMO showed a striking reduction of lung NF-B DNA binding activity, chemokine gene expression, and airway inflammation in response to RSV infection. These findings suggest that IKK␤ may be a potential target for the treatment of acute or chronic inflammatory diseases of the lung.Respiratory syncytial virus (RSV), a single-stranded negativesense RNA virus of the Paramyxoviridae family, is well recognized as the major cause of serious lower respiratory disease in infancy and early childhood as well as in the elderly. In bronchiolitis, the most severe clinical manifestation of RSV infection, an intense peribronchial infiltration of mononuclear cells (lymphocytes and monocytes) occurs concomitantly with considerable edema, sloughing of the respiratory epithelium, and plugging of the small bronchioles with fibrin and mucus (1,8).Chemokines, a superfamily of small, structurally related molecules, induce the migration and activation of leukocytes and have emerged as central regulatory molecules in inflammatory, immune, and infectious processes of the lung (29). Indirect evidence suggests that these inflammatory molecules may play a critical role in the pathogenesis of RSV disease in infants. We recently reported that in the BALB/c mouse model, which shows close similarity to the pathogenesis of RSV-induced lower airway disease in humans, intranasal (i.n.) infection with RSV results in the rapid inducible expression of lung chemokines belonging to the CXC, CC, and C families. The levels of chemokines were dependent on the dose of RSV inoculum and paralleled the intensity of lung cellular inflammation. Furthermore, genetically altered mice with a selective deletion of the chemokine MIP-1␣ gene (Ϫ/Ϫ) had a significant reduction in lung inflammation following RSV infection compared to control (ϩ/ϩ) littermates (14).Studies in vitro and in vivo have also demonstrated that RSV is among the most potent biological stimuli that are able to induce chemokine and cytokine p...