Bacterial pathogen-associated molecular pattern molecules (PAMPs) such as LPS activate the endothelium and can lead to lung injury, but the signaling pathways mediating endothelial injury remain incompletely understood. In a recent issue of the JCI, Gandhirajan et al. identify STIM1, an ER calcium sensor, as a key link between LPS-induced ROS, calcium oscillations, and endothelial cell (EC) dysfunction. In addition, they report that BTP2, an inhibitor of calcium channels, attenuates lung injury. This study identifies a novel endothelial signaling pathway that could be a future target for the treatment of lung injury.

We report findings for a patient that underwent endobronchial ultrasound (EBUS) guided transbronchial needle aspiration (TBNA) for diagnostic purposes after an abnormal chest CT. The patient initially presented with cough and shortness of breath. Chest CT revealed a 6 cm soft tissue mass with mildly enlarged right hilar lymph nodes (LNs) and a small right sided pleural effusion. Based on these radiologic findings, the patient underwent an EBUS guided FNA of the mass. To our surprise, the mass was hypoechoic by EBUS and on aspiration, the syringe filled with yellow fluid. This finding in combination with a re-review of the CT scans with a special focus on the Hounsfield Units of the lesion confirmed the diagnosis of a mediastinal bronchogenic cyst. This case demonstrates the role of Hounsfield units in analyzing mediastinal masses and highlights the effectiveness of EBUS guided TBNA in diagnosis and treatment of bronchogenic cysts.

S-nitrosoglutathione reductase (GSNOR) is a key denitrosylase and critically important for protecting immune and other cells from nitrosative stress. Pharmacological inhibition of GSNOR is being actively pursued as a therapeutic approach to increase S-nitrosoglutathione levels for the treatment of asthma and cystic fibrosis. In the present study, we employed GSNOR-deficient (GSNOR(-/-)) mice to investigate whether inactivation of GSNOR may increase susceptibility to pulmonary infection by Klebsiella pneumoniae, a common cause of nosocomial pneumonia. We found that compared to wild-type mice, bacterial colony forming units 48 h after intranasal infection with K. pneumoniae were increased over 4-folds in lung and spleen and strikingly, over a 1000-folds in blood of GSNOR(-/-) mice. Lung injury was comparable between infected wild-type and GSNOR(-/-) mice, but inflammation and injury was significantly elevated in spleen of GSNOR(-/-) mice. Whereas all wild-type mice survived 48 h after infection, 10 of 23 GSNOR(-/-) mice died. Thus, GSNOR appears to play a crucial role in controlling pulmonary and systemic infection by K. pneumoniae. Our results suggest that patients treated in clinical trials with inhibitors of GSNOR should be carefully monitored for signs of infection.

Effective host defense requires a robust, yet self-limited response to pathogens. A poorly calibrated response can lead to either bacterial dissemination due to insufficient inflammation or organ injury due to excessive inflammation. Recent evidence suggests that the cholinergic anti-inflammatory reflex helps calibrate the immune response. However, the influence of peripheral noradrenergic neurons, which are primarily sympathetic neurons, in regulating immunity remains incompletely characterized. Using a model of 6-hydroxydopamine-mediated noradrenergic nerve ablation, we show that elimination of noradrenergic neurons improves survival during Klebsiella pneumoniae peritonitis (67 versus 23%, p < 0.005) in mice. The survival benefit results from enhanced MCP-1-dependent monocyte recruitment and a subsequent decrease in bacterial loads. Splenectomy eliminated both the survival benefit of 6-hydroxydopamine and monocyte recruitment, suggesting that monocytes recruited to the peritoneum originate in the spleen. These results suggest that noradrenergic neurons regulate the immune response through two pathways. First, sympathetic nerve-derived norepinephrine directly restrains MCP-1 production by peritoneal macrophages during infection. Second, norepinephrine derived from the vagally innervated splenic nerve regulates splenic monocyte egress. Removal of these two modulators of the immune response enhances antibacterial immunity and improves survival. These results may have implications for how states of catecholamine excess influence the host response to bacterial infections.

Abstract Background Multiple studies have identified single variables or composite scores that help risk stratify patients at the time of acute lung injury (ALI) diagnosis. However, few studies have addressed the important question of how changes in pulmonary physiologic variables might predict mortality in patients during the subacute or chronic phases of ALI. We studied pulmonary physiologic variables, including respiratory system compliance, P/F ratio and oxygenation index, in a cohort of patients with ALI who survived more than 6 days of mechanical ventilation to see if changes in these variables were predictive of death and whether they are informative about the pathophysiology of subacute ALI. Methods Ninety-three patients with ALI who were mechanically ventilated for more than 6 days were enrolled in this prospective cohort study. Patients were enrolled at two medical centers in the US, a county hospital and a large academic center. Bivariate analyses were used to identify pulmonary physiologic predictors of death during the first 6 days of mechanical ventilation. Predictors on day 1, day 6 and the changes between day 1 and day 6 were compared in a multivariate logistic regression model. Results The overall mortality was 35%. In multivariate analysis, the PaO2/FiO2 (OR 2.09, p < 0.04) and respiratory system compliance (OR 3.61, p < 0.01) were predictive of death on the 6th day of acute lung injury. In addition, a decrease in respiratory system compliance between days 1 and days 6 (OR 2.14, p < 0.01) was independently associated with mortality. Conclusions A low respiratory system compliance on day 6 or a decrease in the respiratory system compliance between the 1st and 6th day of mechanical ventilation were associated with increased mortality in multivariate analysis of this cohort of patients with ALI. We suggest that decreased respiratory system compliance may identify a subset of patients who have persistent pulmonary edema, atelectasis or the fibroproliferative sequelae of ALI and thus are less likely to survive their hospitalization.

Mammals are serially infected with a variety of microorganisms, including bacteria and parasites. Each infection reprograms the immune system's responses to re-exposure and potentially alters responses to first-time infection by different microorganisms. To examine whether infection with a metazoan parasite modulates host responses to subsequent bacterial infection, mice were infected with the hookworm-like intestinal nematode Nippostrongylus brasiliensis, followed in 2-4 weeks by peritoneal injection of the pathogenic bacterium Klebsiella pneumoniae. Survival from Klebsiella peritonitis two weeks after parasite infection was better in Nippostrongylus-infected animals than in unparasitized mice, with Nippostrongylus-infected mice having fewer peritoneal bacteria, more neutrophils, and higher levels of protective interleukin 6. The improved survival of Nippostrongylus-infected mice depends on IL-4 because the survival benefit is lost in mice lacking IL-4. Because mast cells protect mice from Klebsiella peritonitis, we examined responses in mast cell-deficient Kit(W-sh)/Kit(W-sh) mice, in which parasitosis failed to improve survival from Klebsiella peritonitis. However, adoptive transfer of cultured mast cells to Kit(W-sh)/Kit(W-sh) mice restored survival benefits of parasitosis. These results show that recent infection with Nippostrongylus brasiliensis protects mice from Klebsiella peritonitis by modulating mast cell contributions to host defense, and suggest more generally that parasitosis can yield survival advantages to a bacterially infected host.

FGF-10 can prevent or reduce lung specific inflammation due to traumatic or infectious lung injury. However, the exact mechanisms are poorly characterized. Additionally, the effect of FGF-10 on lung-resident mesenchymal stem cells (LR-MSCs) has not been studied. To better characterize the effect of FGF-10 on LR-MSCs, FGF-10 was intratracheally delivered into the lungs of rats. Three days after instillation, bronchoalveolar lavage was performed and plastic-adherent cells were cultured, characterized and then delivered therapeutically to rats after LPS intratracheal instillation. Immunophenotyping analysis of FGF-10 mobilized and cultured cells revealed expression of the MSC markers CD29, CD73, CD90, and CD105, and the absence of the hematopoietic lineage markers CD34 and CD45. Multipotency of these cells was demonstrated by their capacity to differentiate into osteocytes, adipocytes, and chondrocytes. Delivery of LR-MSCs into the lungs after LPS injury reduced the inflammatory response as evidenced by decreased wet-to-dry ratio, reduced neutrophil and leukocyte recruitment and decreased inflammatory cytokines compared to control rats. Lastly, direct delivery of FGF-10 in the lungs of rats led to an increase of LR-MSCs in the treated lungs, suggesting that the protective effect of FGF-10 might be mediated, in part, by the mobilization of LR-MSCs in lungs.

The early sequence of events leading to the development of the acute respiratory distress syndrome (ARDS) in patients with sepsis remains inadequately understood. The purpose of this study was to identify changes in gene expression early in the course of illness, when mechanisms of injury may provide the most relevant treatment and prognostic targets. We collected whole blood RNA in critically ill patients admitted from the Emergency Department to the intensive care unit within 24 h of admission at a tertiary care center. Whole genome expression was compared in patients with sepsis and ARDS to patients with sepsis alone. We selected genes with >1 log2 fold change and false discovery rate <0.25, determined their significance in the literature, and performed pathway analysis. Several genes were upregulated in 29 patients with sepsis with ARDS compared with 28 patients with sepsis alone. The most differentially expressed genes included key mediators of the initial neutrophil response to infection: olfactomedin 4, lipocalin 2, CD24, and bactericidal/permeability-increasing protein. These gene expression differences withstood adjustment for age, sex, study batch, white blood cell count, and presence of pneumonia or aspiration. Pathway analysis demonstrated overrepresentation of genes involved in known respiratory and infection pathways. These data indicate that several neutrophil-related pathways may be involved in the early pathogenesis of sepsis-related ARDS. In addition, identifiable gene expression differences occurring early in the course of sepsis-related ARDS may further elucidate understanding of the neutrophil-related mechanisms in progression to ARDS.

Objectives

The existing risk prediction model for patients requiring prolonged mechanical ventilation is not applicable until after 21 days of mechanical ventilation. We sought to develop and validate a mortality prediction model for patients earlier in the ICU course using data from day 14 of mechanical ventilation.

Design

Multicenter retrospective cohort study.

Setting

Forty medical centers across the United States.

Patients

Adult patients receiving at least 14 days of mechanical ventilation.

Interventions

None.

Measurements and main results

Predictor variables were measured on day 14 of mechanical ventilation in the development cohort and included in a logistic regression model with 1-year mortality as the outcome. Variables were sequentially eliminated to develop the ProVent 14 model. This model was then generated in the validation cohort. A simplified prognostic scoring rule (ProVent 14 Score) using categorical variables was created in the development cohort and then tested in the validation cohort. Model discrimination was assessed by the area under the receiver operator characteristic curve. Four hundred ninety-one patients and 245 patients were included in the development and validation cohorts, respectively. The most parsimonious model included age, platelet count, requirement for vasopressors, requirement for hemodialysis, and nontrauma admission. The area under the receiver operator characteristic curve for the ProVent 14 model using continuous variables was 0.80 (95% CI, 0.76-0.83) in the development cohort and 0.78 (95% CI, 0.72-0.83) in the validation cohort. The ProVent 14 Score categorized age at 50 and 65 years old and platelet count at 100×10(9)/L and had similar discrimination as the ProVent 14 model in both cohorts.

Conclusion

Using clinical variables available on day 14 of mechanical ventilation, the ProVent 14 model can identify patients receiving prolonged mechanical ventilation with a high risk of mortality within 1 year.

Purpose

Previous studies assessing impact of acute respiratory distress syndrome (ARDS) on mortality have shown conflicting results. We sought to assess the independent association of ARDS with in-hospital mortality among intensive care unit (ICU) patients with sepsis.

Methods

We studied two prospective sepsis cohorts drawn from the Early Assessment of Renal and Lung Injury (EARLI; n = 474) and Validating Acute Lung Injury markers for Diagnosis (VALID; n = 337) cohorts. ARDS was defined by Berlin criteria. We used logistic regression to compare in-hospital mortality in patients with and without ARDS, controlling for baseline severity of illness. We also estimated attributable mortality, adjusted for illness severity by stratification.

Results

ARDS occurred in 195 EARLI patients (41%) and 99 VALID patients (29%). ARDS was independently associated with risk of hospital death in multivariate analysis, even after controlling for severity of illness, as measured by APACHE II (odds ratio [OR] 1.65 (95% confidence interval [CI] 1.02, 2.67), p = 0.04 in EARLI; OR 2.12 (CI 1.16, 3.92), p = 0.02 in VALID). Patients with severe ARDS (P/F < 100) primarily drove this relationship. The attributable mortality of ARDS was 27% (CI 14%, 37%) in EARLI and 37% (CI 10%, 51%) in VALID. ARDS was independently associated with ICU mortality, hospital length of stay (LOS), ICU LOS, and ventilator-free days.

Conclusions

Development of ARDS among ICU patients with sepsis confers increased risk of ICU and in-hospital mortality in addition to other important outcomes. Clinical trials targeting patients with severe ARDS will be best poised to detect measurable differences in these outcomes.