Macrophage-expressed IFN-β contributes to apoptotic alveolar epithelial cell injury in severe influenza virus pneumonia

Influenza viruses (IV) cause pneumonia in humans with progression to lung failure and fatal outcome. Dysregulated release of cytokines including type I interferons (IFNs) has been attributed a crucial role in immune-mediated pulmonary injury during severe IV infection. Using ex vivo and in vivo IV infection models, we demonstrate that alveolar macrophage (AM)-expressed IFN-β significantly contributes to IV-induced alveolar epithelial cell (AEC) injury by autocrine induction of the pro-apoptotic factor TNF-related apoptosis- inducing ligand (TRAIL). Of note, TRAIL was highly upregulated in and released from AM of patients with pandemic H1N1 IV-induced acute lung injury. Elucidating the cell-specific underlying signalling pathways revealed that IV infection induced IFN-β release in AM in a protein kinase R- (PKR-) and NF-κB- dependent way. Bone marrow chimeric mice lacking these signalling mediators in resident and lung-recruited AM and mice subjected to alveolar neutralization of IFN-β and TRAIL displayed reduced alveolar epithelial cell apoptosis and attenuated lung injury during severe IV pneumonia. Together, we demonstrate that macrophage-released type I IFNs, apart from their well-known anti-viral properties, contribute to IV-induced AEC damage and lung injury by autocrine induction of the pro-apoptotic factor TRAIL. Our data suggest that therapeutic targeting of the macrophage IFN-β-TRAIL axis might represent a promising strategy to attenuate IV-induced acute lung injury

Clinical and Operative Determinants of Acute Kidney Injury after Cardiac Surgery.

Introduction: Cardiac surgery-associated acute kidney injury (CSA-AKI) is associated with increased morbidity and mortality. Objectives: We aimed to identify potentially modifiable risk factors for CSA-AKI. Methods: This was asingle-center retrospective cohort study of 495 adult patients undergoing cardiac surgery. AKI was diagnosed and staged using full KDIGO criteria incorporating baseline serum creatinine (SC) levels and correction of postoperative SC levels for fluid balance. We examined the association of routinely available clinical and laboratory data with AKI using multivariate logistic regression modeling. Results: A total of 103 (20.8%) patients developed AKI: 16 (15.5%) patients were diagnosed with AKI upon hospital admission, and 87 (84.5%) patients were diagnosed with CSA-AKI. Correction of SC levels for fluid balance increased the number of AKI cases to 104 (21.0%), with 6 patients categorized to different AKI stages. Univariate logistic regression analysis identified five preoperative (age, sex, diabetes mellitus, preoperative systolic pulmonary arterial pressure [PSPAP], acute decompensated heart failure) and five intraoperative predictors of AKI (age, sex, red blood cell [RBC] volume transfused, use of minimally invasive surgery, duration of cardiopulmonary bypass). When all preoperative and intraoperative variables were incorporated into one model, six predictors remained significant (age, sex, use of minimally invasive surgery, RBC volume transfused, PSPAP, duration of cardiopulmonary bypass). Model discrimination performance showed an area under the curve of 0.69 for the model including only preoperative variables, 0.76 for the model including only intraoperative variables, and 0.77 for the model including all preoperative and intraoperative variables. Conclusions: Use of minimally invasive surgery and therapies mitigating PSPAP and intraoperative blood loss may offer protection against CSA-AKI

Correction: Macrophage-expressed IFN-β Contributes to Apoptotic Alveolar Epithelial Cell Injury in Severe Influenza Virus Pneumonia.

[This corrects the article DOI: 10.1371/journal.ppat.1003188.]