Liver ischemia-reperfusion (I/R) injury occurs through induction of oxidative stress and release of damage-associated molecular patterns (DAMPs), including cytosolic DNA released from dysfunctional mitochondria or from the nucleus. Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) is a cytosolic DNA sensor known to trigger stimulator of interferon genes (STING) and downstream type 1 interferon (IFN-I) pathways, which are pivotal innate immune system responses to pathogen. However, little is known about the role of cGAS/STING in liver I/R injury. We subjected C57BL/6 (WT), cGAS knockout (cGAS), and STING-deficient (STING) mice to warm liver I/R injury and that found cGAS mice had significantly increased liver injury compared with WT or STING mice, suggesting a protective effect of cGAS independent of STING. Liver I/R upregulated cGAS in vivo and also in vitro in hepatocytes subjected to anoxia/reoxygenation (A/R). We confirmed a previously published finding that hepatocytes do not express STING under normoxic conditions or after A/R. Hepatocytes and liver from cGAS mice had increased cell death and reduced induction of autophagy under hypoxic conditions as well as increased apoptosis. Protection could be restored in cGAS hepatocytes by overexpression of cGAS or by pretreatment of mice with autophagy inducer rapamycin. Our findings indicate a novel protective role for cGAS in the regulation of autophagy during liver I/R injury that occurs independently of STING. NEW & NOTEWORTHY Our studies are the first to document the important role of cGAS in the acute setting of sterile injury induced by I/R. Specifically, we provide evidence that cGAS protects liver from I/R injury in a STING-independent manner.

BackgroundShift work can disturb circadian homeostasis and result in fatigue, excessive sleepiness, and reduced quality of life. Light therapy has been shown to impart positive effects in night shift workers. We sought to determine whether or not prolonged exposure to bright light during a night shift reduces sleepiness and enhances psychomotor performance among ICU nurses.MethodsThis is a single-center randomized, crossover clinical trial at a surgical trauma ICU. ICU nurses working a night shift were exposed to a 10-h period of high illuminance (1500–2000 lx) white light compared to standard ambient fluorescent lighting of the hospital. They then completed the Stanford Sleepiness Scale and the Psychomotor Vigilance Test. The primary and secondary endpoints were analyzed using the paired t test. A p value <0.05 was considered significant.ResultsA total of 43 matched pairs completed both lighting exposures and were analyzed. When exposed to high illuminance lighting subjects experienced reduced sleepiness scores on the Stanford Sleepiness Scale than when exposed to standard hospital lighting: mean (sem) 2.6 (0.2) vs. 3.0 (0.2), p = 0.03. However, they committed more psychomotor errors: 2.3 (0.2) vs. 1.7 (0.2), p = 0.03.ConclusionsA bright lighting environment for ICU nurses working the night shift reduces sleepiness but increases the number of psychomotor errors.Trial registrationClinicalTrials.gov, NCT03331822. Retrospectively registered on 6 November 2017.

We conclude that antibiotic therapy is highly time sensitive, and efforts should be made to deliver this critical therapy as early as possible in sepsis, perhaps extending into the first point of medical contact outside the hospital.

BackgroundClinical and biologic phenotypes of sepsis are proposed in human studies, yet it is unknown whether prognostic or drug response phenotypes are present in animal models of sepsis. Using a biotelemetry-enhanced, murine cecal ligation and puncture (CLP) model, we determined phenotypes of polymicrobial sepsis prior to physiologic deterioration, and the association between phenotypes and outcome in a randomized trial of prompt or delayed antibiotics and fluids.MethodsWe performed a secondary analysis of male C57BL/6J mice in two observational cohorts and two randomized, laboratory animal experimental trials. In cohort 1, mice (n = 118) underwent biotelemetry-enhanced CLP, and we applied latent class mixed models to determine optimal number of phenotypes using clinical data collected between injury and physiologic deterioration. In cohort 2 (N = 73 mice), inflammatory cytokines measured at 24 h after deterioration were explored by phenotype. In a subset of 46 mice enrolled in two trials from cohort 1, we tested the association of phenotypes with the response to immediate (0 h) vs. delayed (2 to 4 h) antibiotics or fluids initiated after physiologic deterioration.ResultsLatent class mixture modeling derived a two-class model in cohort 1. Class 2 (N = 97) demonstrated a shorter time to deterioration (mean SD 7.3 (0.9) vs. 9.7 (3.2) h, p < 0.001) and lower heart rate at 7 h after injury (mean (SD) 564 (55) vs. 626 (35) beats per minute, p < 0.001). Overall mortality was similar between phenotypes (p = 0.75). In cohort 2 used for biomarker measurement, class 2 mice had greater plasma concentrations of IL6 and IL10 at 24 h after CLP (p = 0.05). In pilot randomized trials, the effects of sepsis treatment (immediate vs. delayed antibiotics) differed by phenotype (p = 0.03), with immediate treatment associated with greater survival in class 2 mice only. Similar differential treatment effect by class was observed in the trial of immediate vs. delayed fluids (p = 0.02).ConclusionsWe identified two sepsis phenotypes in a murine cecal ligation and puncture model, one of which is characterized by faster deterioration and more severe inflammation. Response to treatment in a randomized trial of immediate versus delayed antibiotics and fluids differed on the basis of phenotype.

Modifying the spectrum of light may offer therapeutic utility in sepsis.