The pathogenesis of sepsis is complex. Mitochondrial dysfunction, which is responsible for energy metabolism, intrinsic apoptotic pathway, oxidative stress, and systemic inflammatory responses, is closely related with severe sepsis induced death. Mitochondria DNA (mtDNA) contain un-methylated cytosine phosphate guanine (CpG) motifs, which exhibit immune stimulatory capacities. The aim of this study was to investigate the role and mechanism of mtDNA release on lipopolysaccharide (LPS) induced acute lung injury (ALI) and systemic inflammation. Following LPS injection, plasma mtDNA copies peak at 8 h. Compared with wild-type (WT) mice, mtDNA in toll like receptor 4 knockout (TLR4 KO) mice were significantly decreased. MtDNA intra-peritoneal administration causes apparent ALI as demonstrated by increased lung injury score, bronchoalveolar lavage fluid (BALF) total protein and wet/dry (W/D) ratio; mtDNA injection also directly provokes systemic inflammation, as demonstrated by increased IL-1β, IL-6, high-mobility group protein B1 (HMGB1) level; while nuclear DNA (nDNA) could not induce apparent ALI and systemic inflammation. However, compared with WT mice, TLR4 KO could not protect from mtDNA induced ALI and systemic inflammation. Specific TLR9 inhibitor, ODN 2088 pretreatment can significantly attenuate mtDNA induced ALI and systemic inflammation, as demonstrated by improved lung injury score, decreased lung wet/dry ratio, BALF total protein concentration, and decreased systemic level of IL-1β, IL-6 and HMGB1. MtDNA administration activates the expression of p-P38 mitogen-activated protein kinases (MAPK) in lung tissue and specific TLR9 inhibitor pretreatment can attenuate this activation. Thus, LPS-induced mtDNA release occurs in a TLR4-dependent manner, and mtDNA causes acute lung injury and systemic inflammation in a TLR9-dependent and TLR4-independent manner.

Sepsis causes many early deaths; both macrophage mitochondrial damage and oxidative stress responses are key factors in its pathogenesis. Although the exact mechanisms responsible for sepsis-induced mitochondrial damage are unknown, the nuclear transcription factor, interferon regulatory factor-1 (IRF-1) has been reported to cause mitochondrial damage in several diseases. Previously, we reported that in addition to promoting systemic inflammation, IRF-1 promoted the apoptosis of and inhibited autophagy in macrophages. In the present study, we hypothesized that lipopolysaccharide (LPS)-induced IRF-1 activation in macrophages may promote mitochondrial damage and oxidative stress. In vitro, LPS was found to promote IRF-1 activation, reactive oxygen species (ROS) production, adenosine triphosphate (ATP) depletion, superoxide dismutase (SOD) consumption, malondialdehyde (MDA) accumulation and mitochondrial depolarization in macrophages in a time- and dose-dependent manner. These effects were abrogated in cells in which IRF-1 was knocked down. Furthermore, IRF-1 overexpression increased LPS-induced oxidative stress responses and mitochondrial damage. In vivo, peritoneal macrophages obtained from IRF-1 knockout (KO) mice produced less ROS and had less mitochondrial depolarization and damage following the administration of LPS, when compared to their wild-type (WT) counterparts. In addition, IRF-1 KO mice exhibited a decreased release of mitochondrial DNA (mtDNA) following the administration of LPS. Thus, IRF-1 may be a critical factor in augmenting LPS-induced oxidative stress and mitochondrial damage in macrophages.

The aim of this study is to investigate whether silencing of Fas could have an influence on type II alveolar epithelial cell (AEC) apoptosis and inflammatory cytokine production, which prevents alveolar healing after acute lung injury (ALI). Rat primary type II AECs were isolated by elastase cell dispersion and IgG panning. The cells were transfected with Fas-specific small interfering RNA (siRNA) followed by treatment with lipopolysaccharide (LPS), Fas ligand (FasL) or both. The effects of siRNA-mediated silencing of Fas on LPS-induced apoptosis and cytokine release were then assessed. Notably, LPS, either alone or together with FasL, significantly stimulated type II AEC apoptosis and the release of tumor necrosis factor-alpha (TNF-α) and monocyte chemoattractant protein 1 (MCP-1) (P < 0.05 versus the control without treatment). Moreover, the effects exerted by both LPS and FasL were considerably counteracted by pretreatment with Fas-siRNA (P < 0.05 versus treatment with LPS and FasL). In conclusion, inhibition of Fas can diminish LPS-induced apoptosis and inflammatory cytokine production in type II AECs, and Fas specific siRNAs may have therapeutic potentials for intervention of ALI/ARDS.

Abstract. The aim of the present study was to explore the regulatory mechanism of heme oxygenase-1 (HO-1) expression induced by sevoflurane (Sevo) in lipopolysaccharide (LPS)-induced acute lung injury (ALI). Sprague-Dawley rats were divided randomly into six groups: (A) Control, (B) 2.4% Sevo only, (C) LY294002 (PI3K inhibitor) only, (D) LPS + 2.4% Sevo, (E) LY294002 + LPS + 2.4% Sevo and (F) LPS only. The pathological changes in wet/dry weight ratio (W/D), the activities of superoxide dismutase, myeloperoxidase (MPO), malondialdehyde, and HO-1, as well as the expression of intercellular adhesion molecule (ICAM-1), HO-1, phospho-phosphatidylinositol 3-kinase (pPI3K) and phospho-Akt (pAkt) were recorded. Sevo post-conditioning was able to effectively protect from ALI with decreasing pathomorphological scores, MPO activity, W/D and the mRNA and protein expression levels of ICAM-1. Sevo promotes HO-1 expression via the PI3K/protein kinase B (PI3K/Akt) pathway with activation of pPI3K and pAkt. Inhibition of the PI3K/Akt pathway by LY294002 partly eliminates the protective effects of Sevo. It is concluded that Sevo post-conditioning has a vital role in inducing the upregulation of HO-1 expression via the PI3K/Akt pathway to alleviate ALI.

NGAL can attenuate kidney injury and apoptosis in the rat CLP model of sepsis. And the protective effect of NGAL was probably due to the inhibition of apoptosis and lipid peroxidation, and increased expression of HO-1.

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Backgrounds: Sepsis induced organ failure is main cause of mortality in intensive care units (ICU), however, the impact of early liver injury on clinical ending of sepsis is not clear and has not been discussed in context of clinical research on sepsis before. Our study aimed at the investigation of the clinical effect of early liver injury within 48h at ICU admission on sepsis outcomes. Methods: A single-centered, retrospective cohort of 198 adult critical patients diagnosed with sepsis were included in different ICU departments of Xiangya hospital from 2016 to 2018. Patients were divided into two groups, early liver injury and non-early liver injury within 48h at ICU admission. Baseline characteristics, clinical outcomes and risk factors of these two groups were studied. Logistic regression analysis, Cox hazard analysis, Kaplan-Meier and log-rank test were used. Results: In total, 198 patients with sepsis were included, with 106 (53.5%) with early liver injury and overall in-hospital mortality was 45.9% (n=91). Compared to non-early liver injury group, patients with early liver injury had significant higher SOFA (7.44±3.83 vs. 5.55±2.61, P<0.001), APACHE II score (15.22±23.14 vs. 9.14±8.72, P=0.013) , procalcitonin (37.10±59.20 vs. 19.24±48.10, P=0.021) , and rate of shock (63.2% vs. 48.9%, P=0.046). Primary outcome showed that early liver injury group had significant higher rate of renal dysfunction (62.3 vs. 33.7%, P<0.001), coagulation (31.1% vs. 13.0%, P=0.004) and hematologic system (72.6% vs. 52.2%, P=0.003) dysfunction hinting at higher organ failure rate. Age (OR 0.966; 95% CI 0.944-0.989; P=0.004), hypertriglyceridemia (OR 1.636; 95% CI 1.049-2.551; P=0.030), serum total bile acid (TBA, OR 1.071; 95% CI 1.030-1.113; P=0.001), hemoglobin (OR 1.030; 95% CI 1.013-1.046; P<0.001) and renal dysfunction (OR 3.403; 95% CI 1.631-7.099; P=0.001) were the independent predictors for early liver injury in sepsis by multiple regression analysis. Kaplan-Meier survival analyze demonstrated early liver injury and non-early liver injury group had similar survival time. Conclusion: Early liver injury within 48 hours on ICU admission is closely related to organ failure for patients with sepsis. Future study with big data is required to verify our viewpoint.

Background Although jaundice have been associated with mortality in critically ill patients, yet no data from large studies demonstrates its effect in sepsis. The aim of the study is to investigate the impact of jaundice on outcomes in septic patients.Methods Propensity-matched analysis of cohort database from Medical Information Mart for Intensive Care III (MIMIC-III), a large database of septic patients at a tertiary care hospital in Boston, Massachusetts (June 2001 to October 2012). Individuals with preexisting jaundice or liver diseases at the time of admission were excluded from analysis. Jaundice was diagnosed in septic patients with total bilirubin levels >2mg/dL at any time during hospitalization. The multivariate Cox was employed to adjust for baseline and confounding parameters.Results A total of 2784 septic patients were enrolled in the study, including 456 patients in jaundice group, and 2328 in non-jaundice group. Before propensity score matching, multivariate Cox hazard analysis showed age [HR 1.029; 95% CI (1.009-1.049); P=0.005], malignancy [HR 3.244; 95% CI (1.729h-6.085); P<0.001], SOFA score [HR 1.179; 95% CI (1.054-1.318); P=0.004], serum total bilirubin at hospital discharge [HR 1.050; 95% CI (1.022-1.079); P<0.001] were the independent risk factors of mortality in sepsis. In 432 pairs after matching according to new presented jaundice status, jaundice group had higher in-hospital mortality (76±17.6 vs. 49±11.3; P=0.012) than non-jaundice group. In multivariate logistic regression model, the only independent risk for jaundice in sepsis was SOFA score [OR 1.314; 95% CI (1.248-1.385); P<0.001], whereas mechanical ventilation [OR 0.310; 95% CI (0.222-0.432); P<0.001], serum platelet [OR 0.998; 95% CI (0.997-1.00); P=0.015] and serum bicarbonate [OR 0.962; 95% CI (0.929-0.996); P=0.030] were jaundice’s independent protective factors.Conclusions New onset of jaundice is associated with higher risk rate of in-hospital mortality in sepsis. In addition, our study demonstrates that serum total bilirubin at hospital discharge is an independent determinant for mortality.