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Platelet and fibrin clots occlude blood vessels in hemostasis and thrombosis. Here we report a noncanonical mechanism for vascular occlusion based on neutrophil extracellular traps (NETs), DNA fibers released by neutrophils during inflammation. We investigated which host factors control NETs in vivo and found that two deoxyribonucleases (DNases), DNase1 and DNase1-like 3, degraded NETs in circulation during sterile neutrophilia and septicemia. In the absence of both DNases, intravascular NETs formed clots that obstructed blood vessels and caused organ damage. Vascular occlusions in patients with severe bacterial infections were associated with a defect to degrade NETs ex vivo and the formation of intravascular NET clots. DNase1 and DNase1-like 3 are independently expressed and thus provide dual host protection against deleterious effects of intravascular NETs.

Melatonin reportedly alleviates sepsis-induced multi-organ injury by inducing autophagy and activating class III deacetylase Sirtuin family members (SIRT1–7). However, whether melatonin attenuates small-intestine injury along with the precise underlying mechanism remain to be elucidated. To investigate this, we employed cecal ligation and puncture (CLP)- or endotoxemia-induced sepsis mouse models and confirmed that melatonin treatment significantly prolonged the survival time of mice and ameliorated multiple-organ injury (lung/liver/kidney/small intestine) following sepsis. Melatonin partially protected the intestinal barrier function and restored SIRT1 and SIRT3 activity/protein expression in the small intestine. Mechanistically, melatonin treatment enhanced NF-κB deacetylation and subsequently reduced the inflammatory response and decreased the TNF-α, IL-6, and IL-10 serum levels; these effects were abolished by SIRT1 inhibition with the selective blocker, Ex527. Correspondingly, melatonin treatment triggered SOD2 deacetylation and increased SOD2 activity and subsequently reduced oxidative stress; this amelioration of oxidative stress by melatonin was blocked by the SIRT3-selective inhibitor, 3-TYP, and was independent of SIRT1. We confirmed this mechanistic effect in a CLP-induced sepsis model of intestinal SIRT3 conditional-knockout mice, and found that melatonin preserved mitochondrial function and induced autophagy of small-intestine epithelial cells; these effects were dependent on SIRT3 activation. This study has shown, to the best of our knowledge, for the first time that melatonin alleviates sepsis-induced small-intestine injury, at least partially, by upregulating SIRT3-mediated oxidative-stress inhibition, mitochondrial-function protection, and autophagy induction.

Sepsis is characterized by a systemic response to severe infection. Although the inflammatory phase of sepsis helps eradicate the infection, it can have detrimental consequences if left unchecked. Therapy directed against inflammatory mediators of sepsis has shown little success and has the potential to impair innate antimicrobial defenses. Heme oxygenase-1 (HO-1) and the product of its enzymatic reaction, CO, have beneficial antiinflammatory properties, but little is known about their effects on microbial sepsis. Here, we have demonstrated that during microbial sepsis, HO-1-derived CO plays an important role in the antimicrobial process without inhibiting the inflammatory response. HO-1-deficient mice suffered exaggerated lethality from polymicrobial sepsis. Targeting HO-1 to SMCs and myofibroblasts of blood vessels and bowel ameliorated sepsis-induced death associated with Enterococcus faecalis, but not Escherichia coli, infection. The increase in HO-1 expression did not suppress circulating inflammatory cells or their accumulation at the site of injury but did enhance bacterial clearance by increasing phagocytosis and the endogenous antimicrobial response. Furthermore, injection of a CO-releasing molecule into WT mice increased phagocytosis and rescued HO-1-deficient mice from sepsis-induced lethality. These data advocate HO-1-derived CO as an important mediator of the host defense response to sepsis and suggest CO administration as a possible treatment for the disease.

Key Points Sepsis is the systemic inflammatory response that occurs following severe infections and is characterized by a range of features, which might include fever, hypotension, altered mental status and shortness of breath. Although the predominant theory has been that the death of patients with sepsis was due to an over-exuberant inflammatory response, it is now apparent that many deaths are due to failure of the host to mount an effective immunological response. As the sepsis progresses, patients develop a state of immunoparalysis, marked by an inability of the host to eradicate the invading pathogen and predisposition to secondary infections. A major cause of the immunoparalysis of sepsis is the loss of key immune effector cells, including dendritic cells and lymphocytes. These cells die owing to sepsis-induced apoptosis. Uptake of apoptotic cells by professional scavenging cells induces a T helper 2 (T H 2) phenotype or anergy in these phagocytic cells, thereby contributing to the immune suppression. Blockade of sepsis-induced apoptosis by a number of methods, including overexpression of B-cell lymphoma 2 (BCL-2) or AKT results in improved survival. This finding suggests that apoptosis is an important process in the pathophysiology of the disorder. It is now clear that caspases have other functions in the immune system in addition to their role as cell-death proteases. Caspases might also regulate inflammation, cellular activation and cellular proliferation. Strategies to block sepsis-induced apoptosis might represent a novel therapy of this highly lethal disorder. An emerging concept is that sepsis is in fact due to an impaired immune response owing to excessive apoptosis of immune cells and the immunosuppressive effect that occurs as a result of the uptake of these cells. Might the use of caspase inhibitors be of therapeutic benefit in the treatment of sepsis? Although the prevailing concept has been that mortality in sepsis results from an unbridled hyper-inflammatory cytokine-mediated response, the failure of more than 30 clinical trials to treat sepsis by controlling this cytokine response requires a 'rethink' of the molecular mechanism underpinning the development of sepsis. As we discuss here, remarkable new studies indicate that most deaths from sepsis are actually the result of a substantially impaired immune response that is due to extensive death of immune effector cells. Rectification of this apoptotic–inflammatory imbalance using modulators of caspases and other components of the cell-death pathway have shown striking efficacy in stringent animal models of sepsis, indicating an entirely novel path forward for the clinical treatment of human sepsis.

Sepsis often results in damage to multiple organ systems, possibly due to severe mitochondrial dysfunction. Two members of the sirtuin family, SIRT1 and SIRT3, have been implicated in the reversal of mitochondrial damage. The aim of this study was to determine the role of SIRT1/3 in acute kidney injury (AKI) following sepsis in a septic rat model. After drug pretreatment and cecal ligation and puncture (CLP) model reproduction in the rats, we performed survival time evaluation and kidney tissue extraction and renal tubular epithelial cell (RTEC) isolation. We observed reduced SIRT1/3 activity, elevated acetylated SOD2 (ac-SOD2) levels and oxidative stress, and damaged mitochondria in RTECs following sepsis. Treatment with resveratrol (RSV), a chemical SIRT1 activator, effectively restored SIRT1/3 activity, reduced acetylated SOD2 levels, ameliorated oxidative stress and mitochondrial function of RTECs, and prolonged survival time. However, the beneficial effects of RSV were greatly abrogated by Ex527, a selective inhibitor of SIRT1. These results suggest a therapeutic role for SIRT1 in the reversal of AKI in septic rat, which may rely on SIRT3-mediated deacetylation of SOD2. SIRT1/3 activation could therefore be a promising therapeutic strategy to treat sepsis-associated AKI.

Damage-associated molecular patterns (DAMPs) are molecules that can be actively or passively released by injured tissues and that activate the immune system. Here we show that nicotinate phosphoribosyltransferase (NAPRT), detected by antibody-mediated assays and mass spectrometry, is an extracellular ligand for Toll-like receptor 4 (TLR4) and a critical mediator of inflammation, acting as a DAMP. Exposure of human and mouse macrophages to NAPRT activates the inflammasome and NF-κB for secretion of inflammatory cytokines. Furthermore, NAPRT enhances monocyte differentiation into macrophages by inducing macrophage colony-stimulating factor. These NAPRT-induced effects are independent of NAD-biosynthetic activity, but rely on NAPRT binding to TLR4. In line with our finding that NAPRT mediates endotoxin tolerance in vitro and in vivo, sera from patients with sepsis contain the highest levels of NAPRT, compared to patients with other chronic inflammatory conditions. Together, these data identify NAPRT as a endogenous ligand for TLR4 and a mediator of inflammation. The enzyme nicotinate phosphoribosyltransferase (NAPRT) mediates the rate-limiting step in NAD salvage pathway starting from nicotinic acid. Here the authors show that NAPRT can be detected extracellularly, binds to Toll like receptor 4, and activates NF-kB signaling and cytokine production in macrophage via NAD synthesis-independent pathways.

The association between lactate dehydrogenase (LDH) and clinical outcomes in sepsis was explored based on MIMIC-IV database. This was a retrospective study. Models including unadjusted model and adjusted models were performed for exploring the association of LDH with 30-day mortality and 1-year mortality. The smooth fitting curves were constructed by using generalized additive model. The predictive value of LDH for clinical outcomes in sepsis was evaluated. The statistical software of EmpowerStats (http://www. empowerstats. com) and R (http://www.R-project.org) were applied for analysis. 6775 sepsis patients were included. After adjusted for all potential confounders, for every 100 IU/L increment in LDH, the risk of 30-day mortality and 1-year mortality increased by 11% (odds ratio (OR)=1.11, 95%CI:1.08-1.13, P < 0.0001) and 12% (OR=1.12, 95%CI:1.09-1.14, P < 0.0001), respectively. The areas under the ROC curve of LDH for predicting mortalities of 30-day and 1-year were 0.667 (95%CI:0.652-0.681) and 0.646 (95%CI: 0.632-0.660), respectively. LDH was positively correlated with 30-day and 1-year mortalities in sepsis and the relationship was nonlinear.

AbstractCardiac dysfunction is a major cause leading to multiple organ failure in sepsis. Beclin-1-dependent autophagy has been evidenced to exert protective effects on hearts in sepsis. However, the mechanisms on how Beclin-1 and autophagy are regulated remains enigmatic. To explore the detailed mechanisms controlling Beclin-1-dependent autophagy in septic heart and whether melatonin could protect against sepsis via regulating cardiac autophagy, adult Sprague-Dawley (SD) rats were subjected to cecal ligation and puncture (CLP) to induce sepsis. Rats were intraperitoneally administrated with 30 mg/kg melatonin within 5-min post-CLP surgery. Our data showed that sepsis induced Becline-1 acetylation and inhibited autophagy in hearts, resulting in impaired cardiac function. However, melatonin treatment facilitated Beclin-1 deacetylation and increased autophagy in septic hearts, thus improved cardiac function. Moreover, melatonin increased the expression and activity of Sirtuin 1 (Sirt1), and inhibition of Sirt1 abolished the protective effects of melatonin on Beclin-1 deacetylation and cardiac function. In conclusion, increased Beclin-1 acetylation was involved in impaired autophagy in septic hearts, while melatonin contributed to Beclin-1 deacetylation via Sirt1, leading to improved autophagy and cardiac function in sepsis. Our study sheds light on the important role of Beclin-1 acetylation in regulating autophagy in sepsis and suggests that melatonin is a potential candidate drug for the treatment of sepsis.

Background Pulmonary fibrosis (PF) severely impacts both the survival and quality of life of patients with acute respiratory distress syndrome (ARDS) and remains a leading cause of late-stage ARDS-related mortality. The role of epithelial-mesenchymal transition (EMT) in alveolar epithelial cells (AECs) is pivotal in the development of PF. Methods This study explored the modulation of mitochondrial dynamics and the induction of EMT by pyruvate kinase M2 (PKM2) in AECs, aiming to identify new strategies for the prevention and treatment of sepsis-associated PF. Results The results demonstrated that exposure to LPS increased the levels of PKM2 and the mitochondrial fission marker dynamin-related protein-1 (DRP1), while reducing the levels of the mitochondrial fusion marker mitofusin-2 (MFN2) and the epithelial marker E-cadherin. Moreover, the mesenchymal markers α-SMA and vimentin were upregulated. Treatment with shikonin effectively reversed these alterations, restoring the balance of mitochondrial dynamics, reversing EMT markers, and alleviating the severity of sepsis-associated PF. Conclusions This study identified PKM2 as a crucial regulator of mitochondrial dynamics and EMT in AECs during sepsis-associated PF. Targeting PKM2 activity offers a promising strategy for developing treatments to mitigate the progression of sepsis-associated PF.

Drug hope for SARS The SARS (severe acute respiratory syndrome) epidemic of 2003 caused almost 800 deaths, many of them due to acute respiratory distress syndrome (ARDS) as a complication. There are no effective drugs available for treating ARDS, but new work in mice suggests that ACE2 (angiotensin-converting enzyme 2) might be an option. ACE2 can protect mice from lung injury in an ARDS-like syndrome, whereas other components of the renin–angiotensin system for controlling blood pressure and salt balance actually make the condition worse. ACE2 is expressed in the healthy lung but downregulated by lung injury and it was shown recently ( Nature 426 , 450–454; 2003) to be a receptor for the SARS coronavirus. Acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury, is a devastating clinical syndrome with a high mortality rate (30–60%) (refs 1–3 ). Predisposing factors for ARDS are diverse 1 , 3 and include sepsis, aspiration, pneumonias and infections with the severe acute respiratory syndrome (SARS) coronavirus 4 , 5 . At present, there are no effective drugs for improving the clinical outcome of ARDS 1 , 2 , 3 . Angiotensin-converting enzyme (ACE) and ACE2 are homologues with different key functions in the renin–angiotensin system 6 , 7 , 8 . ACE cleaves angiotensin I to generate angiotensin II, whereas ACE2 inactivates angiotensin II and is a negative regulator of the system. ACE2 has also recently been identified as a potential SARS virus receptor and is expressed in lungs 9 , 10 . Here we report that ACE2 and the angiotensin II type 2 receptor (AT 2 ) protect mice from severe acute lung injury induced by acid aspiration or sepsis. However, other components of the renin–angiotensin system, including ACE, angiotensin II and the angiotensin II type 1a receptor (AT 1 a), promote disease pathogenesis, induce lung oedemas and impair lung function. We show that mice deficient for Ace show markedly improved disease, and also that recombinant ACE2 can protect mice from severe acute lung injury. Our data identify a critical function for ACE2 in acute lung injury, pointing to a possible therapy for a syndrome affecting millions of people worldwide every year.