Infection-induced Sepsis Research Articles

Human transferrin and lactoferrin cooperatively support Neisseria meningitidis colonization in the murine nasopharynx.

Neisseria meningitidis is a human-restricted bacteria that is a normal nasopharyngeal resident, yet it can also disseminate, causing invasive meningococcal disease. Meningococci are highly adapted to life in humans, with human-specific virulence factors contributing to bacterial adhesion, nutrient acquisition and immune evasion. While these factors have been explored in isolation, their relative contribution during infection has not been considered due to their absence in small animal models and their expression by different human cell types not readily combined in either in vitro or ex vivo systems. Herein, we show that transgenic expression of the iron-binding glycoproteins human transferrin and lactoferrin can each facilitate N. meningitidis replication in mouse serum but that transferrin was required to support infection-induced sepsis. While these host proteins are insufficient to allow nasopharyngeal colonization alone, mice co-expressing these and human CEACAM1 support robust colonization. In this case, meningococcal colonization elicits an acute elevation in both transferrin and lactoferrin levels within the upper respiratory mucosa, with transferrin levels remaining elevated while lactoferrin returns to basal levels after establishment of infection. Competitive infection of triple transgenic animals with transferrin- and lactoferrin- binding protein mutants selects for bacteria expressing the transferrin receptor, implicating the critical contribution of transferrin-based iron acquisition to support colonization. These transgenic animals have thus allowed us to disentangle the relative contribution of three virulence factors during colonization and invasive disease, and provides a novel in vivo model that can support extended meningococcal colonization, opening a new avenue to explore the meningococcal lifestyle within its primary niche.

The beneficial effects of Rosuvastatin in inhibiting inflammation in sepsis.

Microbial infection-induced sepsis causes excessive inflammatory response and multiple organ failure. An effective strategy for the treatment of sepsis-related syndromes is still needed. Rosuvastatin, a typical β-hydroxy β-methylglutaryl-CoA reductase inhibitor licensed for reducing the levels of low-density lipoprotein cholesterol in patients with hyperlipidemia, has displayed anti-inflammatory capacity in different types of organs and tissues. However, its effects on the development of sepsis are less reported. Here, we found that the administration of Rosuvastatin reduced the mortality of sepsis mice and prevented body temperature loss. Additionally, it inhibited the production of inflammatory cytokines such as tumor necrosis factor (TNF-α), Interleukin-6 (IL-6), interleukin-1β (IL-1β), and migration inhibitory factor (MIF) in peritoneal lavage supernatants of animals. The increased number of mononuclear cells in the peritoneum of sepsis mice was reduced by Rosuvastatin. Interestingly, it ameliorated lung inflammation and improved the hepatic and renal function in the sepsis animals. Further in vitro experiments show that Rosuvastatin inhibited lipopolysaccharide (LPS)-induced production of proinflammatory cytokines in RAW 264.7 macrophages by preventing the activation of nuclear factor kappa-B (NF-κB). Our findings demonstrate that the administration of Rosuvastatin hampered organ dysfunction and mitigated inflammation in a relevant model of sepsis.

Clinical analysis of patients with deep sternal wound infection-induced sepsis: a retrospective cohort study

Abstract Background This study aimed to summarize the clinical characteristics of patients with deep sternal wound infection-induced sepsis after median sternotomy and improve the treatment outcomes of infection-related sepsis. Methods A retrospective cohort study was conducted on 21 patients with deep sternal wound infection-induced sepsis after median sternotomy who were admitted to the Department of Critical Care. The clinical manifestations, laboratory test results, infection control, and organ and nutritional support of the patients were summarized, and the follow-up data were obtained. Results The primary symptoms of deep sternal wound infection-induced sepsis included dyspnea, high fever, chills, and altered state of consciousness. Laboratory test results revealed increased inflammatory markers and decreased oxygenation index. Renal and liver function injury were observed in 8 and 4 patients, respectively; 18 and 12 patients demonstrated elevated D-dimer and N-terminal Pro B type natriuretic peptide levels, respectively. Of the 8 patients whose wound secretions tested positive for bacteria, Acinetobacter baumannii and Staphylococcus aureus infections were present in 6 and 2 patients, respectively. One of the 6 patients whose blood cultures tested positive for bacteria demonstrated Candida albicans infection. Fifteen patients received ventilator-assisted ventilation and 2 patients received renal replacement therapy. Of all the 21 patients, 17 were cured, 2 died, and 2 were discharged. Conclusion Postmedian sternotomy sepsis attributed to a deep sternal wound infection usually results from a preexisting condition. The most prominent clinical manifestation is dyspnea, which is sometimes accompanied by the impairment of organ function. Infection prevention, proper nutrition support, and maintenance of healthy organ function are the cornerstones for successful treatment outcomes.

Pathogenic characteristics and influence factors of bloodstream infection-induced severe sepsis in pediatric intensive care unit

Objective: To summarize the pathogenic characteristics of bloodstream infection (BSI)-induced severe sepsis and analyze the influence factors in pediatric intensive care unit (PICU). Methods: Pediatric patients who were diagnosed with severe sepsis caused by BSI in the PICU of Children's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from January 2016 to December 2021 were retrospectively selected and divided into survival group and death group according to their discharge outcomes. Clinical characteristics, laboratory parameters, pathogenic characteristics and drug resistance of the patients were collected. The characteristics of pathogens, clinical and laboratory indicators were summarized, and the influencing factors of death in children with severe sepsis caused by BSI were analyzed based on binary multivariate logistic regression. Results: A total of 132 patients, aged [M (Q1, Q3)] 36 (10, 119) months, with BSI-induced severe sepsis were enrolled in this study, including 81 males and 51 females. There were 38 cases aged 36 (15, 120) months in the death group, including 23 males and 15 females. There were 94 cases, aged 36 (8, 108) months, in the survival group, including 58 males and 36 females. A total of 132 strains of pathogens were isolated, including 87 strains (65.9%) of Gram-negative bacteria. The top 5 pathogens were Klebsiella pneumoniae (24 cases, 18.2%), Escherichia coli (17 cases, 12.9%), Acinetobacter baumannii (13 cases, 9.8%), Pseudomonas aeruginosa (10 cases, 7.6%) and Staphylococcus aureus (10 cases, 7.6%). The proportion of multi-drug resistant bacteria in hospital-acquired BSI was higher than that in community-acquired BSI [52.9% (36/68) vs 15.6% (10/64), P=0.001]. The proportions of community-acquired infection were 58.5% (55/94) and 23.7% (9/38) in the survival and death groups, respectively, the difference was statistically significant (P<0.001). The proportion of central venous catheter insertion before bloodstream infection in the death group was higher than that in the survival group [63.2% (24/38) vs 42.6% (40/94), P=0.034]. According to the binary multivariate logistic regression analysis, hospital-acquired infection (OR=4.80, 95%CI: 1.825-12.621, P=0.001), absolute neutrophil count (ANC) (OR=0.93, 95%CI: 0.863-0.993, P=0.030) and decreased albumin (OR=0.89, 95%CI: 0.817-0.977, P=0.014) were risk factors for death. Conclusions: The common pathogen of BSI-induced severe sepsis in PICU is Gram-negative bacteria. The proportion of multi-drug resistant organisms of BSI obtained in hospitals is high. Children with severe sepsis due to BSI with nosocomial acquired infection, ANC and decreased albumin have a high risk of death.

Compassionate use of a novel β-lactam enhancer-based investigational antibiotic cefepime/zidebactam (WCK 5222) for the treatment of extensively-drug-resistant NDM-expressing Pseudomonas aeruginosa infection in an intra-abdominal infection-induced sepsis patient: a case report

Infections in critically-ill patients caused by extensively-drug-resistant (XDR)-Pseudomonas aeruginosa are challenging to manage due to paucity of effective treatment options. Cefepime/zidebactam, which is currently in global Phase 3 clinical development (Clinical Trials Identifier: NCT04979806, registered on July 28, 2021) is a novel mechanism of action based β-lactam/ β-lactam-enhancer combination with a promising activity against a broad-range of Gram-negative pathogens including XDR P. aeruginosa. We present a case report of an intra-abdominal infection-induced sepsis patient infected with XDR P. aeruginosa and successfully treated with cefepime/zidebactam under compassionate use. The 50 year old female patient with past-history of bariatric surgery and recent elective abdominoplasty and liposuction developed secondary pneumonia and failed a prolonged course of polymyxins. The organism repeatedly isolated from the patient was a New-Delhi metallo β-lactamase-producing XDR P. aeruginosa resistant to ceftazidime/avibactam, imipenem/relebactam and ceftolozane/tazobactam, susceptible only to cefepime/zidebactam. As polymyxins failed to rescue the patient, cefepime/zidebactam was administered under compassionate grounds leading to discharge of patient in stable condition. The present case highlights the prevailing precarious scenario of antimicrobial resistance and the need for novel antibiotics to tackle infections caused by XDR phenotype pathogens.

SAMHD1 Attenuates Acute Inflammation by Maintaining Mitochondrial Function in Macrophages via Interaction with VDAC1.

Over-activation of Toll-like receptor 4 (TLR4) is the key mechanism in Gram-negative bacterial infection-induced sepsis. SAM and HD domain-containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) inhibits multiple viruses, but whether it plays a role during bacterial invasion remains unelucidated. Monocyte-macrophage specific Samhd1 knockout (Samhd1-/-) mice and Samhd1-/- macrophage cell line RAW264.7 were constructed and used as research models to evaluate the role of SAMHD1 in TLR4-activated inflammation. In vivo, LPS-challenged Samhd1-/- mice showed higher serum inflammatory factors, accompanied with more severe inflammation infiltration and lower survival rate. In vitro, Samhd1-/- peritoneal macrophages had more activated TLR4 pathway upon LPS-stimulation, accompanied with mitochondrial depolarization and dysfunction and a higher tendency to be M1-polarized. These results could be rescued by overexpressing full-length wild-type SAMHD1 or its phospho-mimetic T634D mutant into Samhd1-/- RAW264.7 cells, whereas the mutants, dNTP hydrolase-function-deprived H238A and phospho-ablative T634A, did not exert the same effect. Lastly, co-IP and immunofluorescence assays confirmed that SAMHD1 interacted with an outer mitochondrial membrane-localized protein, voltage-dependent anion channel-1 (VDAC1). SAMHD1 inhibits TLR4-induced acute inflammation and M1 polarization of macrophages by interacting with VDAC1 and maintaining mitochondria function, which outlines a novel regulatory mechanism of TLR signaling upon LPS stimulation.

SILENCING M 6 A READER YTHDC1 REDUCES INFLAMMATORY RESPONSE IN SEPSIS-INDUCED CARDIOMYOPATHY BY INHIBITING SERPINA3N EXPRESSION.

Sepsis-induced cardiomyopathy (SIC) is one of the most common complications of infection-induced sepsis. An imbalance in inflammatory mediators is the main factor leading to SIC . N 6 -methyladenosine (m 6 A) is closely related to the occurrence and development of sepsis. N 6 -methyladenosine reader YTH domain containing 1 (YTHDC1) is an m 6 A N 6 -methyladenosine recognition protein. However, the role of YTHDC1 in SIC remains unclear. Herein, we demonstrated that YTHDC1-shRNA inhibits inflammation, reduces inflammatory mediators, and improves cardiac function in a LPS-induced SIC mouse model. Based on the Gene Expression Omnibus database analysis, serine protease inhibitor A3N is a differential gene of SIC. Furthermore, RNA immunoprecipitation indicated that serine protease inhibitor A3N (SERPINA3N) mRNA can bind to YTHDC1, which regulates the expression of SERPINA3N. Serine protease inhibitor A3N-siRNA reduced LPS-induced inflammation of cardiac myocytes. In conclusion, the m 6 A reader YTHDC1 regulates SERPINA3N mRNA expression to mediate the levels of inflammation in SIC. Such findings add to the relationship between m 6 A reader YTHDC1 and SIC, providing a new research avenue for the therapeutic mechanism of SIC.

Sulforaphane reduces lipopolysaccharide-induced inflammation and enhances myogenic differentiation of mouse embryonic myoblasts via the toll-like receptor 4 and NLRP3 pathways.

Muscle loss and muscle weakness are manifestations of infection-induced sepsis, a condition that can lead to organ failure and death. Toll-like receptor 4 (TLR4) signaling and the NLRP3 inflammasome are involved in the inflammatory storm and the development of sarcopenia during sepsis. They are also potential targets for sepsis treatment. To explore the effects and molecular mechanisms of sulforaphane (SFN) on sepsis-associated inflammation and sarcopenia. Mouse C2C12 embryonic myoblasts were treated with lipopolysaccharide (LPS) to simulate sepsis-induced sarcopenia. Molecular mechanisms were investigated using quantitative real-time polymerase chain reaction (qRT-PCR), western blot, immunofluorescence, and enzyme-linked immunosorbent assay (ELISA). Sulforaphane significantly reduced the secretion of the inflammatory cytokine interleukin-1β (IL-1β) by C2C12 cells after LPS treatment, and inhibited the production of intracellular reactive oxygen species (ROS). It also increased the expression of E-myosin heavy chain, myosin ID heavy chain, and myogenin, and induced myogenic differentiation of LPS-treated C2C12 cells. Mechanistically, SFN reduced messenger ribonucleic acid and protein levels of TLR4, NLRP3, apoptosis-associated speck-like protein, and Caspase-1 in C2C12 cells, thereby inhibiting the inflammatory response and promoting myogenic differentiation. In addition, the TLR4 inhibitor TAK-242 induced myogenic differentiation in LPS-pretreated C2C12 cells in a similar manner. Sulforaphane can reduce sepsis-induced inflammatory responses and enhance myogenic differentiation by regulating the TLR4 and NLRP3 inflammasome pathways.

Activation of GPR37 in macrophages confers protection against infection-induced sepsis and pain-like behaviour in mice

GPR37 was discovered more than two decades ago, but its biological functions remain poorly understood. Here we report a protective role of GPR37 in multiple models of infection and sepsis. Mice lacking Gpr37 exhibited increased death and/or hypothermia following challenge by lipopolysaccharide (LPS), Listeria bacteria, and the mouse malaria parasite Plasmodium berghei. Sepsis induced by LPS and Listeria in wild-type mice is protected by artesunate (ARU) and neuroprotectin D1 (NPD1), but the protective actions of these agents are lost in Gpr37−/− mice. Notably, we found that ARU binds to GPR37 in macrophages and promotes phagocytosis and clearance of pathogens. Moreover, ablation of macrophages potentiated infection, sepsis, and their sequelae, whereas adoptive transfer of NPD1- or ARU-primed macrophages reduced infection, sepsis, and pain-like behaviors. Our findings reveal physiological actions of ARU in host cells by activating macrophages and suggest that GPR37 agonists may help to treat sepsis, bacterial infections, and malaria.

Fructose-coated Ångstrom silver prevents sepsis by killing bacteria and attenuating bacterial toxin-induced injuries.

Serious infection caused by multi-drug-resistant bacteria is a major threat to human health. Bacteria can invade the host tissue and produce various toxins to damage or kill host cells, which may induce life-threatening sepsis. Here, we aimed to explore whether fructose-coated Ångstrom-scale silver particles (F-AgÅPs), which were prepared by our self-developed evaporation-condensation system and optimized coating approach, could kill bacteria and sequester bacterial toxins to attenuate fatal bacterial infections.Methods: A series of in vitro assays were conducted to test the anti-bacterial efficacy of F-AgÅPs, and to investigate whether F-AgÅPs could protect against multi-drug resistant Staphylococcus aureus (S. aureus)- and Escherichia coli (E. coli)-induced cell death, and suppress their toxins (S. aureus hemolysin and E. coli lipopolysaccharide)-induced cell injury or inflammation. The mouse models of cecal ligation and puncture (CLP)- or E. coli bloodstream infection-induced lethal sepsis were established to assess whether the intravenous administration of F-AgÅPs could decrease bacterial burden, inhibit inflammation, and improve the survival rates of mice. The levels of silver in urine and feces of mice were examined to evaluate the excretion of F-AgÅPs.Results: F-AgÅPs efficiently killed various bacteria that can cause lethal infections and also competed with host cells to bind with S. aureus α-hemolysin, thus blocking its cytotoxic activity. F-AgÅPs inhibited E. coli lipopolysaccharide-induced endothelial injury and macrophage inflammation, but not by directly binding to lipopolysaccharide. F-AgÅPs potently reduced bacterial burden, reversed dysregulated inflammation, and enhanced survival in mice with CLP- or E. coli bloodstream infection-induced sepsis, either alone or combined with antibiotic therapy. After three times injections within 48 h, 79.18% of F-AgÅPs were excreted via feces at the end of the 14-day observation period.Conclusion: This study suggests the prospect of F-AgÅPs as a promising intravenous agent for treating severe bacterial infections.

The role of NK cells in fighting the virus infection and sepsis.

Natural killer cells, one of the important types of innate immune cells, play a pivotal role in the antiviral process in vivo. It has been shown that increasing NK cell activity may promote the alleviation of viral infections, even severe infection-induced sepsis. Given the current state of the novel coronavirus (SARS-CoV-2) global pandemic, clarifying the anti-viral function of NK cells would be helpful for revealing the mechanism of host immune responses and decipher the progression of COVID-19 and providing important clues for combating this pandemic. In this review, we summarize the roles of NK cells in viral infection and sepsis as well as the potential possibilities of NK cell-based immunotherapy for treating COVID-19.

The Clinical Features and Prognostic Assessment of SARS-CoV-2 Infection-Induced Sepsis Among COVID-19 Patients in Shenzhen, China.

Background: The outbreak of the novel coronavirus disease (COVID-19) that began in December 2019 has posed a great threat to human health and caused a significant loss of life. In Shenzhen, 465 patients were confirmed to have COVID-19 as of August 31, 2020. In the present study, we aimed to describe the clinical characteristics of COVID-19 patients in Shenzhen and identify risk factors for the development of viral sepsis.Methods: In this retrospective study, patients who were confirmed to have a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and were admitted to the Third People's Hospital of Shenzhen from January 11 to April 27, 2020 were included in the cohort. Clinical data were extracted and followed up to May 10, 2020, by using predesigned data collection forms.Results: A total of 422 hospitalized COVID-19 patients were enrolled in this study, including 97 (23%) patients with viral sepsis at hospital admission and 325 (77%) non-septic patients. Patients with sepsis were much older than those without sepsis (57 vs. 43 years, P < 0.001) and presented with more comorbidities. Septic patients showed multiple organ dysfunction and significant abnormalities in immune- and inflammation-related biomarkers, and had poorer outcomes when compared to those without sepsis. Increased levels of interleukin-6, blood urea nitrogen, and creatine kinase were associated with the development of SARS-CoV-2-induced sepsis, and an elevated production of interleukin-6 was found to be an independent risk factor for the progression to critical illness among septic COVID-19 patients.Conclusions: SARS-CoV-2 infection-induced sepsis is critically involved in the severity and prognosis of COVID-19 patients by characterizing both aberrant immune response and uncontrolled inflammation. The development of sepsis might contribute to multiple organ dysfunction and poor outcomes in COVID-19 patients during hospitalization.

Oxidative Stress and Inflammation in COVID-19-Associated Sepsis: The Potential Role of Anti-Oxidant Therapy in Avoiding Disease Progression.

Since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak emerged, countless efforts are being made worldwide to understand the molecular mechanisms underlying the coronavirus disease 2019 (COVID-19) in an attempt to identify the specific clinical characteristics of critically ill COVID-19 patients involved in its pathogenesis and provide therapeutic alternatives to minimize COVID-19 severity. Recently, COVID-19 has been closely related to sepsis, which suggests that most deceases in intensive care units (ICU) may be a direct consequence of SARS-CoV-2 infection-induced sepsis. Understanding oxidative stress and the molecular inflammation mechanisms contributing to COVID-19 progression to severe phenotypes such as sepsis is a current clinical need in the effort to improve therapies in SARS-CoV-2 infected patients. This article aims to review the molecular pathogenesis of SARS-CoV-2 and its relationship with oxidative stress and inflammation, which can contribute to sepsis progression. We also provide an overview of potential antioxidant therapies and active clinical trials that might prevent disease progression or reduce its severity.

The role of Vibrio vulnificus virulence factors and regulators in its infection-induced sepsis.

Due to the development of Marine aquaculture, infections caused by Vibrio vulnificus are common all over the world. Symptoms of V. vulnificus infection vary from gastrointestinal illness to septicemia. After infection with V. vulnificus, some patients showed gastrointestinal symptoms, including vomiting, fever, diarrhea, and so on. Others appeared wound infection at the site of contact with bacteria, and even developed sepsis. Once it develops into sepsis, the prognosis of patients is very poor. However, its underlying pathogenic mechanism remains largely undetermined. Growing evidence shows that it can induce primary septicemia mainly via essential virulence factors and regulators. Therefore, it is important to identify the factors that play roles in sepsis. In this review, we systematically expounded the role of V. vulnificus virulence factors and regulators in its infection-induced sepsis in order to provide useful information for the treatment and prevention of V. vulnificus.

CXCL1 regulates neutrophil homeostasis in pneumonia-derived sepsis caused by Streptococcus pneumoniae serotype 3

AbstractNeutrophil migration to the site of bacterial infection is a critical step in host defense. Exclusively produced in the bone marrow, neutrophil release into the blood is tightly controlled. Although the chemokine CXCL1 induces neutrophil influx during bacterial infections, its role in regulating neutrophil recruitment, granulopoiesis, and neutrophil mobilization in response to lung infection-induced sepsis is unclear. Here, we used a murine model of intrapulmonary Streptococcus pneumoniae infection to investigate the role of CXCL1 in host defense, granulopoiesis, and neutrophil mobilization. Our results demonstrate that CXCL1 augments neutrophil influx to control bacterial growth in the lungs, as well as bacterial dissemination, resulting in improved host survival. This was shown in Cxcl1−/− mice, which exhibited defective amplification of early neutrophil precursors in granulocytic compartments, and CD62L- and CD49d-dependent neutrophil release from the marrow. Administration of recombinant CXCL2 and CXCL5 after infection rescues the impairments in neutrophil-dependent host defense in Cxcl1−/− mice. Taken together, these findings identify CXCL1 as a central player in host defense, granulopoiesis, and mobilization of neutrophils during Gram-positive bacterial pneumonia-induced sepsis.

Inhibition of autophagy protects against sepsis by concurrently attenuating the cytokine storm and vascular leakage

Sepsis is an overwhelming systemic inflammatory response for which no satisfactory therapeutic drug is available. Previous studies have shown that autophagy is involved in the cytokine storm and vascular leakage that occur during sepsis. Therefore, we aimed to evaluate the therapeutic potential of autophagy inhibitors against bacterial infection-induced sepsis. Cytokine production and phagocytosis of bacteria by human leukocytes and the permeability of endothelial cells were determined after the co-incubation of cells with lipopolysaccharide (LPS) or Escherichia coli in the presence or absence of autophagy inhibitors in vitro. Furthermore, the therapeutic effects of the autophagy inhibitors in E. coli-infected mice were analysed. In the presence of the autophagy inhibitors, the LPS-triggered cytokine secretion of human leucocytes and LPS (or LPS-conditioned medium from leucocytes)-induced endothelial hyperpermeability were significantly reduced. Moreover, the inhibition of autophagy enhanced the clearance of E. coli by leucocytes in vitro. Finally, we demonstrated that post-treatment but not pretreatment with an autophagy inhibitor (hydroxychloroquine) completely protected mice against E. coli infection-induced lethality by simultaneously reducing cytokine production and vascular leakage and enhancing bacterial clearance. These results suggest that autophagy plays an important role in the pathogenesis of sepsis and could serve as a potential therapeutic target for sepsis.

Nitric oxide synthase 2 enhances the survival of mice during Salmonella Typhimurium infection-induced sepsis by increasing reactive oxygen species, inflammatory cytokines and recruitment of neutrophils to the peritoneal cavity

Sepsis, a leading cause of death in intensive care units, is primarily caused due to an exaggerated immune response. The hyperactive inflammatory response mediated by immune cells against infectious organisms and their toxins results in host cell death and tissue damage, the hallmarks of septic shock. Therefore, molecules that modulate inflammatory responses are attractive therapeutic targets for sepsis. Nitric oxide (NO) is a signaling molecule, which is implicated in regulating diverse immune functions. Although, the protective roles of NO in infectious diseases are well documented, its importance in sepsis is controversial. In the present study, the effects of intra-peritoneal injection of mice with Salmonella Typhimurium, a Gram-negative intracellular pathogen, were studied which leads to a rapid upregulation of serum cytokines and infiltration of neutrophils to the peritoneal cavity. Surprisingly, the induction of inflammatory cytokines and chemokines, e.g. IL6 and CCL2, and the infiltration of neutrophils into the peritoneal cavity are mitigated in mice lacking Nitric oxide synthase 2 (NOS2). The reduced inflammatory response in Nos2-/- mice is accompanied by greater bacterial burden in the peritoneal cavity, lower thymic atrophy, higher liver damage and cardiovascular dysfunction followed by decreased survival. However, no significant differences are observed in other responses between C57BL/6 wild type (WT) and Nos2-/- mice: induction of glucocorticoids, phagocytic ability and apoptosis of peritoneal cells. This study clearly highlights the NOS2-dependent and -independent responses in this mouse model of peritonitis induced sepsis. Importantly, pre-treatment of Nos2-/- mice with DETA-NO, a NO donor, upon infection, restores neutrophil recruitment, reduces bacterial numbers in the peritoneal cavity, improves liver and cardio-vascular function and enhances survival. Interestingly, DETA-NO treatment does not significantly increase the survival of infected WT mice. The implications of these results and the complex roles of NO as a target molecule during sepsis are discussed.

COST-EFFECTIVENESS ANALYSIS OF CEFTAZIDIME-LEVOFLOXACIN AND CEFOTAXIME-ERYTHROMYCIN AS EMPIRICAL ANTIBIOTIC COMBINATIONS IN RESPIRATORY INFECTION-INDUCED SEPSIS

Objective:Pharmacoeconomics has become an important consideration in the selection of therapies, including in patients with sepsis caused by respiratory infection. The aim of this study was to determine the most cost-effective antibiotic combination for respiratory infection-induced sepsis at a public hospital in Bandung, Indonesia.Methods:This retrospective observational study was conducted at one ofpublic hospitals in Bandung. Two interventions were analyzed: (I1) ceftazidime-levofloxacin and (I2) cefotaxime-erythromycin; and compared to the major treatment (I0, the use of other antibiotic combinations). Data were collected from the medical records of inpatients with respiratory infection-induced sepsis from 2010 until 2012. Healthcare perspective was applied by considering only direct medical costs, which were calculated from variable (drug, administrative andtreatment cost) and fixed cost (hospitalization).Results:Comparing with I0, net cost per life saved was calculated to be $3,350 (I1)and $1,589 (12). Number of patients survived was considered to be the most significant parameter on affecting the calculation of net cost per life saved.Conclusion:I2 was more cost effective than I1, compared to I0.

Snake Venom Disintegrin Inhibits the Activation of Toll-Like Receptors and Alleviates Sepsis through Integrin alphaVbeta3 Blockade.

Bacterial infection-induced sepsis is the leading cause of septic inflammatory disease. Rhodostomin (Rn), a snake venom disintegrin, was previously reported to interact with the αVβ3 integrin and the TLR4 on phagocyte in attenuating LPS-induced endotoxemia. In this report, we further evaluated the effects of Rn on TLR2-activated monocytes and its in vivo efficacy. Rn effectively suppressed the adhesion, migration, and cytokine release of Pam3CSK4-activated THP-1 cells. Rn specifically bound to integrin αVβ3 of TLR2-activated THP-1. Integrin αV and Akt siRNA transfection both restrained Pam3CSK4-elicited cytokine release. Rn decreased the Pam3CSK4-induced phosporylation of MAPKs, degradation of IκB and activation of FAK, Akt, c-Src and Syk. The Pam3CSK4-induced translocation of MyD88, a central adaptor of TLR2, to the cell membrane was also inhibited by Rn treatment. In the polymicrobial inflammatory caecal ligation and puncture model, Rn significantly reduced pro-inflammatory cytokine and chemokine release, alleviated tissue injury and elevated survival rate in vivo. Taken together, in addition to inhibiting the activation of TLR4, Rn exhibits anti-inflammatory activity through antagonizing the activation of phagocytes and interrupting the crosstalk between αVβ3 and TLR2-dependent signaling pathways.

Activation of Hepatic STAT3 Maintains Pulmonary Defense during Endotoxemia.

Pneumonia and infection-induced sepsis are worldwide public health concerns. Both pathologies elicit systemic inflammation and induce a robust acute-phase response (APR). Although APR activation is well regarded as a hallmark of infection, the direct contributions of liver activation to pulmonary defense during sepsis remain unclear. By targeting STAT3-dependent acute-phase changes in the liver, we evaluated the role of liver STAT3 activity in promoting host defense in the context of sepsis and pneumonia. We employed a two-hit endotoxemia/pneumonia model, whereby administration of 18 h of intraperitoneal lipopolysaccharide (LPS; 5 mg/kg of body weight) was followed by intratracheal Escherichia coli (10(6) CFU) in wild-type mice or those lacking hepatocyte STAT3 (hepSTAT3(-/-)). Pneumonia alone (without endotoxemia) was effectively controlled in the absence of liver STAT3. Following endotoxemia and pneumonia, however, hepSTAT3(-/-) mice, with significantly reduced levels of circulating and airspace acute-phase proteins, exhibited significantly elevated lung and blood bacterial burdens and mortality. These data suggested that STAT3-dependent liver responses are necessary to promote host defense. While neither recruited airspace neutrophils nor lung injury was altered in endotoxemic hepSTAT3(-/-) mice, alveolar macrophage reactive oxygen species generation was significantly decreased. Additionally, bronchoalveolar lavage fluid from this group of hepSTAT3(-/-) mice allowed greater bacterial growth ex vivo. These results suggest that hepatic STAT3 activation promotes both cellular and humoral lung defenses. Taken together, induction of liver STAT3-dependent gene expression programs is essential to countering the deleterious consequences of sepsis on pneumonia susceptibility.