Bakgrund: Sepsis är ett livshotande tillstånd med hög dödlighet som drabbar 30 miljoner människor världen över och resulterar i omkring sex miljoner dödsfall årligen. Tecken och symtom är diffusa och det finns idag ett behov av utökad kunskap om sjuksköterskans omvårdnadsåtgärder vid sepsis. Syfte: Syftet var att beskriva sjuksköterskans omvårdnadsåtgärder för att upptäcka sepsis i ett tidigt skede. Metod: Studien genomfördes som en allmän litteraturstudie med inspiration av innehållsanalys där resultatet utgörs av 15 vetenskapliga artiklar. Resultat: Resultatet presenteras i kategorierna klinisk bedömning, kunskap och övervakning. I resultatet framgår det att sjuksköterskans förmåga att kombinera klinisk observation med ett standardiserat mätinstrument möjliggör en tidig upptäckt av sepsis. Det framgår även att sjuksköterskor som har uppdaterat sin kunskap om sepsis och dess progression genom fortbildning blev mer säkra på att upptäcka och identifiera patienter med sepsis. Sjuksköterskor kan även ta hjälp av datoriserade övervakningssystem, som larmar vid misstanke om sepsis. Konklusion: Varje enskild omvårdnadsåtgärd i resultatet kan bidra till att sepsis upptäcks tidigt, framförallt när implementering av mätinstrument, kunskap och utbildning kombineras kan dödligheten och lidandet för patienten minska. Det anses att ytterligare forskning är nödvändig kring sjuksköterskans omvårdnadsåtgärder för att tidigt upptäcka sepsis. / Background:Sepsis is a life-threatening condition that affects 30 million people worldwide and results in about six million deaths annually. Signs and symptoms are diffuse and today there is a need for increased knowledge of the nurse's nursing measures in case of sepsis. Aim:The purpose was to describe the nurse's nursing measures to detect sepsis at an early stage. Method:The study was conducted as a general literature study, inspired bycontent analysisand the result is based on 15scientific articles. Results:The result is presented in the categories clinical assessment, knowledgeand monitoring.Theresult shows that the nurse's ability to combine clinical observation with a standardized measuring instrument enables an early detection of sepsis. It also appears that nurses who have updated their knowledge of sepsis and its progression through continuing education became more confident in detecting and identifying patients with sepsis. Nurses can also use computerized monitoring systemsin nursing care, which alert in case of suspicion of sepsis.Conclusion:Every single nursing measure in the resultcan help to detect sepsis early, especially when combining measuring instruments, knowledge and education. Thiscan reduce mortality and suffering for the patient,butfurther research is necessary regarding the nursing care measures to detect sepsis early.

Le récepteur TREM-1 (Triggering Receptor Expressed on Myeloid cells-1) joue un rôle crucial dans la mise en place du sepsis en amplifiant la réponse immunitaire de l'hôte. TLT-1 (TREM-Like Transcript-1) appartient à la famille des récepteurs TREMs, est exprimé exclusivement sur les plaquettes activées et est connu pour faciliter l'agrégation plaquettaire en liant le fibrinogène. Ces travaux montrent qu'une forme soluble de TLT-1 est impliquée dans la régulation de l'inflammation au cours du sepsis en modulant l'activation leucocytaire et le dialogue plaquette-neutrophile. Un peptide de 17 acides aminés issu de sa portion extracellulaire est porteur de cette activité par compétition avec le ligand de TREM-1. Alors que l'administration tant précoce que tardive de LR17 au cours du sepsis expérimental murin augmentait la survie, les animaux KO TLT-1 étaient hautement susceptibles à l'infection. Nous avons identifié ici un récepteur soluble libéré au cours de l'activation plaquettaire comme un potentiel régulateur de la réaction inflammatoire au cours du sepsis, ouvrant ainsi de nouvelles perspectives thérapeutiques / The Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) plays a crucial role during the onset of sepsis by amplifying the host immune response. The TREM-Like Transcript-1 (TLT-1) belongs to the TREM family, is selectively expressed on activated platelets, and is known to facilitate platelet aggregation through binding to fibrinogen. Here we show that a soluble form of TLT-1 is implicated in the regulation of inflammation during sepsis by dampening leukocytes activation and modulating platelet-neutrophil crosstalk. A 17-aa sequence of the TLT-1 extracellular domain (LR17) is responsible for this activity through competition with the TREM-1 ligand. While early or late LR17 treatment of septic mice improves survival, treml-1-/- animals are highly susceptible to polymicrobial infection. The present findings identify platelet derived sTLT-1 as a potent endogenous regulator of sepsis associated inflammation and open new therapeutic perspectives

Para descrever a incidência, fatores de risco e evolução clínica da sepse neonatal hospitalar por Klebsiella spp. foi realizado um estudo retrospectivo e prospectivo de 45 neonatos com sepse e Klebsiella spp. na hemocultura. A taxa geral de sepse hospitalar por Klebsiella spp foi de 3,7%, identificando K. pneumoniae (91%), K. oxytoca (9%), e 55,6% de cepas multirresistentes. Os principais fatores de risco foram uso prévio de antibióticos, prematuridade, baixo peso e catéter central. Houve complicações em 28,9% dos casos, com mortalidade de 11%. A sepse por Klebsiella spp. foi freqüente nas unidades neonatais, com taxa elevada de complicações e mortalidade, principalmente na infecção por cepas multirresistentes / In order to describe the incidence, risk factors and clinical evolution of hospital-origin sepsis by Klebsiella spp. in neonatal units, a retrospective and prospective study of 45 neonates with sepsis and Klebsiella spp. at the hemoculture was carried out.The overall hospital sepsis rate by Klebsiella spp. was 3.7%, with the identification of K. pneumoniae (91%), K. oxytoca (9%) and 55.6% of multi-resistant strains. The main risk factors were previous antibiotic use, prematurity, low weight and central catheter.There were complications in 28.9% of the cases, with a mortality rate of 11%.The sepsis by Klebsiella spp. was frequent at the neonatal units, with a high rate of complications and mortality, especially in multi-resistant strain infections

A sepse é caracterizada por um desequilíbrio entre a resposta pró- e anti-inflamatória às infecções. Um dos principais componentes da resposta do hospedeiro no choque séptico são as interações recíprocas entre o sistema imune e o sistema nervoso central, desta forma o objetivo deste estudo foi investigar o desenvolvimento de alterações neurológicas e sua associação com alterações imunológicas em fases iniciais e tardias após a sepse por ligação e perfuração cecal (CLP). Dividimos em três experimentos: agudo, crônico e efeito da ACh na evolução tardia da sepse. No experimento agudo utilizamos camundongos Balb/c, induzimos sepse por CLP em diferentes gravidades (leve, moderado e grave), 6 horas após o CLP foi realizado teste comportamental SHIRPA e logo após os animais foram sacrificados. No experimento crônico os camundongos Balb/c foram submetidos ao CLP leve, o SHIRPA foi realizado 6 horas e 15 dias após o CLP e os animais foram sacrificados 15 dias após o CLP. No experimento dos efeitos da ACh utilizamos camundongos Balb/c que receberam a droga donepezila (5 mg/kg/dia, oralmente) sete dias antes do CLP leve até o dia do sacrifício e os camundongos homozigotos mutantes VAChT KD também submetidos ao CLP leve. O teste comportamental SHIRPA foi realizado 6 horas após o CLP e os animais sacríficos 15 dias após o CLP. O plasma, o baço e o hipocampo foram removidos em todos os experimentos. Os níveis do S100? foram medidos no plasma. Os baços foram pesados, e por citometria de fluxo foi caracterizado os linfócitos (linfócitos T citotóxicos, linfócitos T auxiliares, linfócitos B, células T reguladoras e células Th17) e morte celular (Apoptose inicial, necrose e apoptose tardia). Os níveis de citocinas no baço, hipocampo e plasma foram determinados por ELISA. Nossos resultados mostram que no experimento agudo, 6 horas após o CLP a encefalopatia é diferente dependendo da gravidade da sepse, e o perfil de linfócitos no baço não é alterado por nenhuma gravidade da sepse. No entanto, a ativação de células do baço foi indicada no nosso estudo por variações na quantidade de citocinas no baço. No experimento crônico observamos que 15 dias após o CLP os animais apresentam encefalopatia séptica, e esta está correlacionada com a diferenciação e morte celular de linfócitos do baço, o que leva a um alto perfil imunossupressor. No experimento da ACh mostramos que a estimulação da transmissão colinérgica, utilizando donepezila, diminui a inflamação, por aumentar linfócitos, morte linfocitária e diminuir citocinas pró-inflamatória. E, ao contrário, a diminuição da transmissão colinérgica, experimento VAChT KD, observouse uma diminuição de linfócitos, sem morte celular e aumento da inflamação. Desta forma, concluímos que a alteração neurológica nos animais com sepse está associada com as alterações imunológicas tardias e que a ACh tem um importante papel no perfil imunológico 15 dias após o CLP / Sepsis is characterized by an imbalance between pro- and anti-inflammatory responses to infection. One of the main components of the host response in septic shock are the reciprocal interactions between the immune system and the central nervous system, so the aim of this study was to investigate the development of neurological disorders and their association with immunological changes in early and late stages after sepsis by cecal ligation and puncture (CLP). We divided in three experiments: acute, chronic and chronic ACh. In acute experiment we use Balb/c mice, induce sepsis by CLP in different severities (mild, moderate and severe), 6 hours after CLP was conducted behavioral test SHIRPA and after the animals were sacrificed. In the chronic experiment Balb/c mice were subjected to CLP mild, the SHIRPA was performed 6 hours and 15 days after CLP, and animals were sacrificed 15 days after CLP. In chronic ACh experiment use Balb/c mice that received the drug Donepezil (5 mg/kg/day, orally) seven days before the CLP mild until the day of sacrifice and use too mice homozygous mutants KD VAChT also submitted to CLP mild. The SHIRPA behavioral test was performed 6 hours after CLP and the animals were sacrificed 15 days after CLP. The plasma, spleen and hippocampus were removed in all experiments. The levels of S100? were measured in plasma. The spleens were weighed, and flow cytometry was characterized lymphocytes (cytotoxic T lymphocytes, helper T lymphocytes, B lymphocytes, regulatory T cells and Th17 cells) and cell death (apoptosis initial, necrosis and DNA fragmentation). Cytokine levels in the spleen, hippocampus and plasma were determined by ELISA. Our results show that in the acute experiment, 6 hours after CLP encephalopathy is different depending on the severity of sepsis, since the profile of the spleen lymphocytes is not changed by any severity of sepsis. However, the spleen cell activation was shown in this study by variations in the quantity of cytokines in the spleen. In the chronic experiment we observed that 15 days after CLP animals have septic encephalopathy, and this correlates with cell differentiation and the death of spleen lymphocytes, which leads to a high immunosuppressive profile. Since in the chronic ACh experiment have shown that stimulation of cholinergic transmission, using donepezil, reduces inflammation by increasing lymphocytes, lymphocyte death and decreasing proinflammatory cytokine. And, conversely, the reduction in cholinergic transmission, KD VAChT experiment, we observed a decrease of lymphocytes, and increase cell death without inflammation. Thus, we conclude that the neurological deficits in animals with sepsis is associated with immunological late changes and ACh plays an important role in the immune profile 15 days after CLP

La réponse immuno-inflammatoire au cours du choc septique associe une importante réponse inflammatoire initiale responsable de l'état de choc et le développement secondaire d'altérations du système immunitaire. Les polynucléaires neutrophiles (PNN) jouent un rôle central dans la réponse immunitaire. Des données récentes de la littérature décrivent également un rôle immunosuppresseur jusqu'alors méconnu pour ces cellules. Nous avons exploré leur possible implication dans la physiopathologie du choc septique.Le but de ce travail était l'exploration des altérations phénotypiques, fonctionnelles et transcriptomiques des PNN lors de la phase immunosuppressive du choc septique. Nos résultats montrent une diminution de la capacité de migration des PNN ainsi qu'une diminution de la production de composés bactéricides (myéloperoxydase, lactoferrine) alors que la réponse aux cytokines et la phagocytose n'apparaissent pas altérées. Le contenu en myéloperoxydase et la présence de PNN immatures CD10dimCD16dim étaient indépendamment associés à une mortalité plus élevée. De manière intéressante, CD177 était le gène le plus différentiellement exprimé entre les patients et les volontaires sains. CD177 et CD10 étaient inversement corrélés. Ainsi, la diminution du chimiotactisme, la perte de myéloperoxydase, la présence de cellules immatures et leurs liens avec la mortalité pourraient contribuer au contexte d'immunosuppression présent chez les patients septiques. Au final, les pistes d'exploration futures convergent vers la population de PNN immatures et le rôle spécifique du CD177 dans les états septiques sévères / Severe septic syndromes deeply impair innate and adaptive immunity and are responsible for sepsis-induced immunosuppression. While neutrophils represent the first line of defense against infection, little is known about their phenotype and functions few days after sepsis, when the immunosuppressive phase is maximal (i.e., between day 3 and 8). The objective of this study was thus to perform a global evaluation of neutrophil alterations in immunosuppressed septic patients based on phenotypic, functional and transcriptomic studies. Our results highlight a markedly altered neutrophil chemotaxis (functional and chemokine receptor expressions), oxidative burst, lactoferrin content and an increased number of circulating immature granulocytes (i.e., CD10dimCD16dim). In contrast, phagocytosis and activation capacities were conserved. It is interesting to note that a diminished myeloperoxidase expression appeared as the best predictor to identify a group of septic shock patients at high risk of death. Similarly, patients with lower proportions of CD10dimCD16dim granulocytes had a significant better survival compared with patients presenting a higher percentage. CD177 mRNA, coding for an activation molecule in chemotaxis but also known to be overexpressed in immature cells, had the highest fold change modulation between patients and controls. Considering the potential dual roles of CD177 neutrophil (i.e., maturation / chemotaxis), its participation in septic shock pathophysiology deserves further investigation. To conclude, circulating neutrophils present with phenotypic, functional and morphological alterations few days after sepsis onset. These dysfunctions may participate in the deleterious role of sepsis-induced immunosuppression. The present results open new perspectives in the mechanisms favoring nosocomial infections after septic shock. They deserve to be further investigated in a larger clinical study and in animal models recapitulating these alterations

A sepse é caracterizada por um desequilíbrio entre a resposta pró- e anti-inflamatória às infecções. Um dos principais componentes da resposta do hospedeiro no choque séptico são as interações recíprocas entre o sistema imune e o sistema nervoso central, desta forma o objetivo deste estudo foi investigar o desenvolvimento de alterações neurológicas e sua associação com alterações imunológicas em fases iniciais e tardias após a sepse por ligação e perfuração cecal (CLP). Dividimos em três experimentos: agudo, crônico e efeito da ACh na evolução tardia da sepse. No experimento agudo utilizamos camundongos Balb/c, induzimos sepse por CLP em diferentes gravidades (leve, moderado e grave), 6 horas após o CLP foi realizado teste comportamental SHIRPA e logo após os animais foram sacrificados. No experimento crônico os camundongos Balb/c foram submetidos ao CLP leve, o SHIRPA foi realizado 6 horas e 15 dias após o CLP e os animais foram sacrificados 15 dias após o CLP. No experimento dos efeitos da ACh utilizamos camundongos Balb/c que receberam a droga donepezila (5 mg/kg/dia, oralmente) sete dias antes do CLP leve até o dia do sacrifício e os camundongos homozigotos mutantes VAChT KD também submetidos ao CLP leve. O teste comportamental SHIRPA foi realizado 6 horas após o CLP e os animais sacríficos 15 dias após o CLP. O plasma, o baço e o hipocampo foram removidos em todos os experimentos. Os níveis do S100? foram medidos no plasma. Os baços foram pesados, e por citometria de fluxo foi caracterizado os linfócitos (linfócitos T citotóxicos, linfócitos T auxiliares, linfócitos B, células T reguladoras e células Th17) e morte celular (Apoptose inicial, necrose e apoptose tardia). Os níveis de citocinas no baço, hipocampo e plasma foram determinados por ELISA. Nossos resultados mostram que no experimento agudo, 6 horas após o CLP a encefalopatia é diferente dependendo da gravidade da sepse, e o perfil de linfócitos no baço não é alterado por nenhuma gravidade da sepse. No entanto, a ativação de células do baço foi indicada no nosso estudo por variações na quantidade de citocinas no baço. No experimento crônico observamos que 15 dias após o CLP os animais apresentam encefalopatia séptica, e esta está correlacionada com a diferenciação e morte celular de linfócitos do baço, o que leva a um alto perfil imunossupressor. No experimento da ACh mostramos que a estimulação da transmissão colinérgica, utilizando donepezila, diminui a inflamação, por aumentar linfócitos, morte linfocitária e diminuir citocinas pró-inflamatória. E, ao contrário, a diminuição da transmissão colinérgica, experimento VAChT KD, observouse uma diminuição de linfócitos, sem morte celular e aumento da inflamação. Desta forma, concluímos que a alteração neurológica nos animais com sepse está associada com as alterações imunológicas tardias e que a ACh tem um importante papel no perfil imunológico 15 dias após o CLP / Sepsis is characterized by an imbalance between pro- and anti-inflammatory responses to infection. One of the main components of the host response in septic shock are the reciprocal interactions between the immune system and the central nervous system, so the aim of this study was to investigate the development of neurological disorders and their association with immunological changes in early and late stages after sepsis by cecal ligation and puncture (CLP). We divided in three experiments: acute, chronic and chronic ACh. In acute experiment we use Balb/c mice, induce sepsis by CLP in different severities (mild, moderate and severe), 6 hours after CLP was conducted behavioral test SHIRPA and after the animals were sacrificed. In the chronic experiment Balb/c mice were subjected to CLP mild, the SHIRPA was performed 6 hours and 15 days after CLP, and animals were sacrificed 15 days after CLP. In chronic ACh experiment use Balb/c mice that received the drug Donepezil (5 mg/kg/day, orally) seven days before the CLP mild until the day of sacrifice and use too mice homozygous mutants KD VAChT also submitted to CLP mild. The SHIRPA behavioral test was performed 6 hours after CLP and the animals were sacrificed 15 days after CLP. The plasma, spleen and hippocampus were removed in all experiments. The levels of S100? were measured in plasma. The spleens were weighed, and flow cytometry was characterized lymphocytes (cytotoxic T lymphocytes, helper T lymphocytes, B lymphocytes, regulatory T cells and Th17 cells) and cell death (apoptosis initial, necrosis and DNA fragmentation). Cytokine levels in the spleen, hippocampus and plasma were determined by ELISA. Our results show that in the acute experiment, 6 hours after CLP encephalopathy is different depending on the severity of sepsis, since the profile of the spleen lymphocytes is not changed by any severity of sepsis. However, the spleen cell activation was shown in this study by variations in the quantity of cytokines in the spleen. In the chronic experiment we observed that 15 days after CLP animals have septic encephalopathy, and this correlates with cell differentiation and the death of spleen lymphocytes, which leads to a high immunosuppressive profile. Since in the chronic ACh experiment have shown that stimulation of cholinergic transmission, using donepezil, reduces inflammation by increasing lymphocytes, lymphocyte death and decreasing proinflammatory cytokine. And, conversely, the reduction in cholinergic transmission, KD VAChT experiment, we observed a decrease of lymphocytes, and increase cell death without inflammation. Thus, we conclude that the neurological deficits in animals with sepsis is associated with immunological late changes and ACh plays an important role in the immune profile 15 days after CLP

Para descrever a incidência, fatores de risco e evolução clínica da sepse neonatal hospitalar por Klebsiella spp. foi realizado um estudo retrospectivo e prospectivo de 45 neonatos com sepse e Klebsiella spp. na hemocultura. A taxa geral de sepse hospitalar por Klebsiella spp foi de 3,7%, identificando K. pneumoniae (91%), K. oxytoca (9%), e 55,6% de cepas multirresistentes. Os principais fatores de risco foram uso prévio de antibióticos, prematuridade, baixo peso e catéter central. Houve complicações em 28,9% dos casos, com mortalidade de 11%. A sepse por Klebsiella spp. foi freqüente nas unidades neonatais, com taxa elevada de complicações e mortalidade, principalmente na infecção por cepas multirresistentes / In order to describe the incidence, risk factors and clinical evolution of hospital-origin sepsis by Klebsiella spp. in neonatal units, a retrospective and prospective study of 45 neonates with sepsis and Klebsiella spp. at the hemoculture was carried out.The overall hospital sepsis rate by Klebsiella spp. was 3.7%, with the identification of K. pneumoniae (91%), K. oxytoca (9%) and 55.6% of multi-resistant strains. The main risk factors were previous antibiotic use, prematurity, low weight and central catheter.There were complications in 28.9% of the cases, with a mortality rate of 11%.The sepsis by Klebsiella spp. was frequent at the neonatal units, with a high rate of complications and mortality, especially in multi-resistant strain infections

Sepsis is associated with high mortality and morbidity. Immediate recognition and treatment is crucial to prevent complications that can be highly detrimental and cause a significant impact on the U.S. healthcare economy. Numerous studies have been conducted to improve patient outcomes and lower healthcare costs from sepsis and septic shock. Many of these studies were focused on exploring healthcare providers' knowledge and compliance to the Surviving Sepsis Campaign (SSC) guidelines. This study aimed to explore and identify barriers to the implementation of the sepsis bundles and strategies to enhance healthcare providers' adherence to these bundles. A systematic review of articles was conducted using the ACE Star Model of Knowledge Transformation. Studies such as randomized controlled trials (RTC's), systematic reviews, retrospective studies, and prospective observational studies conducted in Intensive Care Units (ICUs) within the past 10 years were utilized, guided by the American Association of Critical Care Nurses' (AACN's) grading system. Sources of evidence were obtained from PubMed, CINAHL, and GoogleScholar. The results of this study are aimed at helping support the evidence-based clinical practice among providers caring for patients with sepsis and septic shock in an ICU setting using evidence-based guidelines. The results of this study provide an opportunity for healthcare systems to relieve financial burdens from sepsis and thus contribute to pos

La septicémie et les troubles associés demeurent une cause majeure de mortalité dans les unités de soins intensifs. Des récents travaux ont mis en lumière un lien inattendu entre les mitochondries et les fonctions des cellules immunitaires. Des modifications des fonctions mitochondriales ont pu être observées dans les cellules sanguines périphériques lors de septicémies. Dans le cadre de ce travail de thèse, nous avons cherché à évaluer si la mitophagie pouvait avoir un impact sur les fonctions des phagocytes dans le contexte d’une infection bactérienne. La mitophagie est une autophagie dédiée aux mitochondries qui régit l'élimination des mitochondries dysfonctionnelles. Nous avons démontré ici in vivo et in vitro que les macrophages exposés aux bactéries à Gram négatif ou à leurs composants de la paroi cellulaire (Lipopolysaccharides, LPS) présentent une inhibition marquée de la mitophagie qui constitue un mécanisme de protection contre la septicémie. L'activation des macrophages avec une combinaison LPS/IFNγ entraîne une inhibition précoce de la mitophagie dépendante de PINK1 selon une voie dépendante de STAT1-Caspase 11. Cette inhibition de la mitophagie contribue à expliquer la reprogrammation métabolique observée dans les macrophages classiquement activés (macrophages M1) et conduit à une augmentation de la production de ROS mitochondriaux (mROS). En tant que molécules de signalisation, les mROS conduisent à l'activation des macrophages de manière dépendante de HIF-1α et NF-κB. En outre, ces molécules contribuent à la clairance bactérienne dans les phagocytes activés. Il est intéressant de noter que nous avons démontré in vitro et in vivo que la modulation pharmacologique de la mitophagie permet d'imiter ou de réprimer les effets du LPS sur la polarisation des macrophages, la libération des cytokines et l'activité bactéricide. Pour conclure, ce travail démontre que l'inhibition de la mitophagie est une caractéristique de l'activation LPS-dépendante des macrophages et un mécanisme de protection contre les bactéries à Gram négatif. Cette étude souligne également une relation inconnue entre la signalisation IFNγ, les caspases inflammatoires et la mitophagie. Enfin, nos travaux mettent en lumière l'impact des modulateurs pharmacologiques de la mitophagie sur la fonction des macrophages et ouvrent de nouvelles opportunités pour le développement de nouvelles stratégies thérapeutiques pour stimuler la défense de l'hôte. / Sepsis and related organ dysfunctions remain a leading cause of mortality in intensive care units. Increasing evidences have shed light on an unexpected link between mitochondria and immune cell functions. Alterations in mitochondrial functions have been reported in peripheral blood cells in sepsis. We hypothesize here that mitophagy might impact on phagocyte functions in the context of bacterial infection. Mitophagy is a mitochondria-dedicated autophagy that governs the elimination of dysfunctional mitochondria. We demonstrated here in vivo and in vitro that macrophages exposed to Gram-negative bacteria or their cell wall component LPS display a marked inhibition of mitophagy that constitutes a protective mechanism against sepsis. LPS/IFNγ-driven macrophage activation results in early inhibition of PINK1-dependent mitophagy through a STAT1-Caspase 4/11 pathway. This inhibition of mitophagy contributes to explain the metabolic reprogramming observed in classically activated macrophages and leads to a rise in mitochondrial ROS (mROS) production. As signaling molecules, mROS lead to macrophages activation in a HIF-1α- and NF-κB-dependent manner. Furthermore, these molecules contribute to bacterial clearance in activated phagocytes. Interestingly, we demonstrated in vitro and in vivo that pharmacological modulation of mitophagy allows either mimicking or repressing the effects of LPS on macrophages polarization, cytokine release and bactericidal activity. To conclude, this work demonstrates that inhibition of mitophagy is a feature of LPS-dependent macrophage activation and a protective mechanism against Gram-negative bacteria. This study also highlights an unknown relationship between IFNγ-signaling, inflammatory caspases and mitophagy. Finally, our work point out the impact of pharmacological modulators of mitophagy on macrophage function and open new opportunities for the development of novel strategies to boost host defense

Background: Inhaled carbon monoxide (CO) appears to have beneficial effects on endotoxemia-induced impairment of hypoxic pulmonary vasoconstriction (HPV). This study aims to specify correct timing of CO application, it’s biochemical mechanisms and effects on inflammatory reactions. Methods: Mice (C57BL/6; n = 86) received lipopolysaccharide (LPS, 30 mg/kg) intraperitoneally and subsequently breathed 50 ppm CO continuously during defined intervals of 3, 6, 12 or 18 h. Two control groups received saline intraperitoneally and additionally either air or CO, and one control group received LPS but breathed air only. In an isolated lung perfusion model vasoconstrictor response to hypoxia (FiO2 = 0.01) was quantified by measurements of pulmonary artery pressure. Pulmonary capillary pressure was estimated by double occlusion technique. Further, inflammatory plasma cytokines and lung tissue mRNA of nitric-oxide-synthase-2 (NOS-2) and heme oxygenase-1 (HO-1) were measured. Results: HPV was impaired after LPS-challenge (p < 0.01). CO exposure restored HPV-responsiveness if administered continuously for full 18 h, for the first 6 h and if given in the interval between the 3rd and 6th hour after LPS-challenge (p < 0.05). Preserved HPV was attributable to recovered arterial resistance and associated with significant reduction in NOS-2 mRNA when compared to controls (p < 0.05). We found no effects on inflammatory plasma cytokines. Conclusion: Low-dose CO prevented LPS-induced impairment of HPV in a time-dependent manner, associated with a decreased NOS-2 expression.