Inflammasomes in Tissue Damages and Immune Disorders After Trauma

Trauma remains a leading cause of death worldwide. Hemorrhagic shock and direct injury to vital organs are responsible for early mortality whereas most delayed deaths are secondary to complex pathophysiological processes. These processes result from imbalanced systemic reactions to the multiple aggressions associated with trauma. Trauma results in the uncontrolled local and systemic release of endogenous mediators acting as danger signals [damage-associated molecular patterns (DAMPs)]. Their recognition by the innate immune system triggers a pro-inflammatory immune response paradoxically associated with concomitant immunosuppression. These responses, ranging in intensity from inappropriate to overwhelming, promote the propagation of injuries to remote organs, leading to multiple organ failure and death. Some of the numerous DAMPs released after trauma trigger the assembly of intracellular multiprotein complexes named inflammasomes. Once activated by a ligand, inflammasomes lead to the activation of a caspase. Activated caspases allow the release of mature forms of interleukin-1β and interleukin-18 and trigger a specific pro-inflammatory cell death termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1, and AIM2, are involved in the generation of tissue damage and immune dysfunction after trauma. Following trauma-induced DAMP(s) recognition, inflammasomes participate in multiple ways in the development of exaggerated systemic and organ-specific inflammatory response, contributing to organ damage. Inflammasomes are involved in the innate responses to traumatic brain injury and contribute to the development of acute respiratory distress syndrome. Inflammasomes may also play a role in post-trauma immunosuppression mediated by dysregulated monocyte functions. Characterizing the involvement of inflammasomes in the pathogenesis of post-trauma syndrome is a key issue as they may be potential therapeutic targets. This review summarizes the current knowledge on the roles of inflammasomes in trauma

Hemodynamic Changes during a Deep Inspiration Maneuver Predict Fluid Responsiveness in Spontaneously Breathing Patients

Objective. We hypothesized that the hemodynamic response to a deep inspiration maneuver (DIM) indicates fluid responsiveness in spontaneously breathing (SB) patients. Design. Prospective study. Setting. ICU of a general hospital. Patients. Consecutive nonintubated patients without mechanical ventilation, considered for volume expansion (VE). Intervention. We assessed hemodynamic status at baseline and after VE. Measurements and Main Results. We measured radial pulse pressure (PP) using an arterial catheter and peak velocity of femoral artery flow (VF) using continuous Doppler. Changes in PP and VF induced by a DIM (ΔPPdim and ΔVFdim) were calculated in 23 patients. ΔPPdim and ΔVFdim ≥12% predicted responders to VE with sensitivity of 90% and specificity of 100%. Conclusions. In a restricted population of SB patients with severe sepsis or acute pancreatitis, ΔPPdim and ΔVFdim are accurate indices for predicting fluid responsiveness. These results should be confirmed in a larger population before validating their use in current practice

Review of the nutritional benefits and risks related to intense sweeteners

Unfortunately, the original version of this article [1] contained an error. The author’s names were included incorrectly, the surnames were presented before the forename: Bruyère Olivier, Ahmed H. Serge, Atlan Catherine, Belegaud Jacques, Bortolotti Murielle, Canivenc-Lavier Marie-Chantal, Charrière Sybil, Girardet Jean-Philippe, Houdart Sabine, Kalonji Esther, Nadaud Perrine, Rajas Fabienne, Slama Gérard and Margaritis Irène The author list has been corrected in the original article and is also included correctly below: Olivier Bruyère, Serge H. Ahmed, Catherine Atlan, Jacques Belegaud, Murielle Bortolotti, Marie-Chantal Canivenc-Lavier, Sybil Charrière, Jean-Philippe Girardet, Sabine Houdart, Esther Kalonji, Perrine Nadaud, Fabienne Rajas, Gérard Slama, Irène Margaritis (NB: erratum 1 p. doi: in volume 73, 49, published 23 October 2015, (eCollection 2015, PMID: 26500771, PMCID: PMC4619575))International audienceBackground : The intense sweeteners currently authorised in Europe comprise ten compounds of various chemical natures. Their overall use has sharply risen in the last 20 years. These compounds are mainly used to formulate reduced-calorie products while maintaining sweetness.Methods : This extensive analysis of the literature reviews the data currently available on the potential nutritional benefits and risks related to the consumption of products containing intense sweeteners.Results and Conclusions : Regarding nutritional benefits, the available studies, while numerous, do not provide proof that the consumption of artificial sweeteners as sugar substitutes is beneficial in terms of weight management, blood glucose regulation in diabetic subjects or the incidence of type 2 diabetes. Regarding nutritional risks (incidence of type 2 diabetes, habituation to sweetness in adults, cancers, etc.), it is not possible based on the available data to establish a link between the occurrence of these risks and the consumption of artificial sweeteners. However, some studies underline the need to improve knowledge of the links between intense sweeteners consumption and certain risks

Role of bacterial kynurenines in Pa-induced lung injury

Pseudomonas aeruginosa (Pa) est un pathogène opportuniste responsable d’infections pulmonaires aigues graves chez les malades prédisposés. Devant l’émergence croissante de la résistance aux antibiotiques, le développement de thérapeutiques alternatives adjuvantes est indispensable et nécessite la compréhension des interactions hôte-pathogènes au cours de l’infection. La voie métabolique de dégradation du tryptophane appelée voie des kynurénines produit chez l’hôte des métabolites aux propriétés immunomodulatrices connues. Récemment, l’existence de cette voie a été mise en évidence chez Pa, bien que la nature et la quantité de métabolites produits ne soient pas parfaitement connus. La production bactérienne de kynurénines pourrait interférer avec la mise en place de la réponse immunitaire de l’hôte et sa régulation au cours des différentes phases de l’infection, altérant la balance immunitaire pulmonaire au profit du pathogène. A ce titre, la voie des kynurénines de Pa constituerait une cible thérapeutique potentielle. L’objectif de ce travail de thèse est d’étudier l’implication de la voie des kynurénines de Pa dans la virulence bactérienne et la réponse immune de l’hôte dans un modèle murin d’agression respiratoire aiguë. Pour cela, les souris sont infectées avec des souches sauvages de Pa, avec des souches mutantes ΔkynA, non productrices de kynurénines, et des souches ΔkynU, surproductrices de kynurénines. Les interactions potentielles avec la voie des kynurénines de l’hôte sont explorées en inhibant la première enzyme de la voie métabolique, l’indoleamine-2,3-dioxygenase (IDO). Enfin, le rôle du récepteur arylhydrocarbone (AhR), récepteur connu des kynurénines et impliqué dans l’immunité pulmonaire, est exploré en comparant la réponse à l’infection de souris AhR KO à celle des souris sauvages. Dans ce travail, nous décrivons tout d’abord la production des différents métabolites de la voie des kynurénines de Pa in vitro et in vivo dans le modèle d’infection respiratoire aigue, en décrivant pour la première fois la production d’acide kynurénique et de 3-hydroxy-kynurénine pour cette bactérie. Ensuite, nous montrons que les kynurénines bactériennes interfèrent avec la réponse immune de l’hôte, en majorant le recrutement cellulaire alvéolaire, tout en atténuant le niveau d’inflammation et l’activation des cellules présentatrices d’antigènes. Enfin, nous rapportons que l’IDO et l’AhR sont impliqués dans cette immunomodulation, faisant des kynurénines bactériennes des agents du dialogue hôte-pathogène au cours de l’infection respiratoire aigue. A la lumière de ces résultats, la voie des kynurénines pourrait constituer une cible thérapeutique d’intérêt dans les infections respiratoires à P. aeruginosa.Pseudomonas aeruginosa (Pa) is a Gram-negative bacteria frequently involved in healthcare-associated pneumonia and considered as a « problem-pathogen ». To face the announced post-antibiotic era due to increasing resistance and lack of new antibiotics, new treatment strategies have to be developed. During pneumonia, lung injury results from both bacterial-mediated virulence and host response. Modulation of an overreacting host response could be an alternative therapeutic target in Pa-induced lung infection. Kynurenines are small molecules resulting from tryptophan degradation with reported immunomodulatory properties. Pa is known to produce kynurenine, but the functional enzymes, types and amounts of secreted metabolites are poorly known. Interestingly, many host cells also possess the kynurenine pathway, whose metabolites are known to control immune system homeostasis. The following experiments aim to determine whether bacterial metabolites can interfere with the host’s immune response, leading to a possible immunomodulatory interplay between bacteria and host kynurenine pathways, impacting on the pathophysiology of P. aeruginosa infection. To that goal, we use a murin model of acute lung injury. Mice were infected with WT strain of Pa, compared to mutant strains unable to produce kynurenine (ΔkynA), and mutant strains overproducing them (ΔkynU). Moreover, we studied the interactions between bacterial and host kynurenine pathways by inhibiting the first enzyme of the host pathway called indoleamine-2,3-dioxygenase (IDO). Finally, we assessed the role of the arylhydrocarbon receptor (AhR), a known receptor to kynurenine involved in lung immunity, using AhR KO mice. First, we assess types and levels of metabolites produced by Pa in an in vitro model, and the relevance of this production in vivo. We show for the first time that Pa is able to secrete kynurenine at clinically relevant levels, and other metabolites such as kynurenic acid and 3 OHkynurenine, what was unknown to date. Second, we show that bacterial metabolites were able to modulate the host innate immune response, by increasing alveolar recruitment of neutrophils, associated with decreased inflammatory cytokines levels and impairment of antigen-presenting cells activation. Finally, we report that IDO and AhR are involved in this kynurenine-mediated immunomodulation. These data suggest that pulmonary infection with a bacteria highly expressing the kynurenine pathway enzymes could lead to an imbalance in the immune response to infection, thus constituting a potential therapeutic target to improve Pa-induced pneumonia outcome

Implications de la production de kynurénines par pseudomonas aeruginosa dans la relation hôte-pathogène

Pseudomonas aeruginosa (Pa) is a Gram-negative bacteria frequently involved in healthcare-associated pneumonia and considered as a « problem-pathogen ». To face the announced post-antibiotic era due to increasing resistance and lack of new antibiotics, new treatment strategies have to be developed. During pneumonia, lung injury results from both bacterial-mediated virulence and host response. Modulation of an overreacting host response could be an alternative therapeutic target in Pa-induced lung infection. Kynurenines are small molecules resulting from tryptophan degradation with reported immunomodulatory properties. Pa is known to produce kynurenine, but the functional enzymes, types and amounts of secreted metabolites are poorly known. Interestingly, many host cells also possess the kynurenine pathway, whose metabolites are known to control immune system homeostasis. The following experiments aim to determine whether bacterial metabolites can interfere with the host’s immune response, leading to a possible immunomodulatory interplay between bacteria and host kynurenine pathways, impacting on the pathophysiology of P. aeruginosa infection. To that goal, we use a murin model of acute lung injury. Mice were infected with WT strain of Pa, compared to mutant strains unable to produce kynurenine (ΔkynA), and mutant strains overproducing them (ΔkynU). Moreover, we studied the interactions between bacterial and host kynurenine pathways by inhibiting the first enzyme of the host pathway called indoleamine-2,3-dioxygenase (IDO). Finally, we assessed the role of the arylhydrocarbon receptor (AhR), a known receptor to kynurenine involved in lung immunity, using AhR KO mice. First, we assess types and levels of metabolites produced by Pa in an in vitro model, and the relevance of this production in vivo. We show for the first time that Pa is able to secrete kynurenine at clinically relevant levels, and other metabolites such as kynurenic acid and 3 OHkynurenine, what was unknown to date. Second, we show that bacterial metabolites were able to modulate the host innate immune response, by increasing alveolar recruitment of neutrophils, associated with decreased inflammatory cytokines levels and impairment of antigen-presenting cells activation. Finally, we report that IDO and AhR are involved in this kynurenine-mediated immunomodulation. These data suggest that pulmonary infection with a bacteria highly expressing the kynurenine pathway enzymes could lead to an imbalance in the immune response to infection, thus constituting a potential therapeutic target to improve Pa-induced pneumonia outcome.Pseudomonas aeruginosa (Pa) est un pathogène opportuniste responsable d’infections pulmonaires aigues graves chez les malades prédisposés. Devant l’émergence croissante de la résistance aux antibiotiques, le développement de thérapeutiques alternatives adjuvantes est indispensable et nécessite la compréhension des interactions hôte-pathogènes au cours de l’infection. La voie métabolique de dégradation du tryptophane appelée voie des kynurénines produit chez l’hôte des métabolites aux propriétés immunomodulatrices connues. Récemment, l’existence de cette voie a été mise en évidence chez Pa, bien que la nature et la quantité de métabolites produits ne soient pas parfaitement connus. La production bactérienne de kynurénines pourrait interférer avec la mise en place de la réponse immunitaire de l’hôte et sa régulation au cours des différentes phases de l’infection, altérant la balance immunitaire pulmonaire au profit du pathogène. A ce titre, la voie des kynurénines de Pa constituerait une cible thérapeutique potentielle. L’objectif de ce travail de thèse est d’étudier l’implication de la voie des kynurénines de Pa dans la virulence bactérienne et la réponse immune de l’hôte dans un modèle murin d’agression respiratoire aiguë. Pour cela, les souris sont infectées avec des souches sauvages de Pa, avec des souches mutantes ΔkynA, non productrices de kynurénines, et des souches ΔkynU, surproductrices de kynurénines. Les interactions potentielles avec la voie des kynurénines de l’hôte sont explorées en inhibant la première enzyme de la voie métabolique, l’indoleamine-2,3-dioxygenase (IDO). Enfin, le rôle du récepteur arylhydrocarbone (AhR), récepteur connu des kynurénines et impliqué dans l’immunité pulmonaire, est exploré en comparant la réponse à l’infection de souris AhR KO à celle des souris sauvages. Dans ce travail, nous décrivons tout d’abord la production des différents métabolites de la voie des kynurénines de Pa in vitro et in vivo dans le modèle d’infection respiratoire aigue, en décrivant pour la première fois la production d’acide kynurénique et de 3-hydroxy-kynurénine pour cette bactérie. Ensuite, nous montrons que les kynurénines bactériennes interfèrent avec la réponse immune de l’hôte, en majorant le recrutement cellulaire alvéolaire, tout en atténuant le niveau d’inflammation et l’activation des cellules présentatrices d’antigènes. Enfin, nous rapportons que l’IDO et l’AhR sont impliqués dans cette immunomodulation, faisant des kynurénines bactériennes des agents du dialogue hôte-pathogène au cours de l’infection respiratoire aigue. A la lumière de ces résultats, la voie des kynurénines pourrait constituer une cible thérapeutique d’intérêt dans les infections respiratoires à P. aeruginosa

New tools for optimizing fluid resuscitation in acute pancreatitis

International audienceAcute pancreatitis (AP) is a frequent disease with degrees of increasing severity responsible for high morbidity. Despite continuous improvement in care, mortality remains significant. Because hypovolemia, together with microcirculatory dysfunction lead to poor outcome, fluid therapy remains a cornerstone of the supportive treatment. However, poor clinical evidence actually support the aggressive fluid therapy recommended in recent guidelines since available data are controversial. Fluid management remains unclear and leads to current heterogeneous practice. Different strategies may help to improve fluid resuscitation in AP. On one hand, integration of fluid therapy in a global hemodynamic resuscitation has been demonstrated to improve outcome in surgical or septic patients. Tailored fluid administration after early identification of patients with high-risk of poor outcome presenting inadequate tissue oxy-genation is a major part of this strategy. On the other hand, new decision parameters have been developed recently to improve safety and efficiency of fluid therapy in critically ill patients. In this review, we propose a personalized strategy integrating these new concepts in the early fluid management of AP. This new approach paves the way to a wide range of clinical studies in the field of AP

Clostridium ventriculi bacteremia following acute colonic pseudo-obstruction: A case report

International audienceClostridium ventriculi (formerly Sarcina ventriculi) is a Gram-positive, obligate anaerobic coccus. Human infections due to this bacterium have rarely been reported, its involvement in the development of gastric ulcers and perforation has been suggested. We present a case of bacteremia due to C. ventriculi following acute colonic pseudo-obstruction