A cute myocardial ischemia induces an intense activation of the immune system leading to cytokines and chemokines production 1,2 and to the recruitment of neutrophils and mononuclear cells in the infarcted area.3,4 Early proinflammatory signals are crucial in mediating the response to injury, regulating clearance of dead cardiac myocytes and initiating the cellular events necessary for wound healing. However, optimal healing requires activation of inhibitory mechanisms that suppress cytokine and chemokine synthesis and mediate resolution of the inflammatory infiltrate. Therefore, limiting the inflammatory response amplification seems to be important for containment of injury and optimal infarct healing. Triggering receptor expressed on myeloid cells-1 (TREM-1) is an immune-receptor expressed by neutrophils, macrophages, and mature monocytes that acts as an amplifier of the innate immune response.6 It has been shown that blockade of TREM-1 activation by short inhibitory peptides or fusion protein protected from hyper-responsiveness and death in various models of severe infections.

IntroductionA rational use of antibiotics is of paramount importance in order to prevent the emergence of multidrug resistant bacteria that can lead to therapeutic impasse, especially in intensive care units (ICUs). A de-escalation strategy is therefore naturally advocated as part of better antibiotics usage. However, the clinical impact of such a strategy has not been widely studied. We aimed to assess the feasibility and the clinical impact of a de-escalation strategy in a medical ICU and to identify factors associated when de-escalation was possible.MethodsWe performed a retrospective study of patients hospitalized in a medical ICU over a period of six months. Independent factors associated with de-escalation and its clinical impact were assessed.ResultsTwo hundred and twenty-nine patients were included in the study. Antibiotics were de-escalated in 117 patients (51%). The appropriateness of initial antibiotic therapy was the only independent factor associated with the performance of de-escalation (OR = 2.9, 95% CI, 1.5-5.7; P = 0.002). By contrast, inadequacy of initial antibiotic therapy (OR = 0.1, 0.0 to 0.1, P <0.001) and the presence of multidrug resistant bacteria (OR = 0.2, 0.1 to 0.7, P = 0.006) prevented from de-escalation. There were no differences in terms of short (ICU) or long-term (at 1 year) mortality rates or any secondary criteria such as ICU length of stay, duration of antibiotic therapy, mechanical ventilation, incidence of ICU-acquired infection, or multi-drug resistant bacteria emergence.ConclusionsDe-escalation appears feasible in most cases without any obvious negative clinical impact in a medical ICU.

Acute myocardial infarction is a common condition responsible for heart failure and sudden death. Here, we show that following acute myocardial infarction in mice, CD8+ T lymphocytes are recruited and activated in the ischemic heart tissue and release Granzyme B, leading to cardiomyocyte apoptosis, adverse ventricular remodeling and deterioration of myocardial function. Depletion of CD8+ T lymphocytes decreases apoptosis within the ischemic myocardium, hampers inflammatory response, limits myocardial injury and improves heart function. These effects are recapitulated in mice with Granzyme B-deficient CD8+ T cells. The protective effect of CD8 depletion on heart function is confirmed by using a model of ischemia/reperfusion in pigs. Finally, we reveal that elevated circulating levels of GRANZYME B in patients with acute myocardial infarction predict increased risk of death at 1-year follow-up. Our work unravels a deleterious role of CD8+ T lymphocytes following acute ischemia, and suggests potential therapeutic strategies targeting pathogenic CD8+ T lymphocytes in the setting of acute myocardial infarction.

EGFR blockade induced T cell anergy in vitro and in vivo and reduced atherosclerosis development. Targeting EGFR may be a novel strategy to combat atherosclerosis.

BackgroundSeptic shock is the leading cause of death in intensive care units. The pathophysiological complexity of this syndrome contributes to an absence of specific treatment. Several preclinical studies in murine models of septic shock have shown improvements to organ injury and survival after administration of mesenchymal stem cells (MSCs). To better mimic a clinical approach in humans, we investigated the impact of randomized controlled double-blind administration of clinical-grade umbilical cord-derived MSCs to a relevant pig model of septic shock.MethodsSeptic shock was induced by fecal peritonitis in 12 male domestic pigs. Animals were resuscitated by an experienced intensivist including fluid administration and vasopressors. Four hours after the induction of peritonitis, pigs were randomized to receive intravenous injection of thawed umbilical cord-derived MSCs (UCMSC) (1 × 106 UCMSCs/kg diluted in 75 mL hydroxyethyl starch (HES), (n = 6) or placebo (HES alone, n = 6). Researchers were double-blinded to the treatment administered. Hemodynamic parameters were continuously recorded. Gas exchange, acid-base status, organ function, and plasma cytokine concentrations were assessed at regular intervals until 24 h after the onset of peritonitis when animals were sacrificed under anesthesia.ResultsPeritonitis induced profound hypotension, hyperlactatemia, and multiple organ failure. These disorders were significantly attenuated when animals were treated with UCMSCs. In particular, cardiovascular failure was attenuated, as attested by a better mean arterial pressure and reduced lactatemia, despite lower norepinephrine requirements. As such, UCMSCs improved survival in this very severe model (60% survival vs. 0% at 24 h).ConclusionUCMSCs administration is beneficial in this pig model of polymicrobial septic shock.

We reported that TREM-1 is expressed and inducible in endothelial cells and plays a direct role in vascular inflammation and dysfunction. The targeted deletion of endothelial Trem-1 conferred protection during septic shock in modulating inflammatory cells mobilization and activation, restoring vasoreactivity, and improving survival. The effect of TREM-1 on vascular tone, while impressive, deserves further investigations including the design of endothelium-specific TREM-1 inhibitors.

Myocardial infarction (MI) is a common condition responsible for mortality and morbidity related to ischemic heart failure. Accumulating experimental and translational evidence support a crucial role for innate immunity in heart failure and adverse heart remodeling following MI. More recently, the role of adaptive immunity in myocardial ischemia has been identified, mainly in rodents models of both transient and permanent heart ischemia. The present review summarizes the experimental evidence regarding the role of lymphocytes and dendritic cells in myocardial remodeling following coronary artery occlusion. Th1 and potentially Th17 CD4+ T cell responses promote adverse heart remodeling, whereas regulatory T cells appear to be protective, modulating macrophage activity, cardiomyocyte survival, and fibroblast phenotype. The role of CD8+ T cells in this setting remains unknown. B cells contribute to adverse cardiac remodeling through the modulation of monocyte trafficking, and potentially the production of tissue-specific antibodies. Yet, further substantial efforts are still required to confirm experimental data in human MI before developing new therapeutic strategies targeting the adaptive immune system in ischemic cardiac diseases.

No abstract