Jean-Marc Tadié

AMP-activated protein kinase enhances the phagocytic ability of macrophages and neutrophils

Although AMPK plays well‐established roles in the modulation of energy balance, recent studies have shown that AMPK activation has potent anti‐inflammatory effects. In the present experiments, we examined the role of AMPK in phagocytosis. We found that ingestion of Escherichia coli or apoptotic cells by macrophages increased AMPK activity. AMPK activation increased the ability of neutrophils or macrophages to ingest bacteria (by 46±7.8 or 85±26%, respectively, compared to control, P<0.05) and the ability of macrophages to ingest apoptotic cells (by 21±1.4%, P<0.05 compared to control). AMPK activation resulted in cytoskeletal reorganization, including enhanced formation of actin and microtubule networks. Activation of PAK1/2 and WAVE2, which are downstream effectors of Rac1, accompanied AMPK activation. AMPK activation also induced phosphorylation of CLIP‐170, a protein that participates in microtubule synthesis. The increase in phagocytosis was reversible by the specific AMPK inhibitor compound C, siRNA to AMPKα1, Rac1 inhibitors, or agents that disrupt actin or microtubule networks. In vivo, AMPK activation resulted in enhanced phagocytosis of bacteria in the lungs by 75 ± 5% vs. control (P<0.05). These results demonstrate a novel function for AMPK in enhancing the phagocytic activity of neutrophils and macrophages.—Bae, H. ‐B., Zmijewski, J. W., Deshane, J. S., Tadie, J. ‐M., Chaplin, D. D., Takashima, S., Abraham, E. AMP‐activated protein kinase enhances the phagocytic ability of macrophages and neutrophils. FASEB J. 25, 4358–4368 (2011). www.fasebj.org

Differential activation of RAGE by HMGB1 modulates neutrophil-associated NADPH oxidase activity and bacterial killing

The receptor for advanced glycation end products (RAGE) plays an important role in host defense against bacterial infection. In the present experiments, we investigated the mechanisms by which RAGE contributes to the ability of neutrophils to eradicate bacteria. Wild-type (RAGE(+/+)) neutrophils demonstrated significantly greater ability to kill Escherichia coli compared with RAGE(-/-) neutrophils. After intraperitoneal injection of E. coli, increased numbers of bacteria were found in the peritoneal fluid from RAGE(-/-) as compared with RAGE(+/+) mice. Exposure of neutrophils to the protypical RAGE ligand AGE resulted in activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and enhanced killing of E. coli, and intraperitoneal injection of AGE enhanced bacterial clearance during peritonitis. However, incubation of neutrophils with high mobility group box 1 protein (HMGB1), which also binds to RAGE, diminished E. coli-induced activation of NADPH oxidase in neutrophils and bacterial killing both in vitro and in vivo. Deletion of the COOH-terminal tail of HMGB1, a region necessary for binding to RAGE, abrogated the ability of HMGB1 to inhibit bacterial killing. Incubation of neutrophils with HMGB1 diminished bacterial or AGE-dependent activation of NADPH oxidase. The increase in phosphorylation of the p40(phox) subunit of NADPH oxidase that occurred after culture of neutrophils with E. coli was inhibited by exposure of the cells to HMGB1. These results showing that HMGB1, through RAGE-dependent mechanisms, diminishes bacterial killing by neutrophils as well as NADPH oxidase activation provide a novel mechanism by which HMGB1 can potentiate sepsis-associated organ dysfunction and mortality.

Trends in Prevalence and Prognosis in Subjects With Acute Chronic Respiratory Failure Treated With Noninvasive and/or Invasive Ventilation

BACKGROUND: The pattern and outcome of noninvasive ventilation (NIV) use in patients with acute or chronic respiratory disease other than COPD is not well known. The aims of this study were to investigate trends over time in underlying respiratory diseases, use of NIV, and outcomes in COPD and non-COPD patients with acute respiratory failure. METHODS: We made a retrospective analysis of data recorded prospectively from 1,113 subjects admitted between 1998 and 2012. RESULTS: Subject diagnoses were distributed as follows: COPD, n = 568 (51%); bilateral bronchiectasis, n = 113 (10%); obesity, n = 166 (15%); chronic diffuse interstitial lung disease, n = 131 (12%); restrictive pulmonary disease, n = 113 (10%); and asthma, n = 22 (2%). The proportion of subjects with bilateral bronchiectasis significantly decreased (OR 0.91, 95% CI 0.865–0.951, P < .001), whereas the proportion of subjects with obesity increased (OR 1.03, 95% CI 1.001–1.063, P = .049) over time. The use of NIV (OR 1.05, 95% CI 1.010–1.090, P = .01) and the proportion of subjects initially treated with NIV (OR 1.05, 95% CI 1.013–1.094, P = .009) increased significantly in COPD subjects only. Time trend of mortality was not significant (OR 0.98, 95% CI 0.95–1.01, P = .23), whereas the severity of illness in subjects significantly increased. Transition from NIV to invasive mechanical ventilation (IMV) (OR 2.05, 95% CI 1.36–3.11, P = < .001), IMV (OR 10.49, 95% CI 4.88–10.56, P < .001) and diffuse interstitial lung disease (OR 10.63, 95% CI 5.43–20.83, P < .001) were independently associated with death in the ICU. CONCLUSIONS: Over time, respiratory diseases have changed in non-COPD subjects and trends in the use and efficacy of NIV differ between COPD and non-COPD subjects. Mortality remained stable while the severity of illness in subjects increased. In COPD and non-COPD subjects, transition from NIV to IMV was associated with a poorer prognosis.

EuroSCORE II underestimates mortality after cardiac surgery for infective endocarditis

OBJECTIVESnTo better select for patients who most likely will benefit from cardiac surgery among those with infective endocarditis (IE), we aimed to identify preoperative markers associated with poor outcome after cardiac surgery for IE, and to evaluate the accuracy of European System for Cardiac Operative Risk Evaluation (EuroSCORE) II to predict mortality.nnnMETHODSnWe enrolled all adult patients who underwent cardiac surgery during the acute phase of definite IE (Duke Criteria) in two referral centres for cardiac surgery. Patients were identified through intensive care unit (ICU) electronic databases, and data were collected from medical charts on standardized questionnaire.nnnRESULTSnBetween 2002 and 2013, 149 patients (117 males), with a median age of 64 years [interquartile range 52-73], fulfilled the inclusion criteria. Main complications before surgery were left ventricular dysfunction (23%), central nervous system symptomatic events (34%) and septic shock (24%). Most patients (95%) presented with valve regurgitation, and 49% had perivalvular abscess. Surgery was performed with a median delay of 12 days [5-24] after IE diagnosis, and mean EuroSCORE II was 15.8 (13.4-18.1). In-hospital mortality was 21%. Preoperative variables associated with mortality in multivariate analysis were obesity [odds ratio (OR) 3.67 [1.10-12.19], P = 0.03], vegetation >15 mm (OR 6.72 [1.46-30.98], P = 0.01), septic shock (OR 4.87 [1.67-14.28], P = 0.004) and mechanical prosthetic valve IE (OR 4.99 [1.72-28.57], P = 0.007). EuroSCORE II underestimated mortality in patients with predicted mortality over 10%.nnnCONCLUSIONnFactors independently predictive of mortality after cardiac surgery for IE are obesity, septic shock, large vegetation and a mechanical prosthetic valve IE. EuroSCORE II underestimates post-cardiac surgery mortality in patients with IE.

Intensive care medical procedures are more complicated, more stressful, and less comfortable with Ebola personal protective equipment: A simulation study

Ebola virus disease (EVD) is a life-threatening condition. Appropriate management of organ failure, hemodynamic instability, and metabolic disorders significantly improves survival. This implies that life-saving procedures are undertaken in case of need, including endotracheal intubation, nasogastric tube placement and central venous catheter (CVC) insertion. The challenge is to provide high quality of care to patients with life-threatening EVD, under optimal safety conditions for health care workers, i.e. with reinforced personal protective equipment (PPE), ensuring that no exposure to patient blood or any other body fluid occur.1, 2 and 3 We assessed the impact of Ebola PPE use on the performance of senior ICU physicians during common intensive care unit (ICU) procedures, and on the workload, in a simulation environment...

Rombencephalitis Caused by Francisella tularensis

ABSTRACT Common presentations of tularemia include pneumonia and ulceroglandular, oropharyngeal, or typhoidal disease. Neuromeningeal involvement is extremely rare. We report a case of a severe rhombencephalitis due to Francisella tularensis. Diagnosis was possible thanks to a very precise interview, and the patient dramatically improved after specific antibiotherapy.

Impaired efferocytosis and neutrophil extracellular traps clearance by macrophages in ARDS

Exaggerated release of neutrophil extracellular traps (NETs) along with decreased NET clearance and inability to remove apoptotic cells (efferocytosis) may contribute to sustained inflammation in acute respiratory distress syndrome (ARDS). Recent studies in experimental models of ARDS have revealed the crosstalk between AMP-activated protein kinase (AMPK) and high-mobility group box 1 (HMGB1), which may contribute to effectiveness of efferocytosis, thereby reducing inflammation and ARDS severity. We investigated neutrophil and NET clearance by macrophages from control and ARDS patients and examined how bronchoalveolar lavage (BAL) fluid from control and ARDS patients could affect NET formation and efferocytosis. Metformin (an AMPK activator) and neutralising antibody against HMGB1 were applied to improve efferocytosis and NET clearance. Neutrophils from ARDS patients showed significantly reduced apoptosis. Conversely, NET formation was significantly enhanced in ARDS patients. Exposure of neutrophils to ARDS BAL fluid promoted NET production, while control BAL fluid had no effect. Macrophage engulfment of NETs and apoptotic neutrophils was diminished in ARDS patients. Notably, activation of AMPK in macrophages or neutralisation of HMGB1 in BAL fluid improved efferocytosis and NET clearance. In conclusion, restoration of AMPK activity with metformin or specific neutralisation of HMGB1 in BAL fluid represent promising therapeutic strategies to decrease sustained lung inflammation during ARDS. Restoration of AMPK activation and specific inhibition of HMGB1 could reduce lung inflammation during human ARDS http://ow.ly/bxCj30ktyiZ

Dysfonction immunitaire induite par la ventilation mécanique

RésuméLa ventilation mécanique (VM), même si elle fait partie de l’arsenal thérapeutique indispensable en réanimation, va induire ou aggraver des lésions pulmonaires. Les cellules du parenchyme pulmonaire ainsi que les cellules immunitaires du poumon vont être capables de convertir les forces mécaniques générées par la VM en un signal biologique qui va entraîner une réaction inflammatoire. Cette inflammation « stérile » locale puis systémique va entraîner une dysfonction du système immunitaire, source de morbidité et de mortalité pour le patient de réanimation.AbstractAlthough mechanical ventilation is an essential support in patients admitted to the intensive care unit, clinical and experimental studies have shown that it could be harmful and could induce lung injury. Pulmonary and immune cells can convert mechanical stimuli into biological signals that will lead to inflammation. This sterile inflammation both locally and systemically will cause immunosuppression.