Sema7A is crucial for resolution of severe inflammation.

Endogenous mediators regulating acute inflammatory responses in both the induction and resolution phases of inflammatory processes are pivotal in host defense and tissue homeostasis. Recent studies have identified neuronal guidance proteins characterized in axonal development that display immunomodulatory functions. Here, we identify the neuroimmune guidance cue Semaphorin 7A (Sema7A), which appears to link macrophage (MΦ) metabolic remodeling to inflammation resolution. Sema7A orchestrated MΦ chemotaxis and chemokinesis, activated MΦ differentiation and polarization toward the proresolving M2 phenotype, and promoted leukocyte clearance. Peritoneal MΦSema7A-/- displayed metabolic reprogramming, characterized by reductions in fatty acid oxidation and oxidative phosphorylation, increases in glycolysis and the pentose phosphate pathway, and truncation of the tricarboxylic acid cycle, which resulted in increased levels of the intermediates succinate and fumarate. The low accumulation of citrate in MΦSema7A-/- correlated with the decreased synthesis of prostaglandins, leading to a reduced impact on lipid-mediator class switching and the generation of specialized pro resolving lipid mediators. Signaling network analysis indicated that Sema7A induced the metabolic reprogramming of MΦ by activating the mTOR- and AKT2-signaling pathways. Administration of Sema7ASL4cd orchestrated the resolution response to tissue homeostasis by shortening the resolution interval, promoting tissue protection in murine peritonitis, and enhancing survival in polymicrobial sepsis.

Sympathetic nervous system controls resolution of inflammation via regulation of repulsive guidance molecule A.

The bidirectional communication between the immune and nervous system is important in regulating immune responses. Here we show that the adrenergic nerves of sympathetic nervous system orchestrate inflammation resolution and regenerative programs by modulating repulsive guidance molecule A (RGM-A). In murine peritonitis, adrenergic nerves and RGM-A show bidirectional activation by stimulating the mutual expression and exhibit a higher potency for the cessation of neutrophil infiltration; this reduction is accompanied by increased pro-resolving monocyte or macrophage recruitment, polymorphonucleocyte clearance and specialized pro-resolving lipid mediators production at sites of injury. Chemical sympathectomy results in hyperinflammation and ineffective resolution in mice, while RGM-A treatments reverse these phenotypes. Signalling network analyses imply that RGM-A and ß2AR agonist regulate monocyte activation by suppressing NF-κB activity but activating RICTOR and PI3K/AKT signalling. Our results thus illustrate the function of sympathetic nervous system and RGM-A in regulating resolution and tissue repair in a murine acute peritonitis model.

Open abdomen and entero-atmospheric fistulae: An interim analysis from the International Register of Open Abdomen (IROA).

INTRODUCTION: No definitive data describing associations between cases of Open Abdomen (OA) and Entero-atmospheric fistulae (EAF) exist. The World Society of Emergency Surgery (WSES) and the Panamerican Trauma Society (PTS) thus analyzed the International Register of Open Abdomen (IROA) to assess this question. MATERIAL AND METHODS: A prospective analysis of adult patients enrolled in the IROA. RESULTS: Among 649 adult patients with OA 58 (8.9%) developed EAF. Indications for OA were peritonitis (51.2%) and traumatic-injury (16.8%). The most frequently utilized temporary abdominal closure techniques were Commercial-NPWT (46.8%) and Bogotà-bag (21.9%). Mean OA days were 7.9 ± 18.22. Overall mortality rate was 29.7%, with EAF having no impact on mortality. Multivariate analysis associated cancer (p = 0.018), days of OA (p = 0.003) and time to provision-of-nutrition (p = 0.016) with EAF occurrence. CONCLUSION: Entero-atmospheric fistulas are influenced by the duration of open abdomen treatment and by the nutritional status of the patient. Peritonitis, intestinal anastomosis, negative pressure and oral or enteral nutrition were not risk factors for EAF during OA treatment.

Inhibition of neogenin fosters resolution of inflammation and tissue regeneration.

The resolution of inflammation is an active process that is coordinated by endogenous mediators. Previous studies have demonstrated the immunomodulatory properties of the axonal guidance proteins in the initial phase of acute inflammation. We hypothesized that the neuronal guidance protein neogenin (Neo1) modulates mechanisms of inflammation resolution. In murine peritonitis, Neo1 deficiency (Neo1-/-) resulted in higher efficacies in reducing neutrophil migration into injury sites, increasing neutrophil apoptosis, actuating PMN phagocytosis, and increasing the endogenous biosynthesis of specialized proresolving mediators, such as lipoxin A4, maresin-1, and protectin DX. Neo1 expression was limited to Neo1-expressing Ly6Chi monocytes, and Neo1 deficiency induced monocyte polarization toward an antiinflammatory and proresolving phenotype. Signaling network analysis revealed that Neo1-/- monocytes mediate their immunomodulatory effects specifically by activating the PI3K/AKT pathway and suppressing the TGF-ß pathway. In a cohort of 59 critically ill, intensive care unit (ICU) pediatric patients, we found a strong correlation between Neo1 blood plasma levels and abdominal compartment syndrome, Pediatric Risk of Mortality III (PRISM-III) score, and ICU length of stay and mortality. Together, these findings identify a crucial role for Neo1 in regulating tissue regeneration and resolution of inflammation, and determined Neo1 to be a predictor of morbidity and mortality in critically ill children affected by clinical inflammation.

Dextran sodium sulfate (DSS) induces necrotizing enterocolitis-like lesions in neonatal mice.

BACKGROUND: Necrotizing enterocolitis (NEC) is an inflammatory bowel disease of preterm human newborns with yet unresolved etiology. An established neonatal murine model for NEC employs oral administration of lipopolysaccharides (LPS) combined with hypoxia/hypothermia. In adult mice, feeding dextran sodium sulfate (DSS) represents a well-established model for experimental inflammatory bowel disease. Here we investigated the effect of DSS administration on the neonatal murine intestine in comparison with the established NEC model. METHODS: 3-day-old C57BL/6J mice were either fed formula containing DSS or LPS. LPS treated animals were additionally stressed by hypoxia/hypothermia twice daily. After 72 h, mice were euthanized, their intestinal tissue harvested and analyzed by histology, qRT-PCR and flow cytometry. For comparison, adult C57BL/6J mice were fed with DSS for 8 days and examined likewise. Untreated, age matched animals served as controls. RESULTS: Adult mice treated with DSS exhibited colonic inflammation with significantly increased Cxcl2 mRNA expression. In contrast, tissue inflammation in neonatal mice treated with DSS or LPS plus hypoxia/hypothermia was present in colon and small intestine as well. Comparative analysis of neonatal mice revealed a significantly increased lesion size and intestinal Cxcl2 mRNA expression after DSS exposure. Whereas LPS administration mainly induced local neutrophil recruitment, DSS treated animals displayed increased monocytes/macrophages infiltration. CONCLUSIONS: Our study demonstrates the potential of DSS to induce NEC-like lesions accompanied by a significant humoral and cellular immune response in the small and large intestine of neonatal mice. The new model therefore represents a good alternative to LPS plus hypoxia/hypothermia administration requiring no additional physical stress.

Erratum to: IROA: International Register of Open Abdomen, preliminary results.

[This corrects the article DOI: 10.1186/s13017-017-0123-8.].

IROA: International Register of Open Abdomen, preliminary results.

BACKGROUND: No definitive data about open abdomen (OA) epidemiology and outcomes exist. The World Society of Emergency Surgery (WSES) and the Panamerican Trauma Society (PTS) promoted the International Register of Open Abdomen (IROA). METHODS: A prospective observational cohort study including patients with an OA treatment. Data were recorded on a web platform (Clinical Registers®) through a dedicated website: www.clinicalregisters.org. RESULTS: Four hundred two patients enrolled. Adult patients: 369 patients; Mean age: 57.39±18.37; 56% male; Mean BMI: 36±5.6. OA indication: Peritonitis (48.7%), Trauma (20.5%), Vascular Emergencies/Hemorrhage (9.4%), Ischemia (9.1%), Pancreatitis (4.2%),Post-operative abdominal-compartment-syndrome (3.9%), Others (4.2%). The most adopted Temporary-abdominal-closure systems were the commercial negative pressure ones (44.2%). During OA 38% of patients had complications; among them 10.5% had fistula. Definitive closure: 82.8%; Mortality during treatment: 17.2%. Mean duration of OA: 5.39(±4.83) days; Mean number of dressing changes: 0.88(±0.88). After-closure complications: (49.5%) and Mortality: (9%). No significant associations among TACT, indications, mortality, complications and fistula. A linear correlationexists between days of OA and complications (Pearson linear correlation = 0.326 p<0.0001) and with the fistula development (Pearson = 0.146 p= 0.016). Pediatric patients: 33 patients. Mean age: 5.91±(3.68) years; 60% male. Mortality: 3.4%; Complications: 44.8%; Fistula: 3.4%. Mean duration of OA: 3.22(±3.09) days. CONCLUSION: Temporary abdominal closure is reliable and safe. The different techniques account for different results according to the different indications. In peritonitis commercial negative pressure temporary closure seems to improve results. In trauma skin-closure and Bogotà-bag seem to improve results. TRIAL REGISTRATION: ClinicalTrials.gov NCT02382770.

Systemic inflammatory response syndrome after pediatric congenital heart surgery: Incidence, risk factors, and clinical outcome.

BACKGROUND: Systemic inflammatory response syndrome (SIRS) is frequent after cardiac surgery, but data on its incidence and perioperative risk factors are scarce for children with congenital heart disease. METHODS: SIRS incidence within 72 hours following cardiac surgery was evaluated in a secondary analysis of children enrolled to a treatment-free control group of a randomized controlled trial. Intraoperative parameters were investigated for their association with SIRS using multivariable fractional polynomial logistic regression models. Effects of SIRS on various organ functions and length of stay were evaluated using time-varying Cox regression models. RESULTS: In 116 children after cardiac surgery (median age [range]: 7.4 month [1 day-16.2 years]) SIRS occurred in n = 39/102 with and n = 1/14 without cardiopulmonary bypass (CPB). Duration of CPB (hazard ratio [HR]: 2.28 per hour; 95% confidence interval [CI] 1.17; 4.42) and amount of fresh frozen plasma (HR: 1.23 per 10 mL/kg; 95%CI 1.06; 1.42) were identified as predictors for SIRS; neonates seemed to be less susceptible for SIRS development (HR: 0.86; 95%CI 0.79; 0.95). SIRS was associated with organ dysfunction (HR: 2.69; 95%CI 1.41; 5.12) and extended stay in the pediatric intensive care unit (PICU) (median: 168 vs. 96 hours; p = 0.007). CONCLUSIONS: SIRS is a frequent complication after pediatric congenital heart surgery; it affects nearly one third of children and prolongs PICU stay significantly. Duration of CPB and amount of fresh frozen plasma were identified as important risk factors. Neonates seem to be less susceptible to SIRS development.

In-line Filtration Decreases Systemic Inflammatory Response Syndrome, Renal and Hematologic Dysfunction in Pediatric Cardiac Intensive Care Patients.

Cardiac surgery with cardiopulmonary bypass (CPB) frequently leads to systemic inflammatory response syndrome (SIRS) with concomitant organ malfunction. Infused particles may exacerbate inflammatory syndromes since they activate the coagulation cascade and alter inflammatory response or microvascular perfusion. In a randomized, controlled, prospective trial, we have previously shown that particle-retentive in-line filtration prevented major complications in critically ill children. Now, we investigated the effect of in-line filtration on major complications in the subgroup of cardiac patients. Children admitted to tertiary pediatric intensive care unit were randomized to either control or filter group obtaining in-line filtration throughout complete infusion therapy. Risk differences and 95 % confidence intervals (CI) of several complications such as SIRS, sepsis, mortality, various organ failure and dysfunction were compared between both groups using the Wald method. 305 children (n = 150 control, n = 155 filter group) with cardiac diseases were finally analyzed. The majority was admitted after cardiac surgery with CPB. Risk of SIRS (-11.3 %; 95 % CI -21.8 to -0.5 %), renal (-10.0 %; 95 % CI -17.0 to -3.0 %) and hematologic (-8.1 %; 95 % CI -14.2 to -0.2 %) dysfunction were significantly decreased within the filter group. No risk differences were demonstrated for occurrence of sepsis, any other organ failure or dysfunctions between both groups. Infused particles might aggravate a systemic hypercoagulability and inflammation with subsequent organ malfunction in pediatric cardiac intensive care patients. Particle-retentive in-line filtration might be effective in preventing SIRS and maintaining renal and hematologic function. In-line filtration offers a novel therapeutic option to decrease morbidity in cardiac intensive care.

Recognition and management of abdominal compartment syndrome among German anesthetists and surgeons: a national survey.

BACKGROUND: Abdominal compartment syndrome (ACS) is a life threatening condition that may affect any critically ill patient. Little is known about the recognition and management of ACS in Germany. METHODS: A questionnaire was mailed to departments of surgery and anesthesia from German hospitals with more than 450 beds. RESULTS: Replies (113) were received from 222 eligible hospitals (51%). Most respondents (95%) indicated that ACS plays a role in their clinical practice. Intra-abdominal pressure (IAP) is not measured at all by 26%, while it is routinely done by 30%. IAP is mostly (94%) assessed via the intra-vesical route. Of the respondents, 41% only measure IAP in patients expected to develop ACS; 64% states that a simpler, more standardized application of IAP measurement would lead to increased use in daily clinical practice. CONCLUSIONS: German anesthesiologists and surgeons are familiar with ACS. However, approximately one fourth never measures IAP, and there is considerable uncertainty regarding which patients are at risk as well as how often IAP should be measured in them.

Abdominal compartment syndrome in childhood: diagnostics, therapy and survival rate.

PURPOSE: The abdominal compartment syndrome (ACS) in childhood is a rare but dire disease if diagnosed delayed and treated improperly. The mortality amounts up to 60% (Beck et al. in Pediatr Crit Care Med 2:51-56, 2001). ACS is defined by a sustained rise of the intraabdominal pressure (IAP) together with newly developed organ dysfunction. The present study reports on 28 children with ACS to evaluate its potential role in the diagnosis, treatment and outcome of ACS. METHODS: Retrospectively, medical reports and outcome of 28 children were evaluated who underwent surgical treatment for ACS. The diagnosis of ACS was established by clinical signs, intravesical pressure-measurements and concurrent organ dysfunction. RESULTS: Primary ACS was found in 25 children (89.3%) predominantly resulting from polytrauma and peritonitis. Three children presented secondary ACS with sepsis (2 cases) and combustion (1 case) being the underlying causative diseases. Therapy of choice was the decompression of the abdominal cavity with implantation of an absorbable Vicryl(®) mesh. In 18 cases the abdominal cavity could be closed later, while in the other ten cases granulation of the mesh was allowed. The overall survival rate was 78.6% (22 of 28 children). The cause of death in the remaining six cases (21.4%) was sepsis with multiorgan failure. CONCLUSION: Our results suggest that early establishment of the specific diagnosis of ACS followed by swift therapy with reduction of intraabdominal hypertension is essential in order to further reduce the high mortality rate associated with this condition.