The gut microbiome alters immunophenotype and survival from sepsis.

The microbiome is increasingly implicated in immune regulation and mortality from sepsis. Mice with identical genetic backgrounds but distinct microbiomes were obtained from different vendors and analyzed following cecal ligation and puncture (CLP). ß diversity of the microbiome measured from feces demonstrated significant differences between The Jackson Laboratory (Jax; Bar Harbor, ME, USA) and Charles River Laboratories (CR; Wilmington, MA, USA) C57/B6 mice. Jax mice had 7-d mortality of 90% following CLP, whereas CR mice had a mortality of 53%. Differences in vendor were associated with altered immunophenotype with increased splenic IFN-γ+CD4+ T cells, effector memory CD4+ T cells, and central memory CD4+ T cells and increased Peyer's patch effector memory CD4+ T cells in septic CR mice. To determine whether differences in the microbiome were responsible for these differences, Jax and CR mice were cohoused for 3 wk, after which they assumed a similar microbiota composition. Cohoused mice had improved survival following CLP compared to Jax mice and had similar survival regardless of their vendor of origin. All differences in immunophenotype between septic Jax and CR mice disappeared following cohousing. These findings suggest that the microbiome plays a crucial role in survival and the host immune response from sepsis and represents a potential target for therapeutic intervention.-Fay, K. T., Klingensmith, N. J., Chen, C.-W., Zhang, W., Sun, Y., Morrow, K. N., Liang, Z., Burd, E. M., Ford, M. L., Coopersmith, C. M. The gut microbiome alters immunophenotype and survival from sepsis.

Cutting Edge: 2B4-Mediated Coinhibition of CD4+ T Cells Underlies Mortality in Experimental Sepsis.

Sepsis is a leading cause of death in the United States, but the mechanisms underlying sepsis-induced immune dysregulation remain poorly understood. 2B4 (CD244, SLAM4) is a cosignaling molecule expressed predominantly on NK cells and memory CD8+ T cells that has been shown to regulate T cell function in models of viral infection and autoimmunity. In this article, we show that 2B4 signaling mediates sepsis lymphocyte dysfunction and mortality. 2B4 expression is increased on CD4+ T cells in septic animals and human patients at early time points. Importantly, genetic loss or pharmacologic inhibition of 2B4 significantly increased survival in a murine cecal ligation and puncture model. Further, CD4-specific conditional knockouts showed that 2B4 functions on CD4+ T cell populations in a cell-intrinsic manner and modulates adaptive and innate immune responses during sepsis. Our results illuminate a novel role for 2B4 coinhibitory signaling on CD4+ T cells in mediating immune dysregulation.

Sepsis reveals compartment-specific responses in intestinal proliferation and apoptosis in transgenic mice whose enterocytes re-enter the cell cycle.

Cell production and death are tightly regulated in the rapidly renewing gut epithelium, with proliferation confined to crypts and apoptosis occurring in villi and crypts. This study sought to determine how stress alters these compartmentalized processes. Wild-type mice made septic via cecal ligation and puncture had decreased crypt proliferation and increased crypt and villus apoptosis. Fabpi-TAg mice expressing large T-antigen solely in villi had ectopic enterocyte proliferation with increased villus apoptosis in unmanipulated animals. Septic fabpi-TAg mice had an unexpected increase in villus proliferation compared with unmanipulated littermates, whereas crypt proliferation was decreased. Cell cycle regulators cyclin D1 and cyclin D2 were decreased in jejunal tissue in septic transgenic mice. In contrast, villus and crypt apoptosis were increased in septic fabpi-TAg mice. To examine the relationship between apoptosis and proliferation in a compartment-specific manner, fabpi-TAg mice were crossed with fabpl-Bcl-2 mice, resulting in expression of both genes in the villus but Bcl-2 alone in the crypt. Septic bi-transgenic animals had decreased crypt apoptosis but had a paradoxical increase in villus apoptosis compared with septic fabpi-TAg mice, associated with decreased proliferation in both compartments. Thus, sepsis unmasks compartment-specific proliferative and apoptotic regulation that is not present under homeostatic conditions.-Lyons, J. D., Klingensmith, N. J., Otani, S., Mittal, R., Liang, Z., Ford, M. L., Coopersmith, C. M. Sepsis reveals compartment-specific responses in intestinal proliferation and apoptosis in transgenic mice whose enterocytes re-enter the cell cycle.

Effect of Remote Ischemic Preconditioning on Outcomes in Adult Cardiac Surgery: A Systematic Review and Meta-analysis of Randomized Controlled Studies.

BACKGROUND: Remote ischemic preconditioning (RIPC) has been demonstrated to prevent organ dysfunction in cardiac surgery patients. However, recent large, prospective, multicenter, randomized controlled trials (RCTs) had controversial results. Thus, a meta-analysis of RCTs was performed to investigate whether RIPC can reduce the incidence of acute myocardial infarction (AMI), acute kidney injury (AKI), and mortality in adult cardiac surgery patients. METHODS: Study data were collected from Medline, Elsevier, Cochrane Central Register of Controlled Trials and Web of Science databases. RCTs involving the effect of RIPC on organ protection in cardiac surgery patients, which reported the concentration or total release of creatine kinase-myocardial band, troponin I/troponin T (TNI/TNT) after operation, or the incidence of AMI, AKI, or mortality, were selected. Two reviewers independently extracted data using a standardized data extraction protocol where TNI or TNT concentrations; total TNI released after cardiac surgery; and the incidence of AKI, AMI, and mortality were recorded. Review Manager 5.3 software was used to analyze the data. RESULTS: Thirty trials, including 7036 patients were included in the analyses. RIPC significantly decreased the concentration of TNI/TNT (standard mean difference [SMD], -0.25 ng/mL; 95% confidence interval [CI], -0.41 to -0.048 ng/mL; P = .004), creatine kinase-myocardial band (SMD, -0.22; 95% CI, -0.07-0.35 ng/mL; P = .46), and the total TNI/TNT release (SMD, -0.49 ng/mL; 95% CI, -0.93 to -0.55 ng/mL; P = .03) in cardiac surgery patients after a procedure. However, RIPC could not reduce the incidence of AMI (relative risk, 0.89; 95% CI, 0.70-1.13; P = .34) and AKI (relative risk, 0.88; 95% CI, 0.72-1.06; P = .18), and there was also no effect of RIPC on mortality in adult cardiac surgery patients. Interestingly, subgroup analysis showed that RIPC reduced incidence of AKI and mortality of cardiac surgery patients who received volatile agent anesthesia. CONCLUSIONS: Our meta-analysis demonstrated that RIPC reduced TNI/TNT release after cardiac surgery. RIPC did not significantly reduce the incidence of AKI, AMI, and mortality. However, RIPC could reduce mortality in patients receiving volatile inhalational agent anesthesia.

Myosin light chain kinase knockout improves gut barrier function and confers a survival advantage in polymicrobial sepsis.

Sepsis-induced intestinal hyperpermeability is mediated by disruption of the epithelial tight junction, which is closely associated with the peri-junctional actin-myosin ring. Myosin light chain kinase (MLCK) phosphorylates the myosin regulatory light chain, resulting in increased permeability. The purpose of this study was to determine whether genetic deletion of MLCK would alter gut barrier function and survival from sepsis. MLCK-/- and wild type (WT) mice were subjected to cecal ligation and puncture and assayed for both survival and mechanistic studies. Survival was significantly increased in MLCK-/- mice (95% vs. 24%, p<0.0001). Intestinal permeability increased in septic WT mice compared to unmanipulated mice. In contrast, permeability in septic MLCK-/- mice was similar to that seen in unmanipulated animals. Improved gut barrier function in MLCK-/- mice was associated with increases in the tight junction mediators ZO-1 and claudin 15 without alterations in claudin 1, 2, 3, 4, 5, 7, 8, 13, occludin or JAM-A. Other components of intestinal integrity (apoptosis, proliferation and villus length) were unaffected by MLCK deletion as were local peritoneal inflammation and distant lung injury. Systemic IL-10 was decreased greater than 10-fold in MLCK-/- mice; however, survival was similar between septic MLCK-/- mice given exogenous IL-10 or vehicle. These data demonstrate that deletion of MLCK improves survival following sepsis, associated with normalization of intestinal permeability and selected tight junction proteins.

New insights into the gut as the driver of critical illness and organ failure.

PURPOSE OF REVIEW: The gut has long been hypothesized to be the 'motor' of multiple organ dysfunction syndrome. This review serves as an update on new data elucidating the role of the gut as the propagator of organ failure in critical illness. RECENT FINDINGS: Under basal conditions, the gut absorbs nutrients and serves as a barrier that prevents approximately 40 trillion intraluminal microbes and their products from causing host injury. However, in critical illness, gut integrity is disrupted with hyperpermeability and increased epithelial apoptosis, allowing contamination of extraluminal sites that are ordinarily sterile. These alterations in gut integrity are further exacerbated in the setting of preexisting comorbidities. The normally commensal microflora is also altered in critical illness, with increases in microbial virulence and decreases in diversity, which leads to further pathologic responses within the host. SUMMARY: All components of the gut are adversely impacted by critical illness. Gut injury can not only propagate local damage, but can also cause distant injury and organ failure. Understanding how the multifaceted components of the gut interact and how these are perturbed in critical illness may play an important role in turning off the 'motor' of multiple organ dysfunction syndrome in the future.

CTLA-4 Checkpoint Inhibition Improves Sepsis Survival in Alcohol-Exposed Mice.

Chronic alcohol use increases morbidity and mortality in the setting of sepsis. Both chronic alcohol use and sepsis are characterized by immune dysregulation, including overexpression of T cell coinhibitory molecules. We sought to characterize the role of CTLA-4 during sepsis in the setting of chronic alcohol exposure using a murine model of chronic alcohol ingestion followed by cecal ligation and puncture. Results indicated that CTLA-4 expression is increased on CD4+ T cells isolated from alcohol-drinking septic mice as compared with either alcohol-drinking sham controls or water-drinking septic mice. Moreover, checkpoint inhibition of CTLA-4 improved sepsis survival in alcohol-drinking septic mice, but not water-drinking septic mice. Interrogation of the T cell compartments in these animals following pharmacologic CTLA-4 blockade, as well as following conditional Ctla4 deletion in CD4+ T cells, revealed that CTLA-4 deficiency promoted the activation and proliferation of effector regulatory T cells and the generation of conventional effector memory CD4+ T cells. These data highlight an important role for CTLA-4 in mediating mortality during sepsis in the setting of chronic alcohol exposure and may inform future approaches to develop targeted therapies for this patient population.

Red Blood Cell DNA Capture and Delivery Drives Host Responses During Polymicrobial Sepsis.

Red blood cells (RBCs), traditionally recognized for their role in transporting oxygen, play a pivotal role in the body's immune response by expressing TLR9 and scavenging excess host cell-free DNA. DNA capture by RBCs leads to accelerated RBC clearance and triggers inflammation. Whether RBCs can also acquire microbial DNA during infections is unknown. Murine RBCs acquire microbial DNA in vitro and bacterial-DNA-induced macrophage activation was augmented by WT but not TLR9-deleted RBCs. In a mouse model of polymicrobial sepsis, RBC-bound bacterial DNA was elevated in WT but not in erythroid TLR9-deleted mice. Plasma cytokine analysis revealed distinct sepsis endotypes, characterized by persistent hypothermia and hyperinflammation in the most severely affected subjects. RBC-TLR9 deletion attenuated plasma and tissue IL-6 production in the most severe endotype. Parallel findings in human subjects confirmed that RBCs from septic patients harbored more bacterial DNA compared to healthy individuals. Further analysis through 16S sequencing of RBC-bound DNA illustrated distinct microbial communities, with RBC-bound DNA composition correlating with plasma IL-6 in patients with sepsis. Collectively, these findings unveil RBCs as overlooked reservoirs and couriers of microbial DNA, capable of influencing host inflammatory responses in sepsis.

Human red blood cells express the RNA sensor TLR7.

Red blood cells (RBCs) express the nucleic acid-binding toll-like receptor 9 (TLR9) and bind CpG-containing DNA. However, whether human RBCs express other nucleic acid-binding TLRs is unknown. Here we show that human RBCs express the RNA sensor TLR7. TLR7 is present on the red cell membrane and is associated with the RBC membrane protein Band 3. In patients with SARS-CoV2-associated sepsis, TLR7-Band 3 interactions in the RBC membrane are increased when compared with healthy controls. In vitro, RBCs bind synthetic ssRNA and RNA from ssRNA viruses. Thus, RBCs may serve as a previously unrecognized sink for exogenous RNA, expanding the repertoire of non-gas exchanging functions performed by RBCs.

European society for trauma and emergency surgery member-identified research priorities in emergency surgery: a roadmap for future clinical research opportunities.

BACKGROUND: European Society for Trauma and Emergency Surgery (ESTES) is the European community of clinicians providing care to the injured and critically ill surgical patient. ESTES has several interlinked missions - (1) the promotion of optimal emergency surgical care through networked advocacy, (2) promulgation of relevant clinical cognitive and technical skills, and (3) the advancement of scientific inquiry that closes knowledge gaps, iteratively improves upon surgical and perioperative practice, and guides decision-making rooted in scientific evidence. Faced with multitudinous opportunities for clinical research, ESTES undertook an exercise to determine member priorities for surgical research in the short-to-medium term; these research priorities were presented to a panel of experts to inform a 'road map' narrative review which anchored these research priorities in the contemporary surgical literature. METHODS: Individual ESTES members in active emergency surgery practice were polled as a representative sample of end-users and were asked to rank potential areas of future research according to their personal perceptions of priority. Using the modified eDelphi method, an invited panel of ESTES-associated experts in academic emergency surgery then crafted a narrative review highlighting potential research priorities for the Society. RESULTS: Seventy-two responding ESTES members from 23 countries provided feedback to guide the modified eDelphi expert consensus narrative review. Experts then crafted evidence-based mini-reviews highlighting knowledge gaps and areas of interest for future clinical research in emergency surgery: timing of surgery, inter-hospital transfer, diagnostic imaging in emergency surgery, the role of minimally-invasive surgical techniques and Enhanced Recovery After Surgery (ERAS) protocols, patient-reported outcome measures, risk-stratification methods, disparities in access to care, geriatric outcomes, data registry and snapshot audit evaluations, emerging technologies interrogation, and the delivery and benchmarking of emergency surgical training. CONCLUSIONS: This manuscript presents the priorities for future clinical research in academic emergency surgery as determined by a sample of the membership of ESTES. While the precise basis for prioritization was not evident, it may be anchored in disease prevalence, controversy around aspects of current patient care, or indeed the identification of a knowledge gap. These expert-crafted evidence-based mini-reviews provide useful insights that may guide the direction of future academic emergency surgery research efforts.

Gut Microbiome in Sepsis.

Abstract The gut has been hypothesized to be the "motor" of multiple organ dysfunction in sepsis. Although there are multiple ways in which the gut can drive systemic inflammation, increasing evidence suggests that the intestinal microbiome plays a more substantial role than previously appreciated. An English language literature review was performed to summarize the current knowledge of sepsis-induced gut microbiome dysbiosis. Conversion of a normal microbiome to a pathobiome in the setting of sepsis is associated with worsened mortality. Changes in microbiome composition and diversity signal the intestinal epithelium and immune system resulting in increased intestinal permeability and a dysregulated immune response to sepsis. Clinical approaches to return to microbiome homeostasis may be theoretically possible through a variety of methods including probiotics, prebiotics, fecal microbial transplant, and selective decontamination of the digestive tract. However, more research is required to determine the efficacy (if any) of targeting the microbiome for therapeutic gain. The gut microbiome rapidly loses diversity with emergence of virulent bacteria in sepsis. Restoring normal commensal bacterial diversity through various therapies may be an avenue to improve sepsis mortality.

Dispelling Dogma: American Association for Surgery of Trauma Prospective, Multicenter Trial of Index vs Delayed Fasciotomy after Extremity Trauma.

BACKGROUND: Surgical dogma states that "if you think about doing a fasciotomy, you do it," yet the benefit of this approach remains unclear. We hypothesized that early fasciotomy during index operative procedures for extremity vascular trauma would be associated with improved patient outcomes. STUDY DESIGN: This prospective, observational multicenter (17 level 1, 1 level 2) analysis included patients ≥15 years old with extremity vascular injury requiring operative management. Clinical variables were analyzed with respect to fasciotomy timing for correlation with outcomes, including muscle necrosis and limb amputation. Associated variables (p < 0.05) were input into multivariable logistic regression models evaluating these endpoints. RESULTS: Of 436 study patients, most were male (87%) with penetrating (57%), lower extremity (77%), arterial (73%), vein (40%), and bony (53%) injury with prolonged hospital length of stay (11 days). Patients who had index fasciotomy (66%) were compared with those who did not (34%), and no differences were appreciated with respect to age, initial systolic blood pressure, tourniquet time, "hard" signs of vascular injury, massive transfusion protocol activation, or Injury Severity Score (all p < 0.05). Of the 289 patients who underwent index fasciotomy, 49% had prophylactic fasciotomy, 11% developed muscle necrosis, 4% required an additional fasciotomy, and 8% required amputation, although only 28 of 147 (19%) required delayed fasciotomy in those without index fasciotomy. Importantly, forgoing index fasciotomy did not correlate (p > 0.05) with additional muscle necrosis or amputation risk in the delayed fasciotomy group. After controlling for confounders, index surgery fasciotomy was not associated with either muscle necrosis or limb salvage in multivariable models. CONCLUSIONS: Routine, index operation fasciotomy failed to demonstrate an outcome benefit in this prospective, multicenter analysis. Our data suggest that a careful observation and fasciotomy-when-needed approach may limit unnecessary surgery and its resulting morbidity in extremity vascular trauma patients.

Missing Bullets: Bullet Embolization Case Series and Review of the Literature.

PURPOSE: Bullet embolization is a rare but dangerous phenomenon. Based on the location of embolization, migration of bullets can cause limb or intra-abdominal ischemia, pulmonary infarction, cardiac valve injury, or cerebrovascular accident. Bullet emboli can present a diagnostic challenge given the varied nature of complications based on location of embolization, which may not coincide with the site of initial injury. The purpose of this study is to present several cases of bullet embolization from our busy urban trauma center and make recommendations for management. METHODS: We present 3 cases of bullet embolization seen in injured patients at our Level 1 trauma center. We describe our management of these injuries and make recommendations for management in the context of our institutional experience and comment on the available literature regarding bullet embolization. RESULTS: Two of our patients presented in extremis and required operative intervention to achieve stability. The intravascular missile was discovered intraoperatively in one patient and removed in the operating room, while the missile was discovered on postoperative imaging in another patient and again removed operatively after an unsuccessful attempt at minimally invasive retrieval. Our third patient remained hemodynamically stable throughout his hospitalization and had endovascular management of his bullet embolus. CONCLUSION: Bullet emboli present a challenging complication of penetrating trauma. We recommend removal of all arterial bullet emboli and those within the pulmonary venous system. In hemodynamically stable patients, we recommend initial attempts of endovascular retrieval followed by open surgical removal. We recommend open removal in cases of hemodynamic instability.

Rethinking protocolized completion angiography following extremity vascular trauma: A prospective observational multicenter trial.

BACKGROUND: Completion angiography (CA) is commonly used following repair of extremity vascular injury and is recommended by the Eastern Association for the Surgery of Trauma practice management guidelines for extremity trauma. However, it remains unclear which patients benefit from CA because only level 3 evidence exists. METHODS: This prospective observational multicenter (18LI, 2LII) analysis included patients 15 years or older with extremity vascular injuries requiring operative management. Clinical variables and outcomes were analyzed with respect to with our primary study endpoint, which is need for secondary vascular intervention. RESULTS: Of 438 patients, 296 patients required arterial repair, and 90 patients (30.4%) underwent CA following arterial repair. Institutional protocol (70.9%) was cited as the most common reason to perform CA compared with concern for inadequate repair (29.1%). No patients required a redo extremity vascular surgery if a CA was performed per institutional protocol; however, 26.7% required redo vascular surgery if the CA was performed because of a concern for inadequate repair. No differences were observed in hospital mortality, length of stay, extremity ischemia, or need for amputation between those who did and did not undergo CA. CONCLUSION: Completion angiogram following major extremity injury should be considered in a case-by-case basis. Limiting completion angiograms to those patients with concern for an inadequate vascular repair may limit unnecessary surgery and morbidity. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Hepatic Arterioportal Fistula Following Liver Trauma: Case Series and Review of the Literature.

PURPOSE: Hepatic arterioportal fistula (HAPF) is an uncommon complication of hepatic trauma, which can manifest with abdominal pain and the sequelae of portal hypertension months to years after injury. The purpose of this study is to present cases of HAPF from our busy urban trauma center and make recommendations for management. METHODS: One hundred and twenty-seven patients with high-grade penetrating liver injuries (American Association for the Surgery of Trauma [AAST] - Grades IV-V) between January 2019 and October 2022 were retrospectively reviewed. Five patients were identified with an acute hepatic arterioportal fistula following abdominal trauma from our ACS-verified adult Level 1 trauma center. Institutional experience with overall surgical management is described and reviewed with the current literature. RESULTS: Four of our patients presented in hemorrhagic shock requiring emergent operative intervention. The first patient had postoperative angiography and coil embolization of the HAPF. Patients 2 through 4 underwent damage control laparotomy with temporary abdominal closure followed by postoperative transarterial embolization with gelatin sponge particles (Gelfoam) or combined Gelfoam/n-butyl cyanoacrylate. The final patient went directly for angiography and Gelfoam embolization after identification of the HAPF. All 5 patients had resolution of HAPF on follow-up imaging with continued post management for traumatic injuries. CONCLUSION: Hepatic arterioportal fistula can present as a complication of hepatic injury and manifest with significant hemodynamic aberrations. Although surgical intervention was required to achieve hemorrhage control in almost all cases, management of HAPF in the setting of high-grade liver injuries was achieved successfully with modern endovascular techniques. A multidisciplinary approach to such injuries is necessary to optimize care in the acute setting following traumatic injury.

CHRONIC ETHANOL USE WORSENS GUT PERMEABILITY AND ALTERS TIGHT JUNCTION EXPRESSION IN A MURINE SEPSIS MODEL.

ABSTRACT: Alcohol use disorder is associated with increased mortality in septic patients. Murine studies demonstrate that ethanol/sepsis is associated with changes in gut integrity. This study examined intestinal permeability after ethanol/sepsis and investigated mechanisms responsible for alterations in barrier function. Mice were randomized to drink either 20% ethanol or water for 12 weeks and then were subjected to either sham laparotomy or cecal ligation and puncture (CLP). Intestinal permeability was disproportionately increased in ethanol/septic mice via the pore, leak, and unrestricted pathways. Consistent with increased permeability in the leak pathway, jejunal myosin light chain (MLC) kinase (MLCK) expression and the ratio of phospho-MLC to total MLC were both increased in ethanol/CLP. Gut permeability was altered in MLCK -/- mice in water/CLP; however, permeability was not different between WT and MLCK -/- mice in ethanol/CLP. Similarly, jejunal IL-1ß levels were decreased while systemic IL-6 levels were increased in MLCK -/- mice in water/CLP but no differences were identified in ethanol/CLP. While we have previously shown that mortality is improved in MLCK -/- mice after water/CLP, mortality was significantly worse in MLCK -/- mice after ethanol/CLP. Consistent with an increase in the pore pathway, claudin 4 levels were also selectively decreased in ethanol/CLP WT mice. Furthermore, mRNA expression of jejunal TNF and IFN-γ were both significantly increased in ethanol/CLP. The frequency of CD4 + cells expressing TNF and IL-17A and the frequency of CD8 + cells expressing IFN-γ in Peyer's Patches were also increased in ethanol/CLP. Thus, there is an ethanol-specific worsening of gut barrier function after CLP that impacts all pathways of intestinal permeability, mediated, in part, via changes to the tight junction. Differences in the host response in the setting of chronic alcohol use may play a role in future precision medicine approaches toward the treatment of sepsis.

Bullet Embolism into the Common Iliac Artery from a Gunshot Wound to the Heart.

We describe the management of bullet embolism from a penetrating cardiac injury, including the clinical, radiographic, and operative considerations in this challenging trauma scenario. Bullet embolism represents a rare but complex subset of ballistic penetrating trauma, and highlights the importance of radiographic correlation with intraoperative findings.

Superior Mesenteric Artery and Vein Injuries: Operative Strategies and Outcomes.

Traumatic injuries to the mesenteric vessels are rare and often lethal. Visceral vessels, such as the superior mesenteric artery (SMA) and vein (SMV), supply blood to the small and large bowel by a rich system of collaterals. Because fewer than 100 such injuries have been described in the literature, they pose challenges in both diagnosis and management and can unfortunately result in high mortality rates. Prompt diagnosis, surgical intervention, and resuscitation can lead to improved outcomes. Here, we review the literature surrounding traumatic injuries of the SMA/SMV and discuss management strategies.

Junctional adhesion molecule-A deletion increases phagocytosis and improves survival in a murine model of sepsis.

Expression of the tight junction-associated protein junctional adhesion molecule-A (JAM-A) is increased in sepsis, although the significance of this is unknown. Here, we show that septic JAM-A -/- mice have increased gut permeability, yet paradoxically have decreased bacteremia and systemic TNF and IL-1ß expression. Survival is improved in JAM-A-/- mice. However, intestine-specific JAM-A-/- deletion does not alter mortality, suggesting that the mortality benefit conferred in mice lacking JAM-A is independent of the intestine. Septic JAM-A-/- mice have increased numbers of splenic CD44hiCD4+ T cells, decreased frequency of TNF+CD4+ cells, and elevated frequency of IL-2+CD4+ cells. Septic JAM-A-/- mice have increased numbers of B cells in mesenteric lymph nodes with elevated serum IgA and intraepithelial lymphocyte IgA production. JAM-A-/- × RAG-/- mice have improved survival compared with RAG-/- mice and identical mortality as WT mice. Gut neutrophil infiltration and neutrophil phagocytosis are increased in JAM-A-/- mice, while septic JAM-A-/- mice depleted of neutrophils lose their survival advantage. Therefore, increased bacterial clearance via neutrophils and an altered systemic inflammatory response with increased opsonizing IgA produced through the adaptive immune system results in improved survival in septic JAM-A-/- mice. JAM-A may be a therapeutic target in sepsis via immune mechanisms not related to its role in permeability.