In vivo phenotyping of the microvasculature in necrotizing enterocolitis with multicontrast optical imaging.

OBJECTIVE: Necrotizing enterocolitis (NEC) is the most prevalent gastrointestinal emergency in premature infants and is characterized by a dysfunctional gut microcirculation. Therefore, there is a dire need for in vivo methods to characterize NEC-induced changes in the structure and function of the gut microcirculation, that is, its vascular phenotype. Since in vivo gut imaging methods are often slow and employ a single-contrast mechanism, we developed a rapid multicontrast imaging technique and a novel analyses pipeline for phenotyping the gut microcirculation. METHODS: Using an experimental NEC model, we acquired in vivo images of the gut microvasculature and blood flow over a 5000 × 7000 µm2 field of view at 5 µm resolution via the following two endogenous contrast mechanisms: intrinsic optical signals and laser speckles. Next, we transformed intestinal images into rectilinear "flat maps," and delineated 1A/V gut microvessels and their perfusion territories as "intestinal vascular units" (IVUs). Employing IVUs, we quantified and visualized NEC-induced changes to the gut vascular phenotype. RESULTS: In vivo imaging required 60-100 s per animal. Relative to the healthy gut, NEC intestines showed a significant overall decrease (i.e. 64-72%) in perfusion, accompanied by vasoconstriction (i.e. 9-12%) and a reduction in perfusion entropy (19%)within sections of the vascular bed. CONCLUSIONS: Multicontrast imaging coupled with IVU-based in vivo vascular phenotyping is a powerful new tool for elucidating NEC pathogenesis.

The administration of a pre-digested fat-enriched formula prevents necrotising enterocolitis-induced lung injury in mice.

Necrotising enterocolitis (NEC) is a devastating gastrointestinal disease of prematurity that typically develops after the administration of infant formula, suggesting a link between nutritional components and disease development. One of the most significant complications that develops in patients with NEC is severe lung injury. We have previously shown that the administration of a nutritional formula that is enriched in pre-digested Triacylglyceride that do not require lipase action can significantly reduce the severity of NEC in a mouse model. We now hypothesise that this 'pre-digested fat (PDF) system' may reduce NEC-associated lung injury. In support of this hypothesis, we now show that rearing newborn mice on a nutritional formula based on the 'PDF system' promotes lung development, as evidenced by increased tight junctions and surfactant protein expression. Mice that were administered this 'PDF system' were significantly less vulnerable to the development of NEC-induced lung inflammation, and the administration of the 'PDF system' conferred lung protection. In seeking to define the mechanisms involved, the administration of the 'PDF system' significantly enhanced lung maturation and reduced the production of reactive oxygen species (ROS). These findings suggest that the PDF system protects the development of NEC-induced lung injury through effects on lung maturation and reduced ROS in the lung and also increases lung maturation in non-NEC mice.

Prolonged In-hospital Time to Appendectomy is Associated With Increased Complicated Appendicitis in Children.

OBJECTIVE: To examine the association between prolonged in-hospital time to appendectomy (TTA) and the risk of complicated appendicitis. SUMMARY BACKGROUND DATA: Historically, acute appendicitis was treated with emergency appendectomy. More recently, practice patterns have shifted to urgent appendectomy, with acceptable in-hospital delays of up to 24 hours. However, the consequences of prolonged TTA remain poorly understood. Herein, we present the largest individual analysis to date of outcomes associated with prolonged in-hospital delay before appendectomy in children. METHODS: Data from patients who underwent appendectomy within 24 hours of hospital presentation were obtained from the American College of Surgeons Pediatric National Surgical Quality Improvement Program Procedure Targeted Appendectomy database from 2016 to 2018. Appendectomy within 16 hours of presentation was considered early, whereas those between 16 to 24 hours were defined as late. The primary outcome was operative findings of complicated appendicitis. Secondary outcomes included 30-day complications and resource utilization. RESULTS: This study consisted of 18,927 patients, with 20.6% undergoing late appendectomy. The rate of complicated appendicitis was significantly higher in the late group (Early: 26.3%, Late: 30.3%, P < 0.05). Additionally, the late group had longer operative times, increased need for postoperative percutaneous drainage, antibiotics at discharge, parenteral nutrition, and an extended hospital length of stay (P < 0.05). On multivariate analysis, late appendectomy remained a predictor of complicated disease (odds ratio 1.17 [95% confidence interval, 1.08-1.27]). CONCLUSIONS: A significant proportion of pediatric patients with acute appendicitis experience prolonged in-hospital delays before appendectomy, which are associated with modestly increased rates of complicated appendicitis. Although this does not indicate appendectomy needs to be done emergently, prolonged in-hospital TTA should be avoided whenever possible.

Toll-like receptor 4-mediated enteric glia loss is critical for the development of necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is a devastating disease of premature infants, whose pathogenesis remains incompletely understood, although activation of the Gram-negative bacterial receptor Toll-like receptor 4 (TLR4) on the intestinal epithelium plays a critical role. Patients with NEC typically display gastrointestinal dysmotility before systemic disease is manifest, suggesting that dysmotility could drive NEC development. Both intestinal motility and inflammation are governed by the enteric nervous system, a network of enteric neurons and glia. We hypothesized here that enteric glia loss in the premature intestine could lead to dysmotility, exaggerated TLR4 signaling, and NEC development. We found that intestinal motility is reduced early in NEC in mice, preceding the onset of intestinal inflammation, whereas pharmacologic restoration of intestinal motility reduced NEC severity. Ileal samples from mouse, piglet, and human NEC revealed enteric glia depletion, and glia-deficient mice (Plp1ΔDTR, Sox10ΔDTR, and BdnfΔDTR) showed increased NEC severity compared with wild-type mice. Mice lacking TLR4 on enteric glia (Sox10-Tlr4ko) did not show NEC-induced enteric glia depletion and were protected from NEC. Mechanistically, brain-derived neurotrophic factor (BDNF) from enteric glia restrained TLR4 signaling on the intestine to prevent NEC. BDNF was reduced in mouse and human NEC, and BDNF administration reduced both TLR4 signaling and NEC severity in enteric glia­deficient mice. Last, we identified an agent (J11) that enhanced enteric glial BDNF release, inhibited intestinal TLR4, restored motility, and prevented NEC in mice. Thus, enteric glia loss might contribute to NEC through intestinal dysmotility and increased TLR4 activation, suggesting enteric glia therapies for this disorder.

Impact of COVID-19 pandemic on injury prevalence and pattern in the Washington, DC Metropolitan Region: a multicenter study by the American College of Surgeons Committee on Trauma, Washington, DC.

BACKGROUND: The COVID-19 pandemic has had far-reaching effects on healthcare systems and society with resultant impact on trauma systems worldwide. This study evaluates the impact the pandemic has had in the Washington, DC Metropolitan Region as compared with similar months in 2019. DESIGN: A retrospective multicenter study of all adult trauma centers in the Washington, DC region was conducted using trauma registry data between January 1, 2019 and May 31, 2020. March 1, 2020 through May 31, 2020 was defined as COVID-19, and January 1, 2019 through February 28, 2020 was defined as pre-COVID-19. Variables examined include number of trauma contacts, trauma admissions, mechanism of injury, Injury Severity Score, trauma center location (urban vs. suburban), and patient demographics. RESULTS: There was a 22.4% decrease in the overall incidence of trauma during COVID-19 compared with a 3.4% increase in trauma during pre-COVID-19. Blunt mechanism of injury decreased significantly during COVID-19 (77.4% vs. 84.9%, p<0.001). There was no change in the specific mechanisms of fall from standing, blunt assault, and motor vehicle crash. The proportion of trauma evaluations for penetrating trauma increased significantly during COVID-19 (22.6% vs. 15.1%, p<0.001). Firearm-related and stabbing injury mechanisms both increased significantly during COVID-19 (11.8% vs. 6.8%, p<0.001; 9.2%, 6.9%, p=0.002, respectively). CONCLUSIONS AND RELEVANCE: The overall incidence of trauma has decreased since the arrival of COVID-19. However, there has been a significant rise in penetrating trauma. Preparation for future pandemic response should include planning for an increase in trauma center resource utilization from penetrating trauma. LEVEL OF EVIDENCE: Epidemiological, level III.

Timeliness of pediatric surgical appendicitis care is associated with time of hospital admission.

BACKGROUND: Despite the frequency of acute appendicitis in children, there is no evidence-based consensus surrounding the urgency of the operation if a diagnosis is made after regular business hours. Although a modest delay in time to operation does not increase disease severity, postponing cases to the next calendar day may be associated with higher resource utilization. We aimed to evaluate the trend of delaying appendectomies to the next calendar day and its associated outcomes. METHODS: We queried the Pediatric Health Information System to analyze appendectomy patients younger than 18 y of age from 2010 to 2018. Same-day appendectomy and next-day appendectomy cohorts were created using admission hour and operative day. Healthcare cost, length of stay, surgical complications, and 30-day readmission rates were collected. Bivariate analyses and multivariable regressions were used to evaluate groups stratified by time of presentation. RESULTS: During the study period, 113,662 appendectomies were performed, comprising 88,715 (78.1%) same-day appendectomies and 24,947 (21.9%) next-day appendectomies. A higher proportion of same-day appendectomies (80.5%) were performed during hours 12:00am to 5:00pm and 19.5% were performed during hours 6:00pm to 11:00pm. The trend of next-day appendectomies increased during the study period from 13.9% to 20.2%. This was primarily evident in the 6:00pm to 11:00pm period. The 5:00pm cutoff was most predictive of a next-day appendectomy. Next-day appendectomies had similar rates of surgical complications; however, they were associated with higher costs, longer lengths of stay, and higher readmission rates. CONCLUSION: As the understanding of appendicitis urgency has changed, a more tempered approach of delivering surgical care has trended. Although short delays appear safe, postponement to the next calendar day is associated with higher resource utilization.

Maternal aryl hydrocarbon receptor activation protects newborns against necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is a disease of premature infants characterized by acute intestinal necrosis. Current dogma suggests that NEC develops in response to post-natal dietary and bacterial factors, and so a potential role for in utero factors in NEC remains unexplored. We now show that during pregnancy, administration of a diet rich in the aryl hydrocarbon receptor (AHR) ligand indole-3-carbinole (I3C), or of breast milk, activates AHR and prevents NEC in newborn mice by reducing Toll-like receptor 4 (TLR4) signaling in the newborn gut. Protection from NEC requires activation of AHR in the intestinal epithelium which is reduced in mouse and human NEC, and is independent of leukocyte activation. Finally, we identify an AHR ligand ("A18") that limits TLR4 signaling in mouse and human intestine, and prevents NEC in mice when administered during pregnancy. In summary, AHR signaling is critical in NEC development, and maternally-delivered, AHR-based therapies may alleviate NEC.

The human milk oligosaccharides 2'-fucosyllactose and 6'-sialyllactose protect against the development of necrotizing enterocolitis by inhibiting toll-like receptor 4 signaling.

BACKGROUND: Necrotizing enterocolitis (NEC) develops through exaggerated toll-like receptor 4 (TLR4) signaling in the intestinal epithelium. Breast milk is rich in non-digestible oligosaccharides and prevents NEC through unclear mechanisms. We now hypothesize that the human milk oligosaccharides 2'-fucosyllactose (2'-FL) and 6'-sialyllactose (6'-SL) can reduce NEC through inhibition of TLR4 signaling. METHODS: NEC was induced in newborn mice and premature piglets and infant formula was supplemented with 2'-FL, 6'-SL, or lactose. Intestinal tissue was obtained at surgical resection. HMO inhibition of TLR4 was assessed in IEC-6 enterocytes, mice, and human tissue explants and via in silico modeling. RESULTS: Supplementation of infant formula with either 2'-FL and/or 6'-SL, but not the parent sugar lactose, reduced NEC in mice and piglets via reduced apoptosis, inflammation, weight loss, and histological appearance. Mechanistically, both 2'-FL and 6'-SL, but not lactose, reduced TLR4-mediated nuclear factor kappa light-chain enhancer of activated B cells (NF-kB) inflammatory signaling in the mouse and human intestine. Strikingly, in silico modeling revealed 2'-FL and 6'-SL, but not lactose, to dock into the binding pocket of the TLR4-MD2 complex, explaining their ability to inhibit TLR4 signaling. CONCLUSIONS: 2'-FL and 6'-SL, but not lactose, prevent NEC in mice and piglet models and attenuate NEC inflammation in the human ileum, in part through TLR4 inhibition. IMPACT: Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in premature infants that occurs in the setting of bacterial colonization of the gut and administration of formula feeds and activation by the innate immune receptor toll-like receptor 4 (TLR4). Breast milk prevents NEC through unclear mechanisms. We now show that breast milk-enriched human milk oligosaccharides (HMOs) that are derived from lactose prevent NEC through inhibition of TLR4. The human milk oligosaccharides 2'-FL and 6'-SL, but not the backbone sugar lactose, prevent NEC in mice and piglets. 2'-FL and 6'-SL but not lactose inhibited TLR4 signaling in cultured enterocytes, in enteroids derived from mouse intestine, and in human intestinal explants obtained at the time of surgical resection for patients with NEC. In seeking the mechanisms involved, 2'-FL and 6'-SL but not lactose were found to directly bind to TLR4, explaining the inhibition and protection against NEC. These findings may impact clinical practice by suggesting that administration of HMOs could serve as a preventive strategy for premature infants at risk for NEC development.

Increased proportion of physical child abuse injuries at a level I pediatric trauma center during the Covid-19 pandemic.

BACKGROUND AND OBJECTIVES: The Covid-19 pandemic has forced mass closures of childcare facilities and schools. While these measures are necessary to slow virus transmission, little is known regarding the secondary health consequences of social distancing. The purpose of this study is to assess the proportion of injuries secondary to physical child abuse (PCA) at a level I pediatric trauma center during the Covid-19 pandemic. METHODS: A retrospective review of patients at our center was conducted to identify injuries caused by PCA in the month following the statewide closure of childcare facilities in Maryland. The proportion of PCA patients treated during the Covid-19 era were compared to the corresponding period in the preceding two years by Fisher's exact test. Demographics, injury profiles, and outcomes were described for each period. RESULTS: Eight patients with PCA injuries were treated during the Covid-19 period (13 % of total trauma patients), compared to four in 2019 (4 %, p < 0.05) and three in 2018 (3 %, p < 0.05). The median age of patients in the Covid-19 period was 11.5 months (IQR 6.8-24.5). Most patients were black (75 %) with public health insurance (75 %). All injuries were caused by blunt trauma, resulting in scalp/face contusions (63 %), skull fractures (50 %), intracranial hemorrhage (38 %), and long bone fractures (25 %). CONCLUSIONS: There was an increase in the proportion of traumatic injuries caused by physical child abuse at our center during the Covid-19 pandemic. Strategies to mitigate this secondary effect of social distancing should be thoughtfully implemented.

Precision-based modeling approaches for necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in premature infants and remains stubbornly difficult to treat in many cases. Much of our understanding of NEC pathogenesis has been gained through the study of highly translational animal models. However, most models of NEC are limited by their overall complexity and by the fact that they do not incorporate human tissue. To address these limitations, investigators have recently developed precision-based ex vivo models of NEC, also termed 'NEC-in-a-dish' models, which provide the opportunity to increase our understanding of this disease and for drug discovery. These approaches involve exposing intestinal cells from either humans or animals with or without NEC to a combination of environmental and microbial factors associated with NEC pathogenesis. This Review highlights the current progress in the field of NEC model development, introduces NEC-in-a-dish models as a means to understand NEC pathogenesis and examines the fundamental questions that remain unanswered in NEC research. By answering these questions, and through a renewed focus on precision model development, the research community may finally achieve enduring success in improving the outcome of patients with this devastating disease.

Case report of extreme gastric distention and perforation with pathologic Sarcina ventriculi colonization and Rett syndrome.

Here we describe a case of a 15-year-old child with Rett syndrome who presented with extreme gastric distension and fatal perforation in the setting of long-standing aerophagia and pathologic colonization with Sarcina ventriculi, a rare bacteria implicated in gastric perforation. This is the first report of gastric perforation associated with colonization by Sarcina in a patient with pathologic aerophagia. Gastric colonization with Sarcina should be considered in intellectually disabled children with pathologic air swallowing who present with severe gastric dilation and/or perforation.

The role of in utero endotoxin exposure in the development of inflammatory bowel disease in mice.

PROBLEM: Although early environmental influences are thought to influence the development of inflammatory bowel disease (IBD), little is known about the role of the in utero environment on subsequent IBD risk. We hypothesized that prenatal exposure to bacterial lipopolysaccharide (LPS) could modify the subsequent development of dextran sulfate sodium (DSS)-induced ulcerative colitis in adulthood by influencing the associated cellular and immune response. METHOD OF STUDY: To test this hypothesis, we exposed developing mice in utero to LPS or saline (PBS) at E17.5, and then induced colitis at 5 weeks. We then assessed colitis severity and effects on the microbiome. In order to define the developmental impact of any potential LPS effect, we also exposed 1-week-old mice to either LPS or saline before inducing colitis at 5 weeks. RESULTS: Mice that had been exposed to LPS but not saline in utero were protected from subsequent colitis development, and their intestinal barrier integrity and tight junction expression distribution were similar to that of control mice that were not exposed to DSS. By contrast, mice exposed to either LPS or saline at day 7 of life all developed severe colitis upon subsequent DSS exposure. CONCLUSION: These results identify an informative time window during fetal development during which exposure to an otherwise pro-inflammatory agent like LPS protects against an inflammatory disease in adulthood.

STEP improves long-term survival for pediatric short bowel syndrome patients: A Markov decision analysis.

INTRODUCTION: Increasingly, for pediatric patients with short bowel syndrome (SBS), intestinal lengthening procedures such as serial transverse enteroplasty (STEP) are being offered with the hope of improving patients' chances for achieving enteral autonomy. However, it remains unclear to what extent STEP reduces the long-term need for intestinal transplant or improves survival. METHODS: Based on existing literature, a decision analytic Markov state transition model was created to simulate the life of 1,000 pediatric SBS patients. Two simulations were modeled: 1) No STEP: patients were listed for transplant once medical management failed and 2) STEP: patients underwent STEP therapy and subsequent transplant listing if enteral autonomy was not achieved. Sensitivity analysis of small bowel length and anatomy was completed. Base case patients were defined as neonates with a small bowel length of 30cm. RESULTS: For base case patients with an ostomy and a NEC SBS etiology, STEP was associated with increased rates of enteral autonomy after 10 years for patients with an ICV (53.9% [STEP] vs. 51.1% [No STEP]) and without an ICV (43.4% [STEP] vs. 36.3% [No STEP]). Transplantation rates were also reduced following STEP therapy for both ICV (17.5% [STEP] vs. 18.2% [No STEP]) and non-ICV patients (20.2% [STEP] vs. 22.1% [No STEP]). 10-year survival was the highest in the (+) STEP and (+) ICV group (85.4%) and lowest in the (-) STEP and (-) ICV group (83.3%). CONCLUSIONS: For SBS patients, according to our model, STEP increases rates of enteral autonomy, reduces need for intestinal transplantation, and improves long-term survival. TYPE OF STUDY: Economic/Decision Analysis or Modeling Studies LEVEL OF EVIDENCE: Level III.

Surgical Residents as Certified Bilingual Speakers: A Quality Improvement Initiative.

BACKGROUND: The objective of this quality improvement initiative was to identify general surgery residents proficient in a non-English language and have each attempt the Clinician Cultural and Linguistic Assessment (CCLA) to become qualified bilingual staff speakers. METHODS: General surgery house staff were asked to self-identify as proficient in a language other than English. Fees for the certification examination were waived, and each resident was excused from clinical duties to complete the exam. McNemar's test was used for statistical analysis. RESULTS: All residents responded to the initial survey, with 18/65 reporting a non-English language proficiency. Of the 12 residents who sat for the CCLA exam, 9 (75.0%) passed, with 5 certifying in the most commonly spoken non-English languages at this institution. The number of certified residents increased from 1 to 10 (1.5 % to 15.4%, p = 0.004). CONCLUSION: Language barriers result in health care disparities for patients with limited English proficiency. This reproducible quality improvement initiative significantly increased the number of qualified bilingual speakers, while 25.0% of self-described proficient speakers did not demonstrate adequate language proficiency. These newly certified providers allow for increased language concordant care, which may be associated with improved outcomes.

A Novel Role for Necroptosis in the Pathogenesis of Necrotizing Enterocolitis.

BACKGROUND & AIMS: Necrotizing enterocolitis (NEC) is a devastating disease of premature infants characterized by Toll-like receptor 4 (TLR4)-dependent intestinal inflammation and enterocyte death. Given that necroptosis is a proinflammatory cell death process that is linked to bacterial signaling, we investigated its potential role in NEC, and the mechanisms involved. METHODS: Human and mouse NEC intestine were analyzed for necroptosis gene expression (ie, RIPK1, RIPK3, and MLKL), and protein activation (phosphorylated RIPK3). To evaluate a potential role for necroptosis in NEC, the effects of genetic (ie, Ripk3 knockout or Mlkl knockout) or pharmacologic (ie, Nec1s) inhibition of intestinal inflammation were assessed in a mouse NEC model, and a possible upstream role of TLR4 was assessed in Tlr4-deficient mice. The NEC-protective effects of human breast milk and its constituent milk oligosaccharides on necroptosis were assessed in a NEC-in-a-dish model, in which mouse intestinal organoids were cultured as either undifferentiated or differentiated epithelium in the presence of NEC bacteria and hypoxia. RESULTS: Necroptosis was activated in the intestines of human and mouse NEC in a TLR4-dependent manner, and was up-regulated specifically in differentiated epithelium of the immature ileum. Inhibition of necroptosis genetically and pharmacologically reduced intestinal-epithelial cell death and mucosal inflammation in experimental NEC, and ex vivo in the NEC-in-a-dish system. Strikingly, the addition of human breast milk, or the human milk oligosaccharide 2 fucosyllactose in the ex vivo system, reduced necroptosis and inflammation. CONCLUSIONS: Necroptosis is activated in the intestinal epithelium upon TLR4 signaling and is required for NEC development, and explains in part the protective effects of breast milk.

Contemporary Outcomes following Redo Autogenous Infrainguinal Bypass.

BACKGROUND: Revascularization after lower extremity bypass failure poses many challenges. Despite nearly 7 decades of experience with lower extremity revascularization, there is little data on the success of redo bypass particularly when autogenous conduit is utilized. The purpose of this study is to review outcomes of redo infrainguinal bypass constructed solely of autogenous vein. METHODS: All patients who underwent redo infrainguinal bypass at a single institution by a single surgeon were retrospectively reviewed. Bypasses were categorized into 3 groups: femoral-popliteal, femoral-distal, and popliteal-distal bypasses. Since the repeat bypasses were all done for limb salvage, freedom from above or below knee amputation (FFA) was primary outcome, which was defined as the number of days from redo bypass to subsequent amputation or the most recent follow-up. RESULTS: From 2006 to 2016, 100 limbs underwent redo bypass. Fifty-nine (59.0%) limbs had undergone one previous bypass while 41 (41.0%) had undergone 2 or more. The redo configurations consisted of 23 (23.0%) femoral-popliteal, 70 (70.0%) femoral-distal, and 7 (7.0%) popliteal-distal bypasses. Ninety-seven (97.0%) underwent redo using autologous vein grafts including 41 (95.5%) of those who had 2 or more previous bypasses. The 3 patients who ultimately underwent prosthetic bypass had bilateral great and small saphenous veins and bilateral basilic and cephalic veins previously harvested. Nine (9.0%) limbs were subsequently amputated: 2 (2.0%) above knee and 7 (7.0%) below knee amputations. Of these, all had had 2 or more previous bypasses and 2 of the 3 patients who ultimately received prosthetic bypasses were in this group. In patients with one previous bypass, FFA was 775 days (IQR: 213-1,626 days). In patients with 2 or more previous bypasses, FFA was 263 days (IQR: 106-1,148 days). No patients with femoral-popliteal bypasses suffered amputation while 7 (10.0%) of the femoral-distal and 2 (28.6%) of the popliteal-distal bypasses suffered subsequent amputations (P = 0.067). CONCLUSIONS: Redo infrainguinal bypass is effective in salvaging threatened lower extremities. Furthermore, once a patient is deemed a bypass candidate, revascularization with autologous vein can be achieved. A significant FFA rate is achieved with redo bypass, although patients with more distal disease are harder to salvage.

Generating an Artificial Intestine for the Treatment of Short Bowel Syndrome.

Intestinal failure is defined as the inability to maintain fluid, nutrition, energy, and micronutrient balance that leads to the inability to gain or maintain weight, resulting in malnutrition and dehydration. Causes of intestinal failure include short bowel syndrome (ie, the physical loss of intestinal surface area and severe intestinal dysmotility). For patients with intestinal failure who fail to achieve enteral autonomy through intestinal rehabilitation programs, the current treatment options are expensive and associated with severe complications. Therefore, the need persists for next-generation therapies, including cell-based therapy, to increase intestinal regeneration, and development of the tissue-engineered small intestine.

A Dynamic Variation of Pulmonary ACE2 Is Required to Modulate Neutrophilic Inflammation in Response to Pseudomonas aeruginosa Lung Infection in Mice.

Angiotensin-converting enzyme 2 (ACE2) is a potent negative regulator capable of restraining overactivation of the renin-angiotensin system, which contributes to exuberant inflammation after bacterial infection. However, the mechanism through which ACE2 modulates this inflammatory response is not well understood. Accumulating evidence indicates that infectious insults perturb ACE2 activity, allowing for uncontrolled inflammation. In the current study, we demonstrate that pulmonary ACE2 levels are dynamically varied during bacterial lung infection, and the fluctuation is critical in determining the severity of bacterial pneumonia. Specifically, we found that a pre-existing and persistent deficiency of active ACE2 led to excessive neutrophil accumulation in mouse lungs subjected to bacterial infection, resulting in a hyperinflammatory response and lung damage. In contrast, pre-existing and persistent increased ACE2 activity reduces neutrophil infiltration and compromises host defense, leading to overwhelming bacterial infection. Further, we found that the interruption of pulmonary ACE2 restitution in the model of bacterial lung infection delays the recovery process from neutrophilic lung inflammation. We observed the beneficial effects of recombinant ACE2 when administered to bacterially infected mouse lungs following an initial inflammatory response. In seeking to elucidate the mechanisms involved, we discovered that ACE2 inhibits neutrophil infiltration and lung inflammation by limiting IL-17 signaling by reducing the activity of the STAT3 pathway. The results suggest that the alteration of active ACE2 is not only a consequence of bacterial lung infection but also a critical component of host defense through modulation of the innate immune response to bacterial lung infection by regulating neutrophil influx.