Philipp-Alexander Neumann

Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair

N-formyl peptide receptors (FPRs) are critical regulators of host defense in phagocytes and are also expressed in epithelia. FPR signaling and function have been extensively studied in phagocytes, yet their functional biology in epithelia is poorly understood. We describe a novel intestinal epithelial FPR signaling pathway that is activated by an endogenous FPR ligand, annexin A1 (ANXA1), and its cleavage product Ac2-26, which mediate activation of ROS by an epithelial NADPH oxidase, NOX1. We show that epithelial cell migration was regulated by this signaling cascade through oxidative inactivation of the regulatory phosphatases PTEN and PTP-PEST, with consequent activation of focal adhesion kinase (FAK) and paxillin. In vivo studies using intestinal epithelial specific Nox1(-/-IEC) and AnxA1(-/-) mice demonstrated defects in intestinal mucosal wound repair, while systemic administration of ANXA1 promoted wound recovery in a NOX1-dependent fashion. Additionally, increased ANXA1 expression was observed in the intestinal epithelium and infiltrating leukocytes in the mucosa of ulcerative colitis patients compared with normal intestinal mucosa. Our findings delineate a novel epithelial FPR1/NOX1-dependent redox signaling pathway that promotes mucosal wound repair.

Annexin A1-containing extracellular vesicles and polymeric nanoparticles promote epithelial wound repair.

Epithelial restitution is an essential process that is required to repair barrier function at mucosal surfaces following injury. Prolonged breaches in epithelial barrier function result in inflammation and further damage; therefore, a better understanding of the epithelial restitution process has potential for improving the development of therapeutics. In this work, we demonstrate that endogenous annexin A1 (ANXA1) is released as a component of extracellular vesicles (EVs) derived from intestinal epithelial cells, and these ANXA1-containing EVs activate wound repair circuits. Compared with healthy controls, patients with active inflammatory bowel disease had elevated levels of secreted ANXA1-containing EVs in sera, indicating that ANXA1-containing EVs are systemically distributed in response to the inflammatory process and could potentially serve as a biomarker of intestinal mucosal inflammation. Local intestinal delivery of an exogenous ANXA1 mimetic peptide (Ac2-26) encapsulated within targeted polymeric nanoparticles (Ac2-26 Col IV NPs) accelerated healing of murine colonic wounds after biopsy-induced injury. Moreover, one-time systemic administration of Ac2-26 Col IV NPs accelerated recovery following experimentally induced colitis. Together, our results suggest that local delivery of proresolving peptides encapsulated within nanoparticles may represent a potential therapeutic strategy for clinical situations characterized by chronic mucosal injury, such as is seen in patients with IBD.

Cutting Edge: IL-36 Receptor Promotes Resolution of Intestinal Damage

IL-1 family members are central mediators of host defense. In this article, we show that the novel IL-1 family member IL-36γ was expressed during experimental colitis and human inflammatory bowel disease. Germ-free mice failed to induce IL-36γ in response to dextran sodium sulfate (DSS)-induced damage, suggesting that gut microbiota are involved in its induction. Surprisingly, IL-36R–deficient (Il1rl2−/−) mice exhibited defective recovery following DSS-induced damage and impaired closure of colonic mucosal biopsy wounds, which coincided with impaired neutrophil accumulation in the wound bed. Failure of Il1rl2−/− mice to recover from DSS-induced damage was associated with a profound reduction in IL-22 expression, particularly by colonic neutrophils. Defective recovery of Il1rl2−/− mice could be rescued by an aryl hydrocarbon receptor agonist, which was sufficient to restore IL-22 expression and promote full recovery from DSS-induced damage. These findings implicate the IL-36/IL-36R axis in the resolution of intestinal mucosal wounds.

Growth factors and gastrointestinal anastomotic healing

BACKGROUND Failure of anastomotic healing in the gastrointestinal tract is a major source of surgery-related morbidity, repeated surgical procedures, and impaired quality of life. Growth factors have been shown to be involved in healing processes in various tissues including the gastrointestinal tract. This opens the perspective to use growth factors therapeutically to support impaired anastomotic healing. The aim of the present study was to review the particular role of several growth factors in different phases of anastomotic healing, experimental approaches of growth factor application, and to discuss possibilities and limitations of growth factor-directed interventions in gastrointestinal surgery. MATERIALS AND METHODS A PubMed search was performed to examine the potential role of fibroblast growth factor, epidermal growth factor, heparin binding EGF-like growth factor, transforming growth factor β, insulin-like growth factor I, vascular endothelial growth factor, and platelet-derived growth factor during anastomotic healing. RESULTS Growth factors show beneficial effects on a broad range of cell types and regulate various processes during all phases of tissue healing. Despite extensive research in the field of growth factors, additional evidence is needed before translating into a clinical setting. CONCLUSIONS Future research should focus on adequate sustained but limited drug delivery. Undesired side effects, such as formation of strictures, development of peritoneal adhesions, and potential induction of malignancies, have to be reflected. Although growth factor application is currently far from clinical routine in gastrointestinal surgery, it might find application in selected patients at risk for impaired anastomotic healing, such as patients with long-time steroid therapy, immunosuppressives, inflammatory disorders, sepsis, hemodynamic shock, malnutrition, or neoadjuvant radiochemotherapy.

Distinct Phospholipase C-β Isozymes Mediate Lysophosphatidic Acid Receptor 1 Effects on Intestinal Epithelial Homeostasis and Wound Closure

ABSTRACT Maintenance of the epithelial barrier in the intestinal tract is necessary to protect the host from the hostile luminal environment. Phospholipase C-β (PLC-β) has been implicated to control myriad signaling cascades. However, the biological effects of selective PLC-β isozymes are poorly understood. We describe novel findings that lysophosphatidic acid (LPA) regulates PLC-β1 and PLC-β2 via two distinct pathways to enhance intestinal epithelial cell (IEC) proliferation and migration that facilitate wound closure and recovery of the intestinal epithelial barrier. LPA acting on the LPA1 receptor promotes IEC migration by facilitating the interaction of Gαq with PLC-β2. LPA-induced cell proliferation is PLC-β1 dependent and involves translocation of Gαq to the nucleus, where it interacts with PLC-β1 to induce cell cycle progression. An in vivo study using LPA1-deficient mice (Lpar1−/−) shows a decreased number of proliferating IECs and migration along the crypt-luminal axis. Additionally, LPA enhances migration and proliferation of IECs in an LPA1-dependent manner, and Lpar1−/− mice display defective mucosal wound repair that requires cell proliferation and migration. These findings delineate novel LPA1-dependent lipid signaling that facilitates mucosal wound repair via spatial targeting of distinct PLC-βs within the cell.

Current status of laparoscopic surgery for patients with Crohn's disease

PurposeMinimally invasive surgery is increasingly utilized in treatment for refractory or complicated Crohn’s disease, and new developments aim at further reducing the abdominal trauma and improving the outcome. This review evaluates current literature about minimally invasive surgery for patients with Crohn’s disease, latest advances in single-incision surgery, and methods of specimen extraction.MethodsLiterature was reviewed with focus on the following topics: indications, surgical procedures, conversions, complications, and short- as well as long-term outcomes of laparoscopic compared to open surgery for refractory, complicated, and recurrent Crohn’s disease.ResultsShort-term benefits such as shorter hospital stay and faster postoperative recovery are accompanied by long-term benefits such as better cosmetic results and lower treatment-associated morbidity. Single-incision surgery and minimally invasive methods of specimen extraction help to further reduce the surgical trauma and are gradually implemented in the treatment.ConclusionIn experienced centers, laparoscopic surgery for Crohn’s disease is safe and as feasible as open operations, even for selected cases with operations for complicated or recurrent disease. However, accurate analysis of the data is complicated by the heterogeneity of clinical presentations as well as the variety of performed procedures. Additional long-term data are needed for evaluation of true benefits of the new techniques.

Pre-emptive endoscopic vacuum therapy for treatment of anastomotic ischemia after esophageal resections

Background and study aims Endoscopic vacuum therapy (EVT) is a promising new approach for the treatment of anastomotic leakage in the gastrointestinal tract. Here, we present the first case series demonstrating successful use of EVT for the treatment of post-esophagectomy anastomotic ischemia prior to development of leakage. Patients and methods Between 2012 and 2015, intraluminal EVT was performed in eight patients with anastomotic ischemia following esophagectomy. The primary outcome measure was successful mucosal recovery. Secondary outcome measures were duration of treatment, number of sponge changes, septic course, and associated complications. Results Complete mucosal recovery was achieved in six patients (75 %) with different degrees of anastomotic ischemia. In two patients (25 %), small anastomotic leaks developed, which resolved by continuing the EVT treatment. Median duration of EVT treatment until mucosal recovery was 16 days (range 6 - 35), with a median of 5 sponge changes per patient (range 2 - 11). No EVT-associated complications were noted. Three patients developed anastomotic stenoses, which were treated by endoscopic dilation therapy. Conclusion This is the first case series to demonstrate that the early use of EVT potentially modulates clinical outcomes and infection parameters in patients with anastomotic ischemia following esophagectomy. Further studies are needed to define the indications and patients who are most likely to benefit from early EVT.

Timing of restorative proctocolectomy in patients with medically refractory ulcerative colitis: the patient's point of view.

Background: Development of biologic agents has led to new therapeutic options for patients with refractory ulcerative colitis, and intensive medical therapy allows delay of restorative colectomy. However, the overall rate of colectomies has not changed. The decision as to timing of the operation is difficult. Objective: Our aim was to elucidate the patients’ views about the timing of their own proctocolectomy. Design: This was a retrospective review of a prospectively designed database combined with a follow-up survey questionnaire. Settings and participants: We included patients who underwent proctocolectomy and ileal pouch-anal anastomosis for refractory ulcerative colitis from 1999 through 2009 at our university hospital. Main outcome measures: A questionnaire was sent to patients asking whether they would have preferred to have had the operation performed earlier, later, or at the same time as it was actually done and to give the number of years or months earlier or later that they would have preferred. They were also asked to give reasons for their preference. Patients who preferred an earlier operation were compared with those satisfied with the timing regarding measures of postoperative quality of life and pouch function collected from the institution’s prospective database. Results: Of 84 eligible patients, 70 (83%) responded. Of these, 37 (53%) would have preferred an earlier operation; 33 patients (47%) were satisfied with the timing. No patient would have chosen a later operation. Patients who preferred an earlier operation wished it to have been a median of 2 years earlier (range, 2–120 months). The main reasons for a preferred earlier time point were postoperative improvement of stool regulation in 89% (33/37), reduction of bleedings in 84% (31/37), and relief of pain in 68% (25/37). No significant differences were observed between groups regarding postoperative quality of life or pouch function. Limitations: Limitations of the study included lack of validation and a nonsymmetrical structure of the questionnaire. Conclusions: About half of the patients of our study would have preferred to have had proctocolectomy earlier than it had been performed, mainly because of the relief of symptoms that they experienced after the operation. For patients with an emerging refractory course of ulcerative colitis, earlier restorative proctocolectomy should be considered as an alternative to further intensified medical treatment.

Minimally invasive surgery for inflammatory bowel disease: Review of current developments and future perspectives.

Patients with inflammatory bowel disease (IBD) comprise a population of patients that have a high likelihood of both surgical treatment at a young age and repetitive operative interventions. Therefore surgical procedures need to aim at minimizing operative trauma with best postoperative recovery. Minimally invasive techniques have been one of the major advancements in surgery in the last decades and are nowadays almost routinely performed in colorectal resections irrespective of underlying disease. However due to special disease related characteristics such as bowel stenosis, interenteric fistula, abscesses, malnutrition, repetitive surgeries, or immunosuppressive medications, patients with IBD represent a special cohort with specific needs for surgery. This review summarizes current evidence of minimally invasive surgery for patients with Crohns disease or ulcerative colitis and gives an outlook on the future perspective of technical advances in this highly moving field with its latest developments in single port surgery, robotics and trans-anal techniques.

Effect of Continuous Motion Parameter Feedback on Laparoscopic Simulation Training: A Prospective Randomized Controlled Trial on Skill Acquisition and Retention

OBJECTIVE To investigate the effect of motion parameter feedback on laparoscopic basic skill acquisition and retention during a standardized box training curriculum. DESIGN A Lap-X Hybrid laparoscopic simulator was designed to provide individual and continuous motion parameter feedback in a dry box trainer setting. In a prospective controlled trial, surgical novices were randomized into 2 groups (regular box group, n = 18, and Hybrid group, n = 18) to undergo an identical 5-day training program. In each group, 7 standardized tasks on laparoscopic basic skills were completed twice a day on 4 consecutive days in fixed pairs. Additionally, each participant performed a simulated standard laparoscopic cholecystectomy before (day 1) and after training (day 5) on a LAP Mentor II virtual reality (VR) trainer, allowing an independent control of skill progress in both groups. A follow-up assessment of skill retention was performed after 6 weeks with repetition of both the box tasks and VR cholecystectomy. SETTING Muenster University Hospital Training Center, Muenster, Germany. PARTICIPANTS Medical students without previous surgical experience. RESULTS Laparoscopic skills in both groups improved significantly during the training period, measured by the overall task performance time. The 6 week follow-up showed comparable skill retention in both groups. Evaluation of the VR cholecystectomies demonstrated significant decrease of operation time (p < 0.01), path length of the left and right instrument, and the number of movements of the left and right instruments for the Hybrid group (all p < 0.001), compared to the box group. Similar results were found at the assessment of skill retention. CONCLUSION Simulation training on both trainers enables reliable acquisition of laparoscopic basic skills. Furthermore, individual and continuous motion feedback improves laparoscopic skill enhancement significantly in several aspects. Thus, training systems with feedback of motion parameters should be considered to achieve long-term improvement of motion economy among surgical trainees.