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.     

Hypertriglyceridemia is associated with insulin levels in adult cystic fibrosis patients

BackgroundRecent studies have identified hypertriglyceridemic cystic fibrosis patients (CF-TG). However, whether hypertriglyceridemia is associated with an altered metabolic profile remains unknown.ObjectiveTo characterize CF-TG and determine whether triglycerides (TG) levels are associated with metabolic alterations.Methods210 adult CF subjects from the Montreal Cystic Fibrosis Cohort without known diabetes were included in the analysis. All subjects underwent an OGTT to assess glucose tolerance, insulin secretion (insulin AUC) and insulin sensitivity (Stumvoll index). Fasting lipid profiles, pulmonary function (%FEV₁) and BMI were determined. Hypertriglyceridemia (TG > 1.7 mmol/L) was observed in 20 CF patients. These subjects were matched for age, sex and glucose tolerance category with 20 CF patients (CF-normal-TG) and 20 healthy controls that had TG levels below 1.7 mmol/L. Pearson correlations were performed in the complete study sample (n = 210) to examine the associations between TG levels and other parameters.ResultsThe prevalence of hypertriglyceridemia was 9.5%. Compared to CF-normal-TG, CF-TG subjects displayed significantly higher %FEV_1, insulin AUC (AUC_0–120, AUC_0–30, AUC_30–120), cholesterol levels and a higher ratio of total cholesterol to HDL-cholesterol. Pearson analysis demonstrated that TG levels were associated with BMI, %FEV₁, fasting insulin, insulin AUC_0–120 and AUC_30–120, Stumvoll index, cholesterol levels and the ratio of total cholesterol to HDL-cholesterol. All these correlations remained significant after correction for BMI except %FEV₁.ConclusionTG levels are associated with a mild alteration of the metabolic profile. Whether these changes will increase the long-term risk of CF patients in developing cardiometabolic complications remains to be investigated.     

Langhans giant cells from M. tuberculosis-induced human granulomas cannot mediate mycobacterial uptake

Tuberculosis is characterized by a tight interplay between Mycobacterium tuberculosis (M. tb) and host cells within granulomas. These cellular aggregates restrain M. tb spreading but do not kill all bacilli, which persist for years. A more detailed investigation of the interaction between M. tb and granuloma cells is needed to improve our understanding of this persistence and to explain the physiopathology of tuberculosis. In the present study, a recently developed in vitro human model of tuberculous granulomas has been used to analyse the modulation of granuloma cell differentiation by M. tb, in comparison to poorly virulent mycobacteria, which do not persist. It is reported that whilst all mycobacteria species induce granuloma formation, only M. tb triggers the differentiation of granuloma macrophages into very large multinucleated giant cells (MGCs) that are unable to mediate any bacterial uptake. This loss of function is not due to cell quiescence, as MGCs still display NADPH oxidase activity, but it correlates with decreased expression of phagocytosis receptors. This phenomenon is specific for the virulent species of M. tuberculosis complex, as poorly virulent species only induce the formation of small multinucleated cells (MCs) with conserved mycobacterial uptake ability, which never reach the MGC differentiation stage. The phenotype of MGCs thus strongly resembles mature dendritic cells with a loss of microbial uptake ability, despite conserved antigen presentation. In M. tb-induced granulomas, MGCs thus seem to be devoted to the destruction of bacilli that have been ingested in previous differentiation stages, ie in macrophages and MCs.     

Morbidity of Loop Ileostomy Closure after Restorative Proctocolectomy for Ulcerative Colitis and Familial Adenomatous Polyposis: a Systematic Review

Background

Temporary loop ileostomy is a routine procedure to reduce the morbidity of restorative proctocolectomy. However, morbidity of ileostomy closure could reduce the benefit of this concept. The objective of this systematic review was to assess the risks of ileostomy closure after restorative proctocolectomy for ulcerative colitis or familial adenomatous polyposis.

Materials and Methods

Publications in English or German language reporting morbidity of ileostomy closure after restorative proctocolectomy were identified by Medline search. Two hundred thirty-two publications were screened, 143 were assessed in full-text, and finally 26 studies (reporting 2146 ileostomy closures) fulfilled the eligibility criteria. Weighted means for overall morbidity and mortality of ileostomy closure, rate of redo operations, anastomotic dehiscence, bowel obstruction, wound infection, and late complications were calculated.

Results

Overall morbidity of ileostomy closure was 16.5 %, there was no mortality. Redo operations for complications were necessary in 3.0 %. Anastomotic dehiscence occurred in 2.0 %. Postoperative bowel obstruction developed in 7.6 %, with 2.9 % of patients requiring laparotomy for this complication. Wound infection rate was 4.0 %. Hernia or bowel obstruction as late complications developed in 1.9 and 9.4 %, respectively.

Conclusion

The considerable morbidity of ileostomy reversal reduces the overall benefit of temporary fecal diversion. However, ileostomy creation is still recommended, as it effectively reduces the risk of pouch-related septic complications.