Endogenous Specialized Proresolving Mediator Profiles in a Novel Experimental Model of Lymphatic Obstruction and Intestinal Inflammation in African Green Monkeys

Abstract

Changes in the intestinal lymphatic vascular system, such as lymphatic obstruction, are characteristic features of inflammatory bowel diseases. The lymphatic vasculature forms a conduit to enable resolution of inflammation; this process is driven by specialized endogenous proresolving mediators (SPMs). To evaluate contributions of lymphatic obstruction to intestinal inflammation and to study profiles of SPMs, we generated a novel animal model of lymphatic obstruction using African green monkeys. Follow-up studies were performed at 7, 21, and 61 days. Inflammation was determined by histology. Luminex assays were performed to evaluate chemokine and cytokine levels. In addition, lipid mediator metabololipidomic profiling was performed to identify SPMs. After 7 days, lymphatic obstruction resulted in a localized inflammatory state, paralleled by an increase in inflammatory chemokines and cytokines, which were found to be up-regulated after 7 days but returned to baseline after 21 and 61 days. At the same time, a distinct pattern of SPMs was profiled, with an increase for D-series resolvins, protectins, maresins, and lipoxins at 61 days. These results indicate that intestinal lymphatic obstruction can lead to an acute inflammatory state, accompanied by an increase in proinflammatory mediators, followed by a phase of resolution, paralleled by an increase and decrease of respective SPMs.

Dynamic gut microbiome changes following regional intestinal lymphatic obstruction in primates

“…The first finding in our study was a decrease in biodiversity in the AGM microbiome 7-dyas after induction of the ATLAS model. This timepoint also represents the peak of the inflammatory state [14]. In support of this, Ott et al [33], reported that the diversity of the gut flora in CD was reduced to 50% of that seen in controls and was even further reduced (30%) in UC.…”

“…An in-depth description of the ATLAS model, along with the physiological and inflammatory data used to define the model was reported in a previous paper [14]. Briefly, animals underwent a laparotomy and intestinal and mesenteric lymphatic vessels of the distal ileum and ascending colon were identified by subserosal injections of Isosulfan blue (300 l, 1%, Lymphazurin TM , Covidien, New Haven, CT, USA).…”

“…Surgically induced lymphatic obstruction was deemed successful if stasis of Isosulfan blue occurred in the mesenteric lymphatics and a complete reuptake occurred in the proximal lymph nodes without any leakage. It is important to state that the ATLAS model had no mortality and that animals in the ATLAS model displayed no signs of morbidity [14].…”

Specialized Pro-Resolving Mediators and the Lymphatic System

“…Indeed, Crohn’s disease can be modelled by surgically obstructing the lymphatics in the African green monkey. This model was used to measure levels of SPMs in the gastrointestinal tract in response to injury ( Table 2 ) [ 110 ]. The peak of the inflammatory response, recorded 7 days post lymphatic obstruction, was characterized by the increase in inflammatory cytokines and chemokines.…”

Resolvin D1 Decreases Severity of Streptozotocin-Induced Type 1 Diabetes Mellitus by Enhancing BDNF Levels, Reducing Oxidative Stress, and Suppressing Inflammation

“…In an extension of these studies, we conducted the present in vivo study to evaluate potential anti-diabetic action of anti-inflammatory metabolite of DHA, resolvin D1. Resolvin D1 (RVD1) reduces inflammation and showed promise in chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, and asthma [ 19 , 20 , 21 , 22 , 23 , 24 ]. However, its role in the prevention of T1DM has not been elucidated.…”