Effect of sGLP-2 analogue in an experimental model of intestinal Ischemia-Reperfusion Injury

MOREIRA, JEREMIAS E.; STRINGA, PABLO; GENTILINI, MARÍA VIRGINIA; ARRIOLA, CONSTANZA; IVANOFF, IVANA; RUMBO, MARTÍN; GONDOLESI, GABRIEL E.

JOURNAL OF GASTROINTESTINAL SURGERY : OFFICIAL JOURNAL OF THE SOCIETY FOR SURGERY OF THE ALIMENTARY TRACT.

SPRINGER

Año: 2024 vol. 16

1091-255X

Introduction: Ischemia-reperfusion injury (IRI) is inherent to intestinal transplant and is responsible for direct (early mucosal damage) and indirect injuries (lung disease). The loss of the mucosal barrier function and the structure of intestinal villi, release pro-inflammatory cytokines, causing tissue damage in remote organs1. Glucagon-like peptide-2 (GLP-2) is a hormone secreted by enteroendocrine L cells of the intestinal epithelium which has a trophic effect on intestinal epithelium2. Although therapeutic use of the semisynthetic form of GLP-2 (sGLP-2) in intestinal rehabilitation has been established3, few experimental studies have shown a potential use to reduce IRI. Our aim was to evaluate a possible protective effect of sGLP-2 in reducing local and remote organ IRI damage in a mouse model, as preliminary analysis to them be applied in further transplant models or in the clinical setting.Materials & Methods: An intestinal IRI model was created by clamping the superior mesenteric artery for 40’ followed by 30’ of reperfusion. The study was approved by the internal review board and ethics committee for the care and use of laboratory animals (CICUAL UF 2019-004, #PICT2016-3677). Five experimental groups were performed: 1) Sham Group without inducing IRI (S) (N=4), 2) Sham Group without inducing IRI but with intraperitoneal sGLP-2 pre-treatment for 3 days before surgery and an intra-operative dose of 250µg/kg/day (SG) (N=4), 3) IRI Control Group (Ct) (N=9), 4) IRI Group with intraperitoneal sGLP-2 pre-treatment for 3 days before surgery and an intra-operative dose (Pret-sGLP-2) (N=9) and 5) IRI Group with only one intra-operative dose of sGLP-2 (Intra-sGLP-2) (N=9). After the reperfusion period, the mice were sacrificed. Intestinal and lung samples were taken. H-E was performed. Park score4,5 and morphological analysis were evaluated using the Villus/Crypt index4. A modified pulmonary score5 was evaluated. Alcian blue staining was performed to evaluate Goblet cells (GC)4. One-way ANOVA and Kruskal-Wallis tests were used for statistical analysis.Results: The Sham groups (S and GS) and sGLP2 treated groups (Pret-sGLP-2 and Intra-sGLP-2), showed less histological intestinal and lung lesions compared to Ct (Fig.1-2). Significant differences were observed in the number of GC between GLP2-Intra (Mean 11.65 ±1.68) and Ct (Mean 7.25 ±0.97) (p=0.0156). Significant differences were observed in the Villus/Crypt index between Ct and sGLP2-treated groups (p≤0.0034) (Fig. 1).Discussion: According to the results of this study, intrasurgical application or pre-treatment with sGLP-2 reduced IRI. Furthermore, intrasurgical treatment decreased remote lung damage. The number of GC was lower in Ct than in other groups; and significant differences were observed between S and Pret-GLP-2 (Fig. 1).The damage identified in treated groups with sGLP-2 demonstrated a score of 2. Despite this, it was observed that the Intra-sGLP-2 samples presented less deviation than Pret-sGLP-2; a significant difference was only found between Ct and Intra-sGLP-2. This is perhaps due to a more homogeneous effect of this fast-acting sGLP-2 analogue in immediate administration protocols3. In our study, the protective effect of Teduglutide in the lung could also be a consequence of a direct action on receptors in the lung6.