Koji Maruta1, Takeshi Takajo1, Yasutada Akiba2,1,3, Hyder Said1, Emi Irie2, Ikuo Kato4, Atsukazu Kuwahara5, Jonathan D Kaunitz6,7,8,9. 1. Department of Medicine, School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. 2. Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles VA Medical Center, Bldg. 114, Suite 217, 11301 Wilshire Blvd., Los Angeles, CA, 90073, USA. 3. Brentwood Biomedical Research Institute, Los Angeles, CA, USA. 4. Department of Medical Biochemistry, Kobe Pharmaceutical University, Kobe, Japan. 5. Research Unit for Epithelial Physiology, Research Organization of Science and Technology, Ritsumeikan University, Kusatsu, Japan. 6. Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles VA Medical Center, Bldg. 114, Suite 217, 11301 Wilshire Blvd., Los Angeles, CA, 90073, USA. jake@ucla.edu. 7. Department of Medicine, School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. jake@ucla.edu. 8. Department of Surgery, School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. jake@ucla.edu. 9. Brentwood Biomedical Research Institute, Los Angeles, CA, USA. jake@ucla.edu.
Abstract
BACKGROUND: Circulating endotoxin (lipopolysaccharide, LPS) increases the gut paracellular permeability. We hypothesized that glucagon-like peptide-2 (GLP-2) acutely reduces LPS-related increased intestinal paracellular permeability by a mechanism unrelated to its intestinotrophic effect. METHODS: We assessed small intestinal paracellular permeability in vivo by measuring the appearance of intraduodenally perfused FITC-dextran 4000 (FD4) into the portal vein (PV) in rats 1-24 h after LPS treatment (5 mg/kg, ip). We also examined the effect of a stable GLP-2 analog teduglutide (TDG) on FD4 permeability. RESULTS: FD4 movement into the PV was increased 6 h, but not 1 or 3 h after LPS treatment, with increased PV GLP-2 levels and increased mRNA expressions of proinflammatory cytokines and proglucagon in the ileal mucosa. Co-treatment with a GLP-2 receptor antagonist enhanced PV FD4 concentrations. PV FD4 concentrations 24 h after LPS were higher than FD4 concentrations 6 h after LPS, reduced by exogenous GLP-2 treatment given 6 or 12 h after LPS treatment. FD4 uptake measured 6 h after LPS was reduced by TDG 3 or 6 h after LPS treatment. TDG-associated reduced FD4 uptake was reversed by the VPAC1 antagonist PG97-269 or L-NAME, not by EGF or IGF1 receptor inhibitors. CONCLUSIONS: Systemic LPS releases endogenous GLP-2, reducing LPS-related increased permeability. The therapeutic window of exogenous GLP-2 administration is at minimum within 6-12 h after LPS treatment. Exogenous GLP-2 treatment is of value in the prevention of increased paracellular permeability associated with endotoxemia.
BACKGROUND: Circulating endotoxin (lipopolysaccharide, LPS) increases the gut paracellular permeability. We hypothesized that glucagon-like peptide-2 (GLP-2) acutely reduces LPS-related increased intestinal paracellular permeability by a mechanism unrelated to its intestinotrophic effect. METHODS: We assessed small intestinal paracellular permeability in vivo by measuring the appearance of intraduodenally perfused FITC-dextran 4000 (FD4) into the portal vein (PV) in rats 1-24 h after LPS treatment (5 mg/kg, ip). We also examined the effect of a stable GLP-2 analog teduglutide (TDG) on FD4 permeability. RESULTS: FD4 movement into the PV was increased 6 h, but not 1 or 3 h after LPS treatment, with increased PV GLP-2 levels and increased mRNA expressions of proinflammatory cytokines and proglucagon in the ileal mucosa. Co-treatment with a GLP-2 receptor antagonist enhanced PV FD4 concentrations. PV FD4 concentrations 24 h after LPS were higher than FD4 concentrations 6 h after LPS, reduced by exogenous GLP-2 treatment given 6 or 12 h after LPS treatment. FD4 uptake measured 6 h after LPS was reduced by TDG 3 or 6 h after LPS treatment. TDG-associated reduced FD4 uptake was reversed by the VPAC1 antagonist PG97-269 or L-NAME, not by EGF or IGF1 receptor inhibitors. CONCLUSIONS: Systemic LPS releases endogenous GLP-2, reducing LPS-related increased permeability. The therapeutic window of exogenous GLP-2 administration is at minimum within 6-12 h after LPS treatment. Exogenous GLP-2 treatment is of value in the prevention of increased paracellular permeability associated with endotoxemia.
Authors: Piero Portincasa; Leonilde Bonfrate; Mohamad Khalil; Maria De Angelis; Francesco Maria Calabrese; Mauro D'Amato; David Q-H Wang; Agostino Di Ciaula Journal: Biomedicines Date: 2021-12-31