Inhibition of Vasoactive Intestinal Polypeptide (VIP) Induces Resistance to Dextran Sodium Sulfate (DSS)-Induced Colitis in Mice

Abstract

VIP is highly expressed in the colon and regulates motility, vasodilatation, and sphincter relaxation. However, its role in the development and progress of colitis is still controversial. Our aim was to determine the participation of VIP on dextran sodium sulfate (DSS)-induced colonic mucosal inflammation using VIP−/− and WT mice treated with VIP antagonists. Colitis was induced in 32 adult VIP−/− and 14 age-matched WT litter-mates by giving 2.5 % DSS in the drinking water. DSS-treated WT mice were injected daily with VIP antagonists, VIPHyb (n=22), PG 97–269 (n=9), or vehicle (n=31). After euthanasia, colons were examined; colonic cytokines mRNA were quantified. VIP−/− mice were remarkably resistant to DSS-induced colitis compared to WT. Similarly, DSS-treated WT mice injected with VIPHyb (1 μM) or PG 97–269 (1 nM) had significantly reduced clinical signs of colitis. Furthermore, colonic expression of IL-1, TNF-α, and IL-6 was significantly lower in VIP−/− and VIPHyb or PG 97–269 compared to vehicle-treated WT. Genetic deletion of VIP or pharmacological inhibition of VIP receptors resulted in resistance to colitis. These data demonstrate a pro-inflammatory role for VIP in murine colitis and suggest that VIP antagonists may be an effective clinical treatment for human inflammatory bowel diseases.

Vasoactive Intestinal Peptide Nanomedicine for the Management of Inflammatory Bowel Disease

“…15 In addition, apart from studies undertaken in VIP knock out mice, there have been no studies conducted to-date, to determine the effectiveness of VIP in DSS colitis. 18,46 Therefore, the current study provides for the first time successful delivery of VIP in a stable form for therapeutic use in DSS induced colitis in mice.…”

Regulation of Appetite, Body Composition, and Metabolic Hormones by Vasoactive Intestinal Polypeptide (VIP)

“…VIP binds with equal high affinity to its G protein-coupled receptors VPAC1 and VPAC2 (Said, 1970; Vaudry; 2000). Physiologically, VIP plays an important role in a variety of gastrointestinal functions including mucosal ion transport, vasodilatation, gastric acid secretion, hemodynamic regulation, gastric and intestinal motility, sphincter relaxation, neuronal excitability and mucosal inflammatory immune responses (Bloom, 1973; Harmar, 2012; Vu, 2014). Initially discovered in the intestine and lung, VIP belongs to the glucagon/secretin family of peptides whose members also include GLP-1 and GLP-2, glucagon, gastric inhibitory peptide (GIP) and growth hormone releasing factor.…”

The Role of Neuropeptides in Mouse Models of Colitis

“…In addition, VIP antagonists were similarly able to reduce colitis in animal models. DSS colitis induced C57Bl6 mice treated with VIPHyb, a broad spectrum VIP antagonist which inhibits mainly VPAC1, but also VPAC2 and PAC1 receptors, or with PG 97-269 which selective inhibits only VPAC1 receptors, were found to have significantly reduced inflammatory parameters of colitis and decreased levels of pro-inflammatory cytokines such as IL-1, TNF-alpha, and IL-6 [64]. Further studies are needed to better understand the nature of neuropeptide signaling in IBD.…”

“…While VPAC2 receptor knockout mice on T-cells were shown to develop a worse course of DSS-induced colitis, VPAC1 knockout were seen to be resistant to colitis [63]. Recent studies by Vu et al [64], using the DSS colitis model, revealed that VIP knockout mice, and wild type mice treated with a VIP or VPAC1 antagonist, became resistance to colitis and had significantly reduced levels of colonic inflammation and expression of inflammatory cytokines. In 2015 Abad et al, using the TNBS model in VIP knockout mice, showed a resistance to colitis and observed lower levels of TNF-alpha and IL-6 inflammatory cytokines as compared to WT littermates [51].…”