Development of a new cannabinoid-based therapy to treat inflammatory bowel disease

• DOI: 10.1152/physiol.2023.38.s1.5733403
• Publication Date: 2023-05-29T14:52:22Z
• Authors: Mario Meza-Segura; Regino Mercado-Lubo; Merran Dunford; Felix Ellett; Daniel Irimia; Randy Mrsny; Beth McCormick
• Keywords: Proinflammatory cytokine; Intestinal mucosa

Dysregulation of gut homeostasis may drive a variety pathological conditions like inflammatory bowel disease (IBD). One the first events associated with induction proinflammatory state is recruitment neutrophils to intestinal lumen. Neutrophils play critical role in maintenance by eliminating pathogens and contributing mucosal healing for resolution inflammation. However, an excessive accumulation activated intestine under conditions, such as IBD, injury. While basolateral release interleukin-8 epithelial cells stimulates from vasculature submucosa, secretion bioactive lipid hepoxilin A3 (HxA3) apical surface required draw across barrier. HxA3 potent neutrophil chemoattractant, derived arachidonic acid 12/15-lipoxygenase (12/15-LO) pathway, that secreted lumen multidrug resistance protein 2 (MRP2) form gradient trans-epithelial migration (TEM). Previous research developed our laboratory demonstrated another protein, P-glycoprotein (P-gp), was responsible endocannabinoids (eCBs) Moreover, these eCBs were shown inhibit HxA3-driven TEM. Given TEM development pathology current therapies IBD suffer damaging sequelae inability prevent relapses, main goal this project characterize mechanisms which cannabinoids (CB) modulate induced develop CB-based treat IBD. We used collagen-coated transwells screen panel eCBs, phytocannabinoids (pCBs), synthetic (SC) their ability migration. These CB showed different efficiency migration, anandamide (100%), cannabidiol (90%), AM1241 exhibiting highest inhibition. experiments using agonist (CP55940) antagonist (SR144528) specific cannabinoid receptor (CB2), revealed although participates modulation mediated CB, there are other still unidentified receptors involved process. Finally, understand fine decision-making process formulate between activation inhibitory signals, we novel microfluidic device coupled on-demand chemotaxis allows us interrogate responses various combinations gradients. Together, results will greatly help define biology health should allow uncover new therapeutic strategies controlling This funded grant R01 DK109677 National Institutes Health full abstract presented at American Physiology Summit 2023 meeting only available HTML format. There no additional versions or content abstract. not peer review