Interplay between NO, prostaglandins and KATP channels in the lymphatic pumping dysfunction observed during experimental intestinal inflammation

Abstract

Lymphatic vessels rhythmically contract to actively propel lymph. This function, critical to tissue fluid homeostasis and immune cell trafficking is impaired in Crohn's disease and in the guinea‐pig model of TNBS ileitis, suggesting compromised lymph flow and lymphatic vessels potential players in the disease. Nitric oxide (NO) and prostaglandins (PGs), abundantly produced during intestinal inflammation, are known to activate ATP‐sensitive potassium (KATP) channels expressed in lymphatic muscle. Our aim was to assess the role of KATP channels, NO and PGs in inflammation‐induced lymphatic pumping dysfunction.After induction of intestinal inflammation, mesenteric lymphatics were collected for qPCR analysis, or isolated to assess their contractile and electrophysiological properties.Expression of mRNA for KATP channel subunits Kir6.1 and SUR2B, nitric oxide synthase iNOS and cyclooxygenase COX2 was significantly upregulated in lymphatics from TNBS‐compared to sham‐treated animals. Vessels from TNBS‐treated animals were dilated, quiescent, with strongly hyperpolarized muscle. Administration of the KATP blocker glibenclamide, iNOS inhibitor 1400W and COX inhibitor indomethacin restored pumping and depolarized lymphatic muscle.Our findings suggest that NO and PGs mediate lymphatic contractile dysfunction seen in TNBS‐treated animals via KATP channel opening.Supported by CIHR