Angiopoietin-2 in experimental colitis

Abstract

The pathophysiology of inflammatory bowel disease (IBD) includes leukocyte infiltration, blood and lymphatic remodeling, weight loss and protein enteropathy. The roles of angiopoietin-2 (Ang-2) in initiating gut inflammation, leukocyte infiltration and angiogenesis are not well understood. Several important differences were seen in the development of experimental IBD in Ang-2-/- mice. Although weight change and disease activity differ only slightly in WT and Ang-2-/- + DSS treated mice, leukocyte infiltration, inflammation and blood and lymphatic vessel density is significantly attenuated compared to WT+ DSS mice. Gut capillary fragility and water export (stool blood and form) appear significantly earlier in Ang-2-/- + DSS mice vs. WT. Colon lengths were also significantly reduced in Ang-2-/- and gut histopathology was less severe in Ang-2-/-compared to WT + DSS. Lastly, the decrease in serum protein content in WT + DSS was less severe in Ang-2-/- + DSS, thus protein losing enteropathy (PLE) a feature of IBD is relieved by Ang-2-/-. These data demonstrate that in DSS colitis, Ang-2 mediates inflammatory hemangiogenesis, lymphangiogenesis and neutrophil infiltration to reduce some, but not all clinical features of IBD. The implications for Ang-2 manipulation in the development of IBD and other inflammatory diseases and treatments involving Ang-2 are discussed.

Angiopoietin-2 promotes inflammatory lymphangiogenesis and its effect can be blocked by the specific inhibitor L1-10

“…These functional data add weight to the suggestion that Ang-2 is a key trigger of inflammatory lymphangiogenesis. A recent study (15) showed that lymphangiogenesis and inflammation are significantly reduced in an inflammatory bowel disease model using Ang-2 Ϫ/Ϫ mice, supporting the hypothesis that Ang-2 is one of the key regulators involved in inflammatory lymphangiogenesis. Previous studies have shown that inflammatory C: significant inhibition of lymphangiogenesis (P Ͻ 0.01, n ϭ 7) by L1-10.…”

Role of Janus Kinase 3 in Mucosal Differentiation and Predisposition to Colitis

“…Serum albumin was determined by densitometry and by the bromcresol purple method as reported (23,24). Densitometric analysis of PAGEseparated proteins were done using Molecular Imager (ChemiDoc Lab TM XRS, Bio-Rad) equipped with Image Lab TM software.…”

Anatomy and roles of lymphatics in inflammatory diseases

“…115,120 Although increased density of lymphatics is a characteristic of experimental and clinical IBD, lymphatic vessel dilation and edema formation in IBD could also be a consequence of impaired contractile function of the intestinal lymphatics. 121,122 In rat and guinea pig models of intestinal inflammation, indeed, the contractile capacity within isolated collecting mesenteric lymphatics is compromised, and this effect correlates with lymphatic dysfunction, lymphatic vessel dilation and mucosal inflammation. 88,103,123,124 Furthermore, these studies have shown cyclooxygenase (cyclooxygenase 1/2) or inducible nitric oxide synthase inhibitors improve lymphatic pumping in non-contracting lymphatics in experimental IBD, suggesting prostanoids and nitric oxide released during intestinal inflammation contribute to diminished lymphatic contractile activity.…”