Mesenteric Lymphatic Obstruction in Crohn’s Disease

Abstract

The lymphatic drainage of diseased and normal bowel was studied in 21 patients undergoing surgery for Crohn’s disease. Mesenteric lymphatic obstruction was a consistent feature, identified in areas of small bowel macroscopically affected by Crohn’s disease. This finding was also observed in some areas of apparently unaffected small bowel. Subsequent examination of these areas confirmed the presence of early Crohn’s disease. This method of study may prove to be of value for determining the extent of operative resection in patients with Crohn’s disease. Experimental lymphatic obstruction in animals failed to produce pathological changes of Crohn’s disease, suggesting that this feature is an epiphenomenon and is not of primary importance in the pathogenesis of regional enteritis.

VEGF-C–dependent stimulation of lymphatic function ameliorates experimental inflammatory bowel disease

“…These novel findings are important because, although the precise pathophysiology of IBD is unknown, LV obstruction and dysfunction are long-recognized features observed in humans with this disease (15,16), and normalizing gut lymphatics with prolymphangiogenic factors such as VEGF-C may improve disease activity. Consistent with altered lymphatic contractile function reported in an animal model of acute intestinal inflammation (19), intestinal lymphatics are known to be grossly abnormal in the gut of CD patients (10).…”

“…For example, mice deficient for angiopoietin-2 show intestinal lymphatic dysplasia and exacerbated colitis in the dextran sulfate sodium (DSS) colitis model (12,13), while selective ablation of the LVs leads to distortion of the intestinal villi architecture and severe bowel inflammation (14). Although the precise pathophysiology of IBD is unknown, LV obstruction and dysfunction are long-recognized features observed in humans with this disease (15,16). The existence of an abnormal lymphatic system is further supported by a recent article describing defective drainage capacity of LVs in human CD bowel strictures (17).…”

“…Since VEGFR3 signaling is essential for lymphangiogenesis in various conditions (26,39), we sought to determine whether the pathway was also important for lymphangiogenesis in chronic experimental colitis. For this purpose, we studied the functional role of the VEGF-C/VEGFR3 pathway in vivo by systemic inhibition of VEGFR3 (15) or by delivery of the human lymphangiogenic factor VEGF-C in DSS and IL-10-KO models of chronic colitis using a blocking Ab or adenoviral transfer, respectively. Mice undergoing 2 cycles of DSS treatment and 15-week-old IL-10-KO animals with established colitis because of the essential importance of maintaining normal flow balance and removing inflammatory cells, mediators, and bacterial antigens away from inflamed sites (25).…”

Inflammation-associated lymphangiogenesis: a double-edged sword?

“…Similarly, antilymphatic treatment with anti-VEGFR-3 antibodies in an animal model of inflammatory bowel disease aggravated inflammation and submucosal edema, increased leukocyte infiltration, and caused the lymphatic vessels to become enlarged and tortuous (67). Although the precise pathophysiology of inflammatory bowel disease is unknown, lymphatic vessel obstruction and dysfunction are long-recognized features observed in humans with this disease (71). Lymphangiectasia and lymphocytic perilymphangitis were also found in patients with Crohn's disease, suggesting that lymphatic derangements are a part of the pathogenesis (72,73).…”

Lymphatic vessel contractile activity and intestinal inflammation

“…A common condition associated with the inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), is submucosal edema; this has been a consistent observation since the first accurate description of CD, and has been described as one of the essential histological features of the disease (Robb-Smith 1971). Examination by Heatley (1980) of human patients undergoing surgery for CD was one of many investigations demonstrating mesenteric lymphatic obstruction during inflammatory processes. In fact, lymphatic obstruction and dilation are frequently observed in IBD, suggesting impaired function and poor drainage of extracellular fluid, proteins, and other macromolecules.…”