Intestinal stasis associated bowel inflammation

Komatsu S, Nimura Y, Granger DN

Subject headings  intestinal stasis;  bowel inflammation; endothelial cell intercellular adhesion molecule-1

Komatsu S, Nimura Y, Granger DN. Intestinal stasis associated bowel inflammation. World J Gastroentero, 1999;5(6):518-521



INTRODUCTION
Anatomical  structures that create reservoirs for stagnant  intestinal contents are a characteristic feature of common inflammatory disorders such as diverticulitis and appendicitis. Intestinal diverticula, surgically constructed  blind loo ps and pouches, obstructing carcinomas of the colon, and Hirschsprung��s disease  are accompanied by chronic inflammatory changes in the intestine, and are occasionally associated with mucosal ulceration followed by massive bleeding. These diseases are etiologically associated with disorders characterized by intestinal stasis and/or an altered fecal stream, resulting from ��cul de sac�� structures (blind loop or pouch) in the intestinal tract, bowel obstructio n or impaired motility. Furthermore, some of these chronic inflammatory conditio ns appear to exhibit similar pathological features, such as ischemic colitis. Although these inflammatory changes have been described individually, often as case reports, relatively little attention has been devoted to the overall clinical impact of these diseases and to understanding the pathophysiology of disease initiation and progression. Studies in our laboratory and by others have provided novel insights into the molecular and cellular basis for the intense inflammatory responses that are associated with intestinal stasis. This review summarizes the findings of these studies and provides a unifying theory to explain the inflammatory responses that result from intestinal stasis.

CLINICOPATHOLOGICAL FEATURES
Whereas most intestinal (duodenal, jejunal, Meckel��s, and colonic) divertic ula remain asymptomatic, gastrointestinal bleeding is the most common complicat ion, associated with mucosal ulceration^{��1-4��}. Meckel��s diverticulum, lo cated on the antimesenteric border of the ileum, is the most common congenital a nomaly of the gastrointestinal tract. Although ulcer formation in Meckel��s divertic ulum is generally thought to result from ectopic gastric tissue, all of the case s cannot be explained by acid production from the functioning gastric mucosa ^{��2��}. The diagnosis of gastrointestinal bleeding due to diverticula of the sm all bowel is difficult, because neither the symptoms  nor physical finding are s pecific and endoscopic  observation is hampered by the length of the intestine. Surgical resection of the involved segment of the intestine is the treatment of choice for the diverticula  identified  as a source of gastrointestinal hemorrha ge^{��1��}.
   The terms ��blind pouch�� or ��blind loop syndrome�� represent the complications  resulting from a stagnant intestine that are usually created by a side-to-sid e anastomosis with or without bowel resection, respectively. In cases of this sy ndrome, diarrhea and occult intestinal bleeding are usually found as well as sym ptoms resulting from malabsorption^{��5-9��}. Shallow and longitudinal  ulcer ations are occasionally observed in the resected blind intestine, similar to tho se of ischemic enteritis^{��5,6��}. Bacterial overgrowth in the blind loop ha s been presented in experimental models of animals^{��8,9��}. While this synd rome is now rare because the safety  of an end-to-end anastomosis has been est ablished, the pathological features of this condition may provide important insi ghts concerning the linkage between intestinal stasis and the resulting inflamma tory response.
   Restorative proctocolectomy with ileal pouch anal anastomosis has become the surgical treatment of choice for both ulcerative colitis and familial adenomatous p olyposis. In spite of the excellent functional results and improved quality of l ife with this procedure, major concerns persist regarding the risks for and con sequences of ileal pouchitis, a long��term complication that is recognized with increasing frequency. Pouchitis is a nonspecific inflammation of an ileal reserv oir that typically results in increased bowel frequency, decreased stool consist ency, diminished continence, low-grade fever, malaise, and arthralgias. Oral treatment with antibiotics, such as metronidazole, is an effective therapy for active pouchitis^{��10-12��}.
   The term ��obstructive colitis�� was originally used to define the ulcerative inflammatory lesions that occur proximal to the colonic lesion and which is partia lly  or potentially obstructive rather than completely obstructed^{��13-16��} . Complications include peritonitis, perforation, and breakdown of anastomoses  made through involved segments of the colon that may appear externally normal at surgery^{��13,15��}. The inflammatory response associated with colonic obs truction exhibits a variety of pathological features, including ischemic^{��13 -16��}, acute necrotizing^{��17��}, or pseudomembranous colitis^{��18��},  resulting in confusion about the definition of this disease^{��14��}. The ar e a of colitis is usually mildly dilated with moderate thickening of the wall. Thus, it is characteristically distinguished from marked distension of the bowel  that is associated with thinning of the wall and transmural necrosis caused by an increased intraluminal pressure, followed by acutely developing arrest of the intramural circulation^{��13��}.
   Enterocolitis associated with Hirschsprung��s disease, which can induce perforation and/or systemic sepsis, remains a major source of morbidity  and mortality , both before and after definitive surgical treatment^{��19-22��}. The risk of postoperative entero colitis is significantly increased by mechanical factors related to anastomotic stricture and intestinal obstruction^{��21,22��}, poss ibly eliciting a delayed intestinal transit. Crypt abscess, intraluminal fibrinopurulent debris, or mucosal ulceration are histologically observed^{��19,20 ��}. The etiology of enterocolitis is uncertain; ischemic and bacterial causes and recently, rotavirus infections, have been suggested^{��23,24��}.
   While much attention has been devoted to defining the relationship between enteric bacteria and the pathogenesis of inflammatory bowel disease (IBD), it remains  unclear whether intestinal stasis, resulting in overgrowth of enteric bacteria,  contributes to the development of IBD. However, there are several interesting p ublished observations that suggest the linkage between intestinal stasis and the  pathogenesis of IBD. A previous study showed evidence that the recurrence of Crohn��s disease in the neoterminal ileum after curative ileal  resection is dep endent on intestinal transit��25��. Although ulcerative  colitis (UC) has been described as a continuous inflammatory process starting from the rectum, isolated inflammatory changes can be observed in the periappendicial area of a n umber of patients with left-sided UC^{��26,27��}. In recent epidemiology-ba sed studies, the risk of progression of UC  was significantly lower after previo us appendectomy^{��28,29��}.
   Although peptic ulcers (gastric or duodenal) have been extensively studied, the mechanisms underlying the ulcerative inflammatory changes in the stagnant intest ine, where acid from the stomach has already been neutralized, remains poorly ch aracterized. Many of the features of the disease suggest an ischemic origin, whi ch cannot be explained  by atherosclerotic obstruction of the feeding arteries. Microvascular dysfunction, due to hypoperfusion following raised   intraluminal pressure, has been assumed to account for the mucosal ischemia^{��13��}. Contribution of enteric bacteria has also been suggested, based on the observati on that treatment with oral antibiotics can often relieve clinical symptoms indu ced by these diseases^{��10-12,30,31��}.

INTESTINAL STASIS AND ENDOTHELIAL CELL ADHESION MOLECULES
Leukocyte-endothelial cell adhesion is now recognized to represent an early and rate-limiting step in the leukocyte infiltration and accompanying tissue injury  associated with acute or chronic inflammation. There is also evidence that  adherent and activated leukocytes produce microvascular  dysfunction by occludi ng microvessels, damaging endothelial cells and increasing vascular  protein lea kage^{��32,33��}. Leukocyte-endothelial cell adhesive interactions, such as rolling, firm adhesion, and transendothelial migration, represent a highly coord inated process that is governed by a number of factors, including the expression  of specific adhesion glycoproteins, physical forces generated within the microc irculation, and inflammatory mediators released by a variety of activated cells ^{��32-37��}. The pivotal role of endothelial cell adhesion molecules (CAMs) in regulating leukocyte recruitment has been demonstrated in differen t models of gastrointestinal  and liver inflammation using either blocking monoclonal antibodies directed against specific CAMs or mice that is genetically  deficient in one or more endothelial CAMs^{��34,35��}. The ��2 subfamily of integrins (CD18) are expressed on leukocytes and these integrins firmly bind to glycoproteins of the immunoglobulin  superfamily, such as intercellular adhesion molecule-1 (ICAM-1) and ICAM₂, which are expressed on  vascular endothelium. ICAM-1 is constitutively expressed  on the surface of en dothelial cells and this expression can be enhanced by endotoxin or cytokines^{��36,37��}.

Figure1 Mechanism underlying the influence  of ente ric bacteria  on ICAM-1 expression on endothelial cells of the intestinal vasc ulature. Intestinal stasis likely causes an increased production bacterial factors that promote ICAM-1 expression and consequently enhances the recruitment and activation of leukocytes in the intestine.

   Our previous study, which employed surgical procedures to improve cecal stool fl ow in the rats^{��38��}, represented the first attempt to address the issue o f how intestinal stasis results in an inflammatory response. The findings of thi s study indicate that intestinal stasis is associated with an increased expressi on of ICAM-1 on endothelial cells and granulocyte infiltration. This study also  suggested that it be the bacterial load of a stagnant intestine that determines  the activation of mechanisms leading to infiltration of inflammatory cells, bas ed on the responses noted in animals receiving oral antibiotics. This view is supported by a previous study, in which  pretreatment with metroni dazole inhibited the leukocyte-endothelial cell adhesion in rat mesenteric venu les elicited by indomethacin  or leukotriene B₄^{��39��}.
   A definitive explanation concerning how enteric bacteria enhance ICAM-1 express ion on endothelial cells in the stagnant intestine is not readily available. How ever, our recent work on germfree mice demonstrated that the expression of ICAM -1, but not other endothelial CAMs such as ICAM-2, vascular cell adhesion mole cule-1 (VCAM-1), or E-selectin, is altered by germfree  conditions_{��40��}. The ICAM-1 specificity of this response argues against a role for systemic levels of bacterial endotoxin or tumor necrosis factor-�� released from macrophages, which are powerful stimuli for VCAM-1 and E-selectin as well  as ICAM-1^{��34��}, as mediators of the response. There is a growing body of evidence, derived from germ free animals, that enteric microflora  contribute to  the basal level of activation of the immune system, such as antibody-forming p otential, phagocytosis, T-cell population and responsiveness to cytokines^{�� 41-47��}. As illustrated in Figure 1, some unique factor that is normally released from enteric bacteria promotes the increased constitutive expression of  ICAM-1 in the intestinal microvasculature. Events associated with an altered enteric microflora, such as intestinal stasis or an altered fecal stream, are li kely to affect the amount of this bacteria- derived factor that regulates ICAM-1 expression. In doing so, the enteric  bacteria can exert a profound influenc e on the trafficking of leukocytes in the intestinal  microcirculation. As intes tinal stasis and overgrowth  of enteric bacteria are associated with increased I CAM-1 expression, subsequently affecting leukocyte-endothelial cell adhesion, it is tempting to speculate that the ischemic and inflammatory changes observed in the several disorders  associated with intestinal stasis may have share a com mon underlying mechanism that largely explains the ulcerative inflammatory lesio ns.

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¹First Department of Surgery, Nagoya University School of Medicine , Nagoya, Japan
²Department of Molecular & Cellular Physiology, Louisiana Stat e University Health Sciences Center, Shreveport, LA, USA
Supported by Grant-in Aid for Scientific Research (C), 11671230, by the Ministry of Education, Science, Sports and Culture of Japan.
Correspondence to: Shunichiro Komatsu, MD, First Department of S urgery, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoy a City 466-8550, Japan
Tel. +81-52-744-2220,  Fax. +81-52-744-2230
Email. skomat@atnet.ne.jp
Received  1999-09-22