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NEUROREGULATION AND MOTILITY

Muscularis inflammation and the loss of interstitial cells of Cajal in the endothelin ETB receptor null rat

Departments of ¹Veterinary Pharmacology and ²Veterinary Public Health, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657; ³Department of Anatomy and Cell Biology, Nagoya University Graduate School of Medicine, Nagoya 466-8550; ⁴National Institute of Animal Health, Tsukuba 305-0856, Japan; and ⁵Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada 89557

Submitted 16 February 2004 ; accepted in final form 22 April 2004

Endothelin receptor null rats [ETB(–/–)] are a model for long-segment Hirschsprung’s disease. These animals have significant intestinal distension (megaileum) proximal to a constricted region of the gastrointestinal tract lacking enteric ganglia. Experiments were performed to determine the pathophysiological changes that occur in these animals and to examine the tunica muscularis as a unique, immunologically active compartment. We observed abnormal intestinal flora in ETB(–/–) rats, which included a marked increase in gram-negative aerobes (Enterobacteriaceae) and anaerobes (Bacteroidaceae) in the distended region of the small intestine. Histochemical observations showed that neutrophilic infiltration was rarely or not observed, but the number of ED2 positive macrophages was increased in the tunica muscularis. Expression of IL-1 and IL-6 mRNA was also significantly increased, and the level of CD14 (LPS receptors) were increased significantly in the tunica muscularis. Spontaneous phasic contractions were irregular in the distended intestinal regions of ETB(–/–) rats, and this was associated with an increased number of macrophages and damage to interstitial cells of Cajal (ICC) as revealed by using Kit-like immunoreactivity and electron microscopy. These results suggest that ED2-positive resident macrophages may play an important role in the inflammation of tunica muscularis in ETB(–/–) rats. Increased numbers and activation of macrophages may result in damage to ICC networks leading to disordered intestinal rhythmicity in regions of the gut in which myenteric ganglia are intact.

congenital aganglionosis rats; megaileum; Hirschsprung's disease; macrophages; microflora

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