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Am J Physiol Gastrointest Liver Physiol (April 29, 2004). doi:10.1152/ajpgi.00077.2004
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Submitted on February 16, 2004
Accepted on April 22, 2004

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

Toshihiko Suzuki1, Kyung-Jong Won1, Kazuhide Horiguchi1, Kazuya Kinoshita1, Masatoshi Hori1, Shigeko Torihashi2, Eiichi Momotani3, Kikuji Itoh4, Kazuhiro Hirayama4, Sean M. Ward5, Kenton M Sanders5, and Hiroshi Ozaki1*

1 Department of Veterinary Pharmacology, The University of Tokyo, Tokyo, Japan
2 Department of Anatomy and Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan
3 National Institute of Animal Health, Tsukuba, Japan
4 Veterinary Public Health, The University of Tokyo, Tokyo, Japan
5 Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, USA

* To whom correspondence should be addressed. E-mail: aozaki{at}mail.ecc.u-tokyo.ac.jp.

Endothelin receptor null rats (ETB (-/-)) are a model for long segment Hirschsprung's disease. These animals have significant intestinal distention (megaileum) proximal to a constricted region of the GI 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 that included a marked increase in Gram (-) 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{beta} 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 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 where myenteric ganglia are intact.




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