title: Muscularis inflammation and the loss of interstitial cells of Cajal in the endothelin ETB receptor null rat.
abstract: 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-1beta 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.
authors.affiliation: Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Suzuki
authors.forename: Kyung-Jong
authors.initials: KJ
authors.lastname: Won
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Horiguchi
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kinoshita
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hori
authors.forename: Shigeko
authors.initials: S
authors.lastname: Torihashi
authors.forename: Eiichi
authors.initials: E
authors.lastname: Momotani
authors.forename: Kikuji
authors.initials: K
authors.lastname: Itoh
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Hirayama
authors.forename: Sean M
authors.initials: SM
authors.lastname: Ward
authors.forename: Kenton M
authors.initials: KM
authors.lastname: Sanders
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ozaki
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D016207:Cytokines / Q000096:biosynthesis; D017931:DNA Primers; D004731:Endotoxins / Q000097:blood; D004751:Enteritis / Q000235:genetics* / Q000382:microbiology / Q000473:pathology*; D005260:Female; D005724:Ganglia / Q000502:physiology; D005769:Gastrointestinal Motility / Q000235:genetics / Q000502:physiology; D007082:Ileum / Q000473:pathology; D007421:Intestine, Small / Q000294:innervation / Q000382:microbiology / Q000473:pathology*; D007958:Leukocyte Count; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D008264:Macrophages / Q000502:physiology; D008297:Male; D008854:Microscopy, Electron; D009119:Muscle Contraction / Q000502:physiology; D009220:Myositis / Q000235:genetics* / Q000382:microbiology / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D044023:Receptor, Endothelin B / Q000235:genetics* / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016207:Cytokines; D017931:DNA Primers; D004731:Endotoxins; D018950:Lipopolysaccharide Receptors; D012333:RNA, Messenger; D044023:Receptor, Endothelin B