Biomedical subjects

Kazuya Kinoshita

Publications and source records attributed to Kazuya Kinoshita.

6 recordsLinked to original sources

PubMed2006

Possible involvement of muscularis resident macrophages in impairment of interstitial cells of Cajal and myenteric nerve systems in rat models of TNBS-induced colitis.

Resident macrophages are distributed in the network of interstitial cells of Cajal (ICC) and the myenteric nerve within the myenteric plexus. We evaluated changes in chemoattractant protein mRNA expression in macrophages and neutrophils, the ICC, nerve and macrophages in the myenteric plexus of model rats with TNBS-induced colitis. Chemoattractant proteins, MCP-1, GRO, MIP-2 and CINC-2alpha were upregulated in the colonic muscle layer after inflammation. Leukocyte infiltration and MPO activity were increased in the muscle layer. Electron microscopy indicated an irregular contour of the myenteric ganglia into which numerous macrophages had penetrated. Macrophages were also distributed near the ICC in the inflamed myenteric plexus. Immunohistochemistry showed that the ICC network and myenteric nerve system had disappeared from the inflamed region, whereas the number of resident macrophages was increased. TTX-insensitive, possibly ICC-mediated, rhythmic contractions of circular smooth muscle strips and enteric neuron-mediated TTX-sensitive peristalsis in the whole proximal colon tissue were significantly inhibited in the inflamed colon, indicating that the ICC-myenteric nerve system was dysfunctional in the inflamed muscle layer. Their accumulation around the myenteric nerve plexus and the ICC network suggests that macrophages play an important role in inducing intestinal dysmotility in gut inflammation.

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PubMed2005

Statin protects endothelial nitric oxide synthase activity in hypoxia-induced pulmonary hypertension.

OBJECTIVE: We investigated the effects of fluvastatin on hypoxia-induced (1 to 3 weeks, 10% O2) pulmonary hypertension with focus on endothelial nitric oxide synthase (eNOS) activity. METHODS AND RESULTS: Oral fluvastatin treatment (1 mg/kg daily) prevented the causing and progression of pulmonary hypertension as determined by the right ventricular pressure, right ventricular hypertrophy, and muscularization of pulmonary artery. We also revealed that fluvastatin treatments prevented the hypoxia-induced decrease in cGMP production in the rat lung and restored the endothelium-dependent relaxation in the pulmonary artery. We revealed that this beneficial effect was not dependent on the increase in eNOS mRNA or protein expression, but was dependent on the inhibition of the eNOS-tight coupling with caveolin-1, the eNOS dissociation from heat shock protein 90, and the decrease in eNOS Ser1177-phosphorylation induced by hypoxia. Furthermore, in a whole-mount immunostaining the hypoxia-induced eNOS protein condensation with caveolin-1 of pulmonary endothelial cells was restored by the fluvastatin-treatment. CONCLUSIONS: These results suggest that the fluvastatin exerts beneficial effects on chronic hypoxia-induced pulmonary hypertension by protecting against the eNOS activity at the post-transcriptional level.

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PubMed2005

Intestinal dysmotility in inflammatory bowel disease: mechanisms of the reduced activity of smooth muscle contraction.

Inflammation suppresses intestinal motility, which secondarily induces abnormal growth of intestinal flora. Disturbance of this flora plays a role in the pathogenesis of mucosal inflammation, which in turn aggravates the intestinal dysmotility. Therefore, it is important to know the mechanism of alteration in motor function in the inflamed intestine. Recent studies have shown molecular mechanisms responsible for the motility disorder in the inflamed gut. These include an increase in the activity of myosin light-chain phosphatase and an alteration of ion channel activity in smooth muscle cells.

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PubMed2004

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

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.

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PubMed2003

Decrease in activity of smooth muscle L-type Ca2+ channels and its reversal by NF-kappaB inhibitors in Crohn's colitis model.

We investigated the mechanisms of dysmotility of the colonic circular muscle of the Crohn's disease rat model. Contractions induced by KCl, carbachol, and Bay K 8644 were decreased in circular smooth muscles isolated from 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis rat colon. However, the absolute force and Ca2+ sensitivity of contractile proteins were not affected as assessed in alpha-toxin permeabilized smooth muscle. The current density of the L-type Ca2+ channel in circular smooth muscle cells was significantly decreased in the TNBS-treated colonic cells. However, expressions of the L-type Ca2+ channel mRNA and protein did not differ between control and TNBS-treated preparations. Pretreatment with the NF-kappaB inhibitors pyrrolidinedithiocarbamate and sulfasalazine partially recovered the decreased contractility and current density of the L-type Ca2+ channel by TNBS treatment. These results suggest that the decrease in the contraction of circular smooth muscle isolated from TNBS-induced colitis rat colon, which may be related to gut dysmotility in Crohn's disease, is attributable to the decreased activity of the L-type Ca2+ channel. The dysfunction of the L-type Ca2+ channel may be mediated by NF-kappaB-dependent pathways.

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PubMed2003

[Mechanism of the intestinal dysmotility in the inflammatory bowel diseases: possible involvement of muscularis resident macrophages].

We evaluated the changes in interstitial cells of Cajal (ICCs) and myenteric nerve system in relation to the activity and number of muscularis resident macrophage at a level of myenteric nerve plexus in the Crohn's disease model treated with 2,4,6-trinitrobenzene sulfonic acid (TNBS). In the TNBS-treated rat colon, ICCs network and also myenteric nerve system were damaged or disappeared in the inflamed region. The number of ED2-immunoreactive resident macrophage significantly increased where the ICCs or myenteric nerve systems changed. Although resident macrophage appeared morphologically ramified in control intestine, TNBS-treatment changed it to round shape, possibly an indication of functionally activated state. In fact, the round shape of macrophage expressed marked MHC class II comparing ramified macrophage in control intestine. Physiological study indicated that the motility index, the amplitude and frequency of spontaneous contractions were significantly decreased in the TNBS-induced colitis intestine. Moreover, the index of peristalsis observed in whole proximal colon tissue was inhibited by the treatment with TNBS. Electron microscopic analysis indicated that the contour of the myenteric ganglia became irregular in TNBS-treated rat colon, and numerous macrophages were observed around the ganglia. Similar results were obtained in the Hirschsprung's disease colitis model rats. In conclusion, the inhibition of spontaneous contractions and peristalsis in circular smooth muscle from TNBS-induced colitis rat colon may be attributable to the impairment of ICCs and myenteric nerve systems. Because of an indication of the macrophage activation and the close correlation between the degeneration and macrophage accumulation, it is suggested that the macrophages are involved in the degenerative pathology of intestinal motility.

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