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Minoru Inage,
Hidenori Nakamura,
Hiroshi Saito,
Shuichi Abe,
Toshihiko Hino,
Noriaki Takabatake,
Kyoko Terashita,
Manabu Ogura, Shuichi Kato,
Tetsumi Hosokawa,
Makoto Sata,
Hitonobu Tomoike
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ABSTRACT: We investigated the potential usefulness of vesnarinone, a novel cytokine inhibitor, for the treatment of lung fibrosis using a murine model of bleomycin (BLM)-induced pulmonary fibrosis. Mice were fed a control diet (n=42), or a diet containing low (n=42) or high (n=42) dose of vesnarinone. Dietary intake of vesnarinone minimized the BLM toxicity as reflected by significant decreases in numbers of inflammatory cells, KC, and soluble TNF receptors in the bronchoalveolar lavage fluid. A quantitative evaluation of histology demonstrated significantly mild lung parenchymal lesions in BLM-treated mice fed with diet containing high dose of vesnarinone than in the control diet group. Consistent with the histopathology, hydroxyproline levels in lung tissue from BLM-treated mice fed with diet containing vesnarinone were significantly lower than that from mice fed with control diet. We concluded that vesnarinone inhibits BLM-induced pulmonary fibrosis, at least in part, by the inhibition of acute lung injuries in the early phase.
International journal of biological sciences 02/2009; 5(4):304-10. · 2.70 Impact Factor
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ABSTRACT: Pulmonary fibrosis in sarcoidosis is a significant cause of morbidity and mortality. Various factors have been intensely studied to define the pathogenesis of lung fibrosis in sarcoidosis. Endothelin (ET) consists of three isoforms and is known for its potent vasoconstrictor properties. ET plays an important role in the fibroproliferative process of interstitial lung diseases.
To investigate the role of ET in the progression of pulmonary fibrosis in sarcoidosis, ET-1 and ET-3 concentrations were measured in BAL fluid (BALF) in 22 non-smoking patients with sarcoidosis and in control subjects (n = 12). Immunoreactivity of ET-1 was also evaluated in alveolar macrophages (AMs) from sarcoidosis patients. To assess the effects of ET in BALF on fibroblast proliferation, human foetal lung fibroblasts were cultured with sarcoidosis or control BALFs in the presence or absence of the ET-receptor antagonist TAK-044.
ET-1 levels in sarcoidosis BALF were significantly higher than those in control, whereas ET-3 levels were not different between sarcoidosis and control. ET-1 levels were correlated with the number of AMs in BALF. ET-1-immunoreactivity was found mainly in AM of sarcoidosis BALF. Sarcoidosis BALF significantly stimulated fibroblast proliferation, compared with control BALF, and the fibroblast proliferation induced by sarcoidosis BALF was inhibited by TAK-044.
Increased levels of ET-1 in AM could enhance fibrogenesis in pulmonary sarcoidosis.
Respirology 04/2006; 11(2):145-51. · 2.42 Impact Factor
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ABSTRACT: Cardiac microvascular endothelial cells (EC) play an important role in the physiological regulation of coronary blood flow, but their function has not been rigorously examined, because suitable in vitro models have not been available. Cardiac macrovascular and microvascular EC were isolated and cultured from 14-16-week-old Sprague-Dawley rats to examine the pharmacological responses of carbachol-induced nitric oxide (NO) production using a Griess method. Carbachol-induced NO production was only detected in cardiac macrovascular EC, which suggests that endothelial production of NO differs between macrovascular and microvascular EC. Next, cardiac microvascular EC was treated with either vehicle, angiotensin-converting enzyme (ACE) inhibitor (captopril, 10 micromol/L) or angiotensin II type 1 (AT1) receptor antagonist (CV11974, 10 micromol/L) for 4 days. Carbachol-induced NO production was improved by captopril (136+/-45nmol, p<0.01 vs vehicle) and CV11974 (146+/-30nmol, p<0.01 vs vehicle). Angiotensin II concentration in the culture medium and protein expressions of endothelial nitric oxide synthase and AT1 receptor in the EC were similar among the 3 groups. Interestingly, the level of muscarinic subtype 3 (M3) receptor was significantly increased in the EC treated with captopril (214%, p<0.01) and CV11974 (296%, p<0.01). When cardiac microvascular EC were treated with neomycin (non-selective phospholipase C inhibitor), carbachol-induced NO production was also improved (146+/-35nmol, p<0.01, neomycin I mmol/L) together with increased expression of M3 receptor (p<0.01). These data suggest that the upregulation of the M3 receptor by captopril or CV11974 occurs via a phospholipase C-dependent pathway. Cardiac microvascular EC also produced NO constitutively, as did the macrovascular EC, but carbachol-induced NO production was decreased. The present data suggest that the upregulation of the M3 receptor by the ACE inhibitor and AT1 receptor antagonist is a new beneficial effect of these drugs on microvascular endothelial function.
Circulation Journal 05/2002; 66(5):511-5. · 3.77 Impact Factor
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ABSTRACT: BackgroundThese studies were designed to investigate chronologic changes of transforming growth factor-β1 (TGF-β1) expression during
the evolution of glomerulosclerosis in rats after partial nephrectomy.
MethodsThe time course of TGF-β1 expression and its localization at the renal cortex was examined immunohistochemically in thirty-six
5/6 nephrectomized (Nx) and 30 sham-operated Wistar rats serially at 3 days and at 1,2,4,8 and 12 weeks after surgery. The
extent of glomerulosclerosis was assessed by using the sclerosis index (index range, 0 to 4). Monocyte/macrophage infiltration
and type IV collagen were immunohistochemically identified using the monoclonal antibody ED1 and monoclonal anti-type IV collagen
antibody, respectively.
ResultsAt 12 weeks, the sclerosis index was 1.64±0.20 and 0.06±0.01 (P<0.0001, analysis of variance) in 5/6 nephrectomized and sham-operated rats, respectively. In the nephrectomized rats, the
area of positive-TGF-β1 staining increased time-dependently, concomitant with positive results for ED1 and type IV collagen
stainings. There was a strong topologic relationship among TGF-β1, ED1, and type IV collagen expression. Northern blot analysis
of TGF-β1 messenger ribonucleic acid (mRNA) showed time-dependently augmented expression in nephrectomized, but not in shamoperated,
rats (0.8-, 2.2-, 1.6,- and 3.4-fold at 1, 4, 8 and 12 weeks, respectively).
ConclusionTGF-β1 plays a pivotal role in the progression of glomerulosclerosis in nephrectomized rats, in association with infiltration
of monocytes/macrophages.
Clinical and Experimental Nephrology 04/1997; 1(3):187-194. · 1.37 Impact Factor
