[show abstract][hide abstract] 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. · 3.17 Impact Factor
[show abstract][hide abstract] 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.
[show abstract][hide abstract] ABSTRACT: Thymidine phosphorylase (TP) is expressed at higher levels in a variety of human cancers than in adjacent normal tissue. It is reported that the higher expression is associated with an increase of intratumoral microvessel density and a poor prognosis. We investigated the role of TP in human non small cell lung cancers (NSCLCs). The concentrations of TP in the tumors and the adjacent normal tissue from surgically resected specimens of 54 cases of NSCLCs were measured by using an enzyme-linked immunosorbent assay. Tumor specimens were also examined immunohistochemically. TP concentrations in the tumors were 169 +/- 18 units/mg protein (mean +/- SD), whereas those in normal tissue were 43 +/- 4 units/mg protein (mean +/- SD), consistent with TP staining patterns. There was no correlation between TP expression and microvessel density. Among clinicopathologic factors examined, the concentrations of TP but not TP immunoreactivity correlated with tumor differentiation in lung adenocarcinoma. Although a specific TP inhibitor (TPI) and overexpression of TP did not affect the growth of A549 lung adenocarcinoma cells, Matrigel invasion assay showed that A549 transfected with TP had higher invasive potential than mock transfectant, and such enhanced invasive activity was markedly diminished by treatment with TPI. Furthermore, administration of TPI suppressed lung metastasis of TP-overexpressing A549 cells in nude mice. These results demonstrate that TP may play an important role in tumor differentiation, invasiveness and metastasis in lung adenocarcinoma, and suggest that TP could be a novel target for treatment of TP-overexpressing lung adenocarcinoma.
International Journal of Cancer 11/2003; 106(6):863-70. · 6.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Little is known about why patients with chronic obstructive pulmonary disease are susceptible to bacterial infections. Using an animal model of pulmonary emphysema, we investigated the inflammatory responses to bacterial infection. After intratracheal infection with Streptococcus pneumoniae (10(3)-10(7) cfu/mouse), the control mice did not die. However, the mice with emphysema died in a dose-dependent manner. Bronchoalveolar lavage fluid, examined 24 hours after infection showed that the numbers of total cells and neutrophils, in addition to murine tumor necrosis factor-alpha and macrophage inflammatory protein-2 concentrations, were significantly less in the mice with emphysema compared with the control mice. Histopathologic findings revealed that the alveoli were filled with inflammatory cells and exudate in the control mice but not in the mice with emphysema. Seventy-two hours after infection, serum cytokine levels were significantly higher in the mice with emphysema, and significant numbers of S. pneumoniae were detected in both the whole lung tissues and the blood of mice with emphysema. These findings suggest that the inflammatory response in mice with emphysema was impaired at the site of bacterial infection despite the bacteremia, which accelerated severe systemic inflammatory responses. Accordingly, intra-alveolar but not systemic immune responses to bacterial infection were impaired in the presence of experimental emphysema.
American Journal of Respiratory and Critical Care Medicine 04/2003; 167(5):764-70. · 11.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: To maintain the integrity of tissues, endothelial cells play critical roles. Fas ligand (FasL) is well known to deliver a death signal through its receptor, Fas. The Fas/FasL system may concomitantly induce expressions of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) besides triggering apoptosis in endothelial cells. We also investigated whether an inhibitor of caspase-8 (Z-IETD-FMK) does modulate IL-8 and MCP-1 secretion.
After treatment with interferon-gamma (IFN-gamma), human recombinant FasL (hr FasL) or Fas agonistic antibody (CH-11) was added to cultured human endothelial cells. IFN-gamma up-regulated Fas mRNA levels. Fas ligation promoted apoptosis assessed by fluorescent-activated cell sorter (FACS) analysis in a dose-dependent manner and induced prominent DNA fragmentation. Simultaneously, IL-8 and MCP-1 were secreted from the endothelial cells in response to hr FasL or CH-11 in a dose-dependent manner (P < 0.01). Fas-neutralizing agent (Fas-Fc) suppressed the Fas-mediated secretions of IL-8 and MCP-1 (P < 0.01) both as well as the Fas-mediated apoptosis. On the other hand, whereas Z-IETD-FMK suppressed apoptosis, the inhibitor enhanced the Fas-mediated secretions of both IL-8 and MCP-1 beyond the value of the Fas stimulation alone (P < 0.01), suggesting an enhanced signalling for the chemokine expression.
In human endothelial cells, the Fas/FasL system induces both IL-8 and MCP-1 secretions probably via a caspase-8 independent pathway. The Fas/FasL system may amplify the inflammatory cascade in the vascular injury and atherogenesis by recruiting leukocytes at the region of apoptotic endothelial damage.
[show abstract][hide abstract] ABSTRACT: Although circulating tumor necrosis factor (TNF)- a levels have been found to be increased in weight-losing patients with chronic obstructive pulmonary disease (COPD), the main causes for this phenomenon remain to be elucidated. Since hypoxia itself can en- hance the production of the TNF- a in vitro , we studied the rela- tionship between hypoxemia and activities of the TNF- a system, including circulating TNF- a and soluble TNF-receptors (sTNF-R; sTNF-R55 and -R75) levels, in 27 COPD patients and 15 age- matched healthy controls. The COPD patients showed a signifi- cant weight loss (body mass index 5 18.1 6 2.8 versus 22.8 6 2.2 (mean 6 SD) kg/m 2 ; p , 0.0001. % fat 5 16.3 6 5.9 versus 24.3 6 4.9 %; p , 0.001), and hypoxemia (Pa O2 5 62.2 6 9.5 versus 88.6 6 5.9 mm Hg; p , 0.0001) as compared with the healthy controls. Serum TNF- a (6.15 6 1.08 versus 5.41 6 1.60 pg/ml; p , 0.05) and plasma sTNF-R55 (1.15 6 0.49 versus 0.67 6 0.13 ng/ml; p , 0.0001) and sTNF-R75 (3.54 6 1.16 versus 2.25 6 0.43; p , 0.0001) levels were significantly higher in the COPD patients than in the healthy controls. There were inverse correlations between Pa O2 and circulating TNF- a and sTNF-R levels in patients with COPD (TNF- a ; r 5 2 0.426, p 5 0.0297; sTNF-R55: r 5 2 0.587, p 5 0.0027; sTNF-R75: r 5 2 0.573, p 5 0.0035). In addition, we found inverse cor- relations between sTNF-R levels and % fat in COPD patients (sTNF- R55: r 5 2 0.442, p 5 0.0272; sTNF-R75: r 5 2 0.484, p 5 0.0155). TNF- a levels correlated well with sTNF-R levels (sTNF-R55: r 5 0.488, p 5 0.0127; sTNF-R75: r 5 0.609, p 5 0.0019). These relationships were not observed in the healthy controls. These data suggest that systemic hypoxemia noted in patients with COPD is associ- ated with activation of the TNF- a system in vivo , which may be a factor contributing to the weight loss in patients with the disease.
American Journal of Respiratory and Critical Care Medicine 04/2000; 161(4 Pt 1). · 11.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: We experienced a rare case of lung adenocarcinoma associated with lymphocytic interstitial pneumonitis caused by primary Sjögren’s syndrome. A 78-year-old woman was referred to our hospital because of progressive sicca syndrome and nodular opacities in the right lower lobe on chest radiograph. This patient was diagnosed as primary Sjögren’s syndrome by a labial gland biopsy and classical clinical features including xerophthalmia, xerostomia and immunoserological findings. Pathological findings including immunohistochemical studies in a surgically resected lung revealed adenocarcinoma in lymphocytic interstitial pneumonitis associated with primary Sjögren’s syndrome. There was no evidence of malignant lymphoma in the lymph nodes or resected lung tissue. Pulmonary involvement of Sjögren’s syndrome is now regarded both clinically and histopathologically as a wide spectrum of lymphoproliferative disorders ranging from benign to malignant. However, lung cancer associated with primary Sjögren’s syndrome, as in our case, has apparently not been reported previously.
[show abstract][hide abstract] ABSTRACT: Background and objective: Bacterial infection is one of the most important causes of acute exacerbation of respiratory failure in patients with chronic obstructive pulmonary disease (COPD). There were few studies evaluating the effects of early intervention by antibiotic on respiratory bacterial infection in COPD subjects. We investigated the effect of early intervention by respiratory quinolone antibiotic on the systemic inflammatory responses induced by streptococcal pneumonia using a mouse model of experimental emphysema. Methods: Experimental pulmonary emphysema was developed by a single intratracheal instillation of porcine pancreatic elastase in ICR mice. Three weeks later, lethal doses of Streptococcus pneumoniae were intratracheally inoculated, followed by oral administration of 50 mg/kg body weight of Grepafloxacin (GPFX) every day from a day after tracheal inoculation. Results: While all emphysematous mice without GPFX treatment died within 8 days, all emphysematous mice with GPFX treatment survived. Seventy two hrs after infection, serum levels of tumor necrosis factor alpha, chemokine (C-X-C motif) ligand 1, and CXCL2 (Macrophage inflammatory protein-2) in emphysematous mice with antibiotic therapy were significantly lower than those without therapy. Conclusions: Thus, the early intervention using a respiratory quinolone antibiotic prevents emphysematous mice with pneumonia from severe systemic inflammation, and rescues these mice from death. These results suggest that early intervention using a respiratory quinolone may improve the outcome of the exacerbated COPD patients.