Interleukin-1␤ (IL-1␤) has been implicated in the pathogenesis of inflammatory diseases of the airway. In this study, we investigated the regulation of MUC2 and MUC5AC expression and of their regulatory mechanisms through cyclooxygenase-2 (COX-2) and prostaglandin E 2 (PGE 2 ). Cells activated by IL-1␤ showed increased COX-2, MUC2, and MUC5AC expressions at both the mRNA and protein levels. Mucin production was blocked by the selective COX-2 inhibitor NS398, and PGE 2 directly induced MUC2 and MUC5AC expression at both the mRNA and protein levels in a dose-dependent manner. These results suggest a role for PGE 2 in IL-1␤-induced mucin synthesis in NCI-H292 cells. To investigate the roles of molecules upstream of COX-2 in mucin regulation, we examined the role of mitogen-activated protein kinases (MAPKs). Cells activated by IL-1␤ showed increased extracellular signal-regulated kinase (ERK)1/2 and p38 phosphorylation, and IL-1␤-induced MUC2 and MUC5AC production was blocked by the ERK pathway inhibitor PD98059 or the p38 inhibitor SB203580. The inhibition of both MAPKs reduced IL-1␤-induced COX-2 expression and PGE 2 synthesis. Furthermore, the addition of PGE 2 to cells overcame the inhibitory effects of both MAPK inhibitors in IL-1␤-induced mucin production. These results indicate that in human pulmonary epithelial cells, IL-1␤ activates ERK or p38 to induce COX-2 production, which in turn induces MUC2 and MUC5AC production.

Chronic unilateral maxillary sinusitis, a calcified density in the involved sinus on radiological studies, and unresponsiveness to antibiotics are characteristics of actinomycotic sinusitis. Surgical removal of the involved tissues and the restoration of sinus ventilation seem to be important factors for treating the disease.

Background: Proteolytic shedding of the ectodomain of a variety of transmembrane proteins, including cell-to-cell adhesion molecules, has been observed in solid cancers. We have investigated whether extracellular cleavage of E-cadherin mediated by matrix metalloproteinase-7 (MMP-7) is involved in hepatocyte growth factor (HGF) induced in vitro invasion in stomach cancer cells. Methods: The effects of HGF on the expression of E-cadherin/β-catenin and MMP-7 at both the protein and mRNA levels were assessed in stomach cancer cells, NUGC-3 and MKN-28, and in cells in which the expression of MMP-7 was downregulated by transfection with a MMP-7 short hairpin RNA plasmid. Results: Treatment with HGF increased the extracellular cleavage of E-cadherin and the release of MMP-7 and reduced the level of E-cadherin in a dose- and time-dependent manner. HGF treatment repressed the phosphorylation of β-catenin in a Triton-soluble fraction, but enhanced this phosphorylation in a Triton-insoluble fraction. The association of E-cadherin with β-catenin was decreased by HGF treatment in the Triton-soluble fraction. In addition, treatment of MMP-7 short hairpin RNA transfected NUGC-3 cells with HGF resulted in no extracellular cleavage of E-cadherin and also decreased the in vitro cell invasion. Conclusions: These results suggest that incubation with HGF mediated the release of MMP-7, resulting in extracellular cleavage of E-cadherin from stomach cancer cells. This might be a key mechanism in HGF-induced in vitro invasion and metastasis.

Leptin, an adipocyte-secreted hormone that regulates food intake and metabolic response, has been recently reported to increase in the serum during inflammatory airway disease associated with mucus-hypersecretion. We investigated the effects of leptin on mucin expression in human airway epithelial cells and the signaling pathways. The expression of the leptin receptor was evaluated in human nasal mucosa and NCI-H292 cells. Leptin-induced expression of major respiratory mucins in NCI-H292 cells was analyzed. Mutant leptin, which acts as a receptor antagonist, and specific inhibitors of extracellular signal-regulated kinase (ERK1/2), p38 and Janus kinase-2 (JAK2)/signal transducer and activator of transcription-3 (STAT3) were used. Leptin receptors were expressed in the nasal mucosa and NCI-H292 cells. Treatment with leptin significantly increased the expression of MUC5AC and MUC5B in NCI-H292 cells; these effects were blocked by mutant leptin. The cells activated by leptin showed increased ERK1/2, p38, and STAT3 phosphorylation. Leptin-induced MUC5B expression was blocked by the ERK1/2 and p38 pathway inhibitors, but not by the JAK2/STAT3 pathway inhibitor. Leptin might significantly contribute to the production of major gel-forming mucins by direct stimulation of airway epithelial cells and the activation of leptin receptors coupled with the activation of ERK1/2 or p38, but not the JAK2/STAT3 pathway.

Pneumolabyrinth is a rare clinical manifestation seen in the practice of otology. It occurs usually after head trauma with temporal bone fracture. However, pneumolabyrinth without temporal bone fracture is a very rare occurrence. When it occurs, it is usually diagnosed by high-resolution computed tomography of the temporal bone. Therapy for pneumolabyrinth is conservative treatment or an exploratory tympanotomy. Recently, we saw two cases of pneumolabyrinth after trauma without temporal bone fracture. The patients were treated with conservative management for the pneumolabyrinth. However, the degree of recovery from hearing loss was different for each patient.

Objective: The serine protease urokinase-type plasminogen (uPA) and its receptor (uPAR) appear to have a major function in tumor invasion and metastasis. Interleukin-8 (IL-8) acts as an angiogenic factor in solid cancer. The purpose of this study was to determine whether the expression of IL-8 and the uPAR gene correlates with clinicopathological parameters in human gastric carcinoma. Methods: We examined the expression of uPAR mRNA and IL-8 mRNA using Northern blot analysis and RT-PCR in 35 gastric carcinomas and the surrounding normal mucosa. Macroscopic and histopathological tumor findings and survival rates were obtained from the patient records. Results: uPAR and IL-8 mRNA expression levels were higher in most neoplasms compared to the corresponding normal mucosal tissue. A correlation between uPAR and IL-8 expression in tumors was observed (r = 0.447, p < 0.01). uPAR mRNA expression in the tumors correlated well with lymph node metastasis (p < 0.02), and its stage (p < 0.01). The IL-8 MRNA expression in the tumors correlated with diffuse-type gastric cancer (p < 0.05). The survival rates of patients with tumors displaying high uPAR expression levels were significantly lower (p < 0.04) than those of patients without uPAR expression, but patients with IL-8 expression only showed a tendency to a lower survival rate. Conclusion: These results suggest that uPAR and IL-8 may be important prognostic factors in human gastric carcinomas.

Histone acetylation and deacetylaion play important roles in chromatin remodeling and gene expression. An imbalance of these reactions leads to aberrant behavior of the cells in the cell cycle, which in turn contributes to carcinogenesis. Histone deacetylase (HDAC) inhibitors have been shown to have anti-tumor effects in clinical trials. However, the exact mechanisms by which HDAC inhibitors exert anti-tumor effects and modulate gene expression are not completely understood, and remain a subject of intense investigation. In the current study, we determined whether HDACs regulate urokinase plasminogen activator (uPA), matrix metalloproteinase-9 (MMP-9), and tumor invasion. Using cDNA microarray analysis, we found that hepatocyte growth factor (HGF) induced HDAC5 expression in gastric cancer cell lines, NUGC-3 and MKN-28. TSA, a HDAC inhibitor, decreased HGF-induced HADC-5 expression and also repressed uPA and MMP-9 expression. TSA inhibited cell proliferation in both cell lines. In vitro Matrigel invasion assays showed that the HDAC inhibitor decreased cancer cell invasion. Furthermore, GO6976, a PKC inhibitor, significantly inhibited not only HGF-induced HDAC5 expression but also cell invasion. These results demonstrated that HDACs regulate HGF-induced uPA and MMP-9 expression through a PKC-dependent signal pathway in gastric cancer cells. Our data probably suggest that such activities serve as anti-tumor mechanisms of the HDAC inhibitor.

We investigated whether the abnormal expression of E-cadherin (ECD), in conjunction with the overexpression of matrix metalloproteinase-7 (MMP-7), is correlated with clinicopathological parameters such as metastasis and the prognosis for human gastric carcinoma. Using RT-PCR, we examined the expression of ECD and MMP-7 mRNA in 42 gastric carcinoma tissues and in the surrounding non-neoplastic mucosa. The macroscopic and histopathological tumor findings and the survival rates were obtained from the patient records. The level of ECD mRNA expression was lower in most of the neoplasms as compared to the corresponding nonneoplastic tissues (50 vs. 80.9%, respectively). The abnormal expression of ECD mRNA was significantly correlated to the microscopic classification and lymph node metastases (p<0.05), and its stage (p<0.05). The level of MMP-7 mRNA expression was higher in most neoplasms compared to the corresponding non-neoplastic tissues (66.6 vs. 50%, respectively). The overexpression of MMP-7 mRNA was significantly correlated with the microscopic classification, lymph node metastases (p<0.05), and its stage (p<0.01). However, a correlation between the abnormal expression of ECD and the overexpression of MMP-7 was not obtained. The survival rate of the patients with an ECD mRNA expression was longer than that of the patients without this expression, but this finding was not statistically significant (p=0.2162). The survival rates of patients with MMP-7 mRNA expression was significantly shorter than that of the patients without MMP-7 mRNA expression (p=0.0025). Overexpression of MMP-7 may be considered as a useful marker for determining metastasis and the prognosis of human gastric carcinoma rather than the abnormal expression of E-cadherin.