Glucocorticoids enhance airway epithelial barrier integrity.

Asthma is a chronic inflammatory disorder of the airways, but its pathogenesis is incompletely understood. While asthma is a complex disease caused by multiple factors, epithelial barrier damage is a cardinal feature. Glucocorticoids (GCs) are the most effective anti-inflammatory drugs in the treatment of asthma. However, the effects of GCs on the airway epithelial barrier have not been evaluated. Epithelial barrier functions were evaluated in cultured human airway epithelial cell monolayers, Calu-3 and 16HBE. Then, the cells were treated with dexamethasone (Dex), fulticasone propionate (FP), or budesonide (BD) for 5 days. Permeability measured by transepithelial electrical resistance was increased by treatment with Dex, FP, and BD in a dose-dependent manner. Permeability to fluorescein isothiocyanate-labeled dextran was markedly reduced by these treatments. Immunocytostaining revealed that Dex treatment potentiated tight junction formation in these polarized epithelial cells. Knockdown of epidermal growth factor receptor (EGFR) by small interference RNA blunted the effects of Dex on barrier integrity. Although EGFR expression was not affected by Dex treatment, EGFR phosphorylation was enhanced in Dex-treated cells. This is suggesting that EGFR are important for this phenomenon. These findings suggest that GC inhalation therapy can improve epithelial barrier integrity and might contribute to the therapeutic effects of GCs for treating asthma.

Acute myocardial infarction associated with small-size lung cancer in a young woman.

A 34-year-old woman visited our hospital with chest pain and was diagnosed with acute myocardial infarction (AMI) on admission. Echocardiography imaging revealed the presence of complex masses in the aortic valve. As serum tumor marker CA19-9 was elevated, she was screened for malignant disease. A computed tomography (CT) scan revealed a solitary pulmonary nodule, but because the nodule was small and non-specific, CT follow-up was considered appropriate. However, she developed hemorrhagic stroke in the short term and was subsequently diagnosed with lung adenocarcinoma. Clinicians should be on alert for the occurrence of AMI in patients with small-size lung cancer.

Heregulin activation of ErbB2/ErbB3 signaling potentiates the integrity of airway epithelial barrier.

BACKGROUND: Members of the ErbB family of the receptor protein tyrosine kinase superfamily mediate heregulin (HRG)-induced cell responses. Here we investigated HRG activation of ErbB receptors, and the role of this activation in the development of the permeability barrier in airway epithelial cells (AECs). METHODS: Two airway epithelial-like cell lines, Calu-3 and 16HBE were exposed to HRG or no stimulus and were evaluated with respect to their paracellular permeability as determined by transepithelial electric resistance (TER) and fluorescein isothiocyanate (FITC)-dextran flux. Tight junctions (TJs) were assessed by immunocytochemical localization of occludin and zonula occludens-1. RESULTS: HRG promoted the development of the permeability barrier and TJ formation by monolayers of Calu-3 and 16HBE cells. Calu-3 cells expressed ErbB1, ErbB2, and ErbB3, but not ErbB4, on their surface. ErbB3 knockdown by small interference RNA (siRNA) blunted the effects of HRG on the permeability barrier. ErbB3 is known as a kinase-dead receptor and relies on other members of the family for its phosphorylation. To identify its heterodimerization partner, we knocked down the expression of other ErbB family receptors. We found that HRG's effect on the permeability barrier could be significantly attenuated by transfecting cells with ErbB2 siRNA but not with EGFR siRNA. CONCLUSION: These results indicate that HRG activation of ErbB2/ErbB3 heterodimers is essential for regulation of the permeability barrier in AECs.

The Rac1/JNK pathway is critical for EGFR-dependent barrier formation in human airway epithelial cells.

The airway epithelial barrier provides defenses against inhaled antigens and pathogens, and alterations of epithelial barrier function have been proposed to play a significant role in the pathogenesis of chronic airway diseases. Although the epidermal growth factor receptor (EGFR) plays roles in various physiological and pathological processes on the airway epithelium, the role of EGFR on barrier function in the airway remains largely unknown. In the present study, we assessed the effects of EGFR activation on paracellular permeability in airway epithelial cells (AECs). EGFR activation induced by the addition of EGF increased transepithelial electrical resistance (TER) in AECs. An EGFR-blocking antibody eradicated the development of TER, paracellular influx of dextran, and spatial organization of tight junction. Moreover, the effects of EGFR activation on paracellular permeability were eradicated by knockdown of occludin. To identify the EGFR signaling pathway that regulates permeability barrier development, we investigated the effects of several MAP kinase inhibitors on permeability barrier function. Pretreatment with a JNK-specific inhibitor, but not an ERK- or p38-specific inhibitor, attenuated the development of TER induced by EGFR activation. Rac1 is one of the upstream activators for JNK in EGFR signaling. Rac1 knockdown attenuated the phosphorylation of JNK activation and EGFR-mediated TER development. These results suggest that EGFR positively regulates permeability barrier development through the Rac1/JNK-dependent pathway.

[A case of synovial sarcoma of the mediastinum].

A 65-year-old man consulted our hospital with a complaint of bloody sputum in February 2006, and chest computed tomography (CT) showed a mediastinal tumor. Percutaneous needle biopsy was performed. Pathological examination of the specimen revealed spindle-shaped cells; on immunohistochemical testing the tumor cells were positive for vimentin, keratin, EMA, CD99, actin, alpha-SMA, CD56, NF, and S100, and amplication of the SYT-SSX fusion gene was also seen. Thus, we confirmed a diagnosis of synovial sarcoma. The patient received chemotherapy, radiation therapy and hyperthermia therapy, but the tumor progressed and he died in October 2007. Synovial sarcoma commonly occurs in the vicinity of the large joints. We report an important case of mediastinal synovial sarcoma, which is comparatively rare.

Activation of Valpha24NKT cells in malignant pleural effusion in patients with lung cancer.

Valpha24NKT cells are lymphocytes expressing both T-cell antigen receptors and NK-cell antigen receptors on their cell surface and are involved in tumor immunity. They exert their antitumor effects after being activated by a specific ligand, alpha-galactosyl ceramide (alpha-GalCer). Malignant pleural effusion, a frequently occurring complication in patients with lung cancer, contains numerous lymphocytes. In the present study, we examined the presence and functions of Valpha24NKT cells in the lymphocytes in pleural effusion in vitro. The subjects were 13 untreated patients with primary lung cancer, who suffered malignant pleural effusion as a complication and who were treated between April 2004 and October 2007 at our hospital. Mononuclear cells were separated from the malignant pleural effusion and incubated with alpha-GalCer and IL-12. The production of IFN-gamma and IL-4 after incubation and the proportion of the Valpha24NKT cells before and after incubation were determined and compared. In the group cultured with alpha-GalCer alone, no significant increase in IFN-gamma production was observed in comparison with the control group. In the group cultured with alpha-GalCer+IL-12, IFN-gamma production increased significantly in comparison with the control group, and the proportion of Valpha24NKT cells increased after incubation. IL-4 production was very much lower than IFN-gamma production. Valpha24NKT cells were present in malignant pleural effusion in patients with lung cancer, but IFN-gamma production did not increase after addition of alpha-GalCer alone. The Valpha24NKT cells were activated by alpha-GalCer in the presence of IL-12. The Valpha24NKT cells in malignant pleural effusion were not activated by alpha-GalCer alone, suggesting that Valpha24NKT cell function is attenuated in malignant pleural effusion.

Influence of lymphocytes in malignant pleural effusion on the therapeutic efficacy of intrapleural OK-432 in lung cancer patients.

OBJECTIVES: Malignant pleural effusion, a common complication seen in advanced lung cancer patients, is often treated with intrapleural administration of chemical agents. In Japan, OK-432, a biological response modifiers, which activates the cytotoxic activity of lymphocytes and boosts antitumor immunity, is among the most frequently used chemical agents. The purpose of this study was to determine, in a case-control study, whether or not the rate of lymphocytes in malignant pleural effusion (lymphocyte rate) influences the therapeutic efficacy of intrapleural OK-432. PATIENTS AND METHODS: We enrolled 20 lung cancer patients with malignant pleural effusion treated with intrapleural OK-432 who were admitted to our hospital between January 2000 and December 2004. Therapeutic efficacy was assessed from the response rate, duration of chest drainage after treatment with intrapleural OK-432, time to progression of malignant pleural effusion, and survival time. RESULTS: Response rate in patients who had a high lymphocyte rate (the High lymphocyte rate group) was significantly higher than in patients who had a low lymphocyte rate (the Low lymphocyte rate group). Lymphocyte rate did not correlate with duration of chest drainage after treatment with intrapleural OK-432, time to progression of malignant pleural effusion, or survival time. CONCLUSIONS: The lymphocyte rate in malignant pleural effusion influences the response rate to treatment by intrapleural OK-432. In the High lymphocyte rate group, intrapleural OK-432 for malignant pleural effusion was effective. We conclude that intrapleural OK-432 is useful for malignant pleural effusion patients with a high lymphocyte rate before treatment.

[Comparison of intrapleural OK-432 and cisplatin for malignant pleural effusion in lung cancer patients].

Malignant pleural effusion is typical of complications in advanced lung cancer patients, most of whom complain of dyspnea. The standard treatment for symptomatic pleural effusion is intrapleural administration of a chemical agent. In Japan, OK-432, a streptococcal preparation, and cisplatin (CDDP) have been among the most frequently used chemical agents. There have been very few reports on the efficacy of chemical agents for malignant pleural effusion. We compared therapeutic efficacy and toxicity of intrapleural OK-432 with CDDP in a case-control study. The subjects consisted of 32 lung cancer patients with malignant pleural effusion who were admitted to our hospital between January 2000 and June 2004. The therapeutic efficacy was assessed from duration of chest drainage after intrapleural administration, response rate, time to progression of malignant pleural effusion, and survival time. No statistically significant difference was observed for therapeutic efficacy. Although the OK-432-treated group had only grade 1 fever, chest pain, nausea, the CDDP-treated group had a grade 2 increase in creatinine and grade 3 nausea. Intrapleural OK-432 seemed to be better tolerated in the treatment of malignant pleural effusion than intrapleural CDDP.

Situs inversus totalis with malignant lymphoma of the stomach: report of a case.

Situs inversus totalis is a rare congenital anomaly that often occurs concomitantly with other disorders. We report a case of situs inversus totalis with malignant lymphoma of the stomach, which was successfully treated by surgery followed by chemotherapy and irradiation. The patient was a 51-year-old woman who present with colicky pain in the left upper quadrant of her abdomen. Chest X-ray showed a right-sided heart, and ultrasonography and computed tomography (CT) of the abdomen showed a situs inversus totalis with multiple gallstones in the gallbladder. Tree-dimensional reconstructed CT of the abdomen showed no other malformations coexisting with situs inversus totalis, but a barium upper gastrointestinal series found an inverted stomach and an elevated tumor with ulceration in the center, localized in the antrum of the stomach. First, we performed a cholecystectomy, followed by a total gastrectomy with dissection of the lymph nodes and splenectomy, and Roux-en-Y reconstruction. Histopathological examination confirmed a diagnosis of malignant lymphoma of the stomach (diffuse large B-cell type) with metastasis to the regional lymph nodes. Chemotherapy using the CHOP regimen was given three times, starting 1 month postoperatively. A followup CT scan showed enlargement of one lymph node around the abdominal aorta and irradiation was delivered to the area of the inverted Y in the abdomen. At the time of writing, 10 months after surgery, the patient is well with no signs of recurrence and leading a normal life. Careful preoperative assessment is very important for determining the most appropriate surgical procedure in patients with situs inversus totalis associated with a malignancy.

Adrenal metastasis from rectal cancer: report of a case.

We report a case of heterochronic adrenal metastasis from colorectal carcinoma in a 51-year-old woman. A left adrenal metastasis was found by computed tomography and magnetic resonance imaging 8 months after an anterior resection for advanced rectal carcinoma, and a left hepatectomy for a solitary liver metastasis. The level of serum carcinoembryonic antigen was still within the normal range. A left adrenalectomy was performed, and histopathological examination revealed adenocarcinoma, compatible with the rectal carcinoma resected 8 months earlier. The patient died of lung metastases 6 months after the adrenalectomy. A review of autopsy series in the world literature revealed that adrenal metastasis from colorectal cancer is not rare. Therefore, the possibility of adrenal metastasis should be considered in the follow-up of patients after primary surgery for colorectal cancer, even though the liver and lung are the main metastatic sites.