Shu Hashimoto

Nihon University, Edo, Tōkyō, Japan

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Publications (56)89.05 Total impact

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    ABSTRACT: Background: Omalizumab, a monoclonal anti-IgE antibody, is currently indicated for the treatment of moderate-to-severe allergic asthma. To measure active IgE levels in sera from patients treated with omalizumab, the IgE subfraction in complex with omalizumab should be eliminated from total IgE, and free IgE levels can then be determined. With the aim of therapeutic monitoring for anti-IgE therapy, we developed a new ELISA for free IgE. Methods: We used recombinant human soluble FcεRIα as a capture antigen and a biotinylated polyclonal anti-IgE antibody for detection. Using the newly developed ELISA, we measured the serum free IgE levels weekly in four asthmatic patients after their first omalizumab injection. We also measured the serum free IgE levels in 54 patients treated with omalizumab for over 4 weeks. Results: This assay was technically robust, the mean recovery rate in serum was 93.16% ± 5.34%. For all patients, omalizumab treatment significantly reduced serum free IgE levels prior to the second omalizumab injection. To maintain the benefit of omalizumab, serum free IgE concentrations should be <50ng/ml. However, in 14 of 54 patients treated with omalizumab for over 4 weeks, serum free IgE concentrations measured by our ELISA were >50ng/ml. Conclusions: Our data suggest that the measurement of free IgE levels using our newly developed ELISA would be useful for monitoring serum free IgE levels during omalizumab therapy.
    Allergology International 05/2014; 63 Suppl 1:37-47.
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    ABSTRACT: Diffuse alveolar hemorrhage (DAH) has a varied etiology, including anticoagulation drugs. There is conflicting evidence whether low molecular weight heparin (LMWH) has a low risk of bleeding complications compared to unfractionated heparin. We report here a case of DAH in a 74-year-old woman who was administered enoxaparin, a LMWH, after bilateral total knee arthroplasty. Although congestive heart failure after blood transfusion and fluid infusion could in part be associated with the bleeding, LMWH may be a major cause of DAH since the patient quickly recovered after its cessation. DAH should be of concern when acute respiratory failure with ground-glass shadow develops in both lungs during anticoagulation therapy with LMWH.
    Respirology Case Reports. 09/2013; 1(1).
  • Yasuhiro Gon, Shu Hashimoto
    Nihon Naika Gakkai Zasshi 06/2013; 102(6):1370-7.
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    ABSTRACT: Advanced lung cancer is primarily treated with platinum combination chemotherapy, however, its prognosis remains poor. The aim of this study was to examine the correlation between the expression of thymidylate synthase (TS) in cancer tissues and the efficacy of chemotherapy in patients with advanced lung cancer in order to clarify the role of TS in the overall response. In total, 120 patients diagnosed with lung cancer between June 2004 and December 2010 at Nihon University Hospital, Tokyo, Japan, were included in this study. Cancer tissue specimens were obtained from the included patients by surgery or bronchofiberscopy prior to treatment. The expression of TS protein was evaluated using specimens immunostained with anti-TS antibody and H-scoring. TS protein expression tended to be higher in smokers compared with non-smokers. Overall survival (OS) (median value) was significantly prolonged in the low TS expression group compared with the high TS expression group. More favorable therapeutic effects were observed in the high TS expression group compared with the low TS expression group, when carboplatin + paclitaxel combined chemotherapy (CbPac therapy) was used. When the therapeutic effects were compared between CbPac therapy and carboplatin + pemetrexed combined chemotherapy (CbPem therapy) in the high TS expression group, prolongation of OS (median value) was observed with CbPac therapy. The present study suggests that TS protein expression is a critical factor in determining the efficacy of CbPac therapy in lung cancer. CbPac therapy is more effective when TS protein is highly expressed in lung cancer tissue.
    Molecular and clinical oncology. 05/2013; 1(3):411-417.
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    ABSTRACT: In patients with inoperable advanced non-small cell lung carcinomas (NSCLCs), histological subtyping using small-mount biopsy specimens was often required to decide the indications for drug treatment. The aim of this study was to assess the utility of highly sensitive mRNA quantitation for the subtyping of advanced NSCLC using small formalin fixing and paraffin embedding (FFPE) biopsy samples. Cytokeratin (CK) 6, CK7, CK14, CK18, and thyroid transcription factor (TTF)-1 mRNA expression levels were measured using semi-nested real-time quantitative (snq) reverse-transcribed polymerase chain reaction (RT-PCR) in microdissected tumor cells collected from 52 lung biopsies. Our results using the present snqRT-PCR method showed an improvement in mRNA quantitation from small FFPE samples, and the mRNA expression level using snqRT-PCR was correlated with the immunohistochemical protein expression level. CK7, CK18, and TTF-1 mRNA were expressed at significantly higher levels (P<0.05) in adenocarcinoma (AD) than in squamous cell carcinoma (SQ), while CK6 and CK14 mRNA expression was significantly higher (P<0.05) in SQ than in AD. Each histology-specific CK, particularly CK18 in AD and CK6 in SQ, were shown to be correlated with a poor prognosis (P=0.02, 0.02, respectively). Our results demonstrated that a quantitative CK subtype mRNA analysis from lung biopsy samples can be useful for predicting the histology subtype and prognosis of advanced NSCLC.
    Acta histochemica et cytochemica official journal of the Japan Society of Histochemistry and Cytochemistry 04/2013; 46(2):85-96. · 1.48 Impact Factor
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    ABSTRACT: Background: Cysteinyl leukotriene (LT) induces bronchoconstriction as well as airway inflammation and remodeling. Heparin-binding EGF-like growth factor (HB-EGF) is associated with remodeling in airway smooth muscle (ASM) cells in bronchial asthma. A disintegrin and metalloproteinase (ADAM) 12 is an enzyme implicated in the ectodomain shedding of membrane-anchored proHB-EGF and release of HB-EGF. Objective: To determine the role of LTD4 in HB-EGF and ADAM12 expression and the regulatory mechanism in human ASM cells, we analyzed a functioning signaling molecule in LTD4-induced HB-EGF and ADAM12 expression in human ASM cells by focusing on the role of mitogen-activated protein kinase (MAPK) cascades. Method: Human ASM cells were stimulated LTD4 in a time-dependent manner. We observed phosphorylation of MAPK by western blot analysis and the expression of HB-EGF and ADAM12 by quantitative PCR analysis of mRNA. Furthermore, we pretreated with specific inhibitors of MAPK and LTD4. Results: LTD4 induced an extracellular-signal regulated kinase (ERK), p38 MAPK and c-Jun-NH2-terminal kinase (JNK) phosphorylation in human ASM cells. LTD4 induced HB-EGF and ADAM12 mRNA expression. Furthermore, the regulation of LTD4-induced HB-EGF and ADAM12 mRNA expression is associated with ERK and p38 MAPK, not but JNK. Conclusion: we conclude that p38 MAPK and ERK are capable of regulating LTD4-induced HB-EGF and ADAM12 expression in human ASM cells. In bronchial asthma, the specific inhibitor of p38 MAPK and ERK may produce beneficial effects in controlling airway remodeling and inflammation.
    Asian Pacific journal of allergy and immunology / launched by the Allergy and Immunology Society of Thailand 03/2013; 31(1):58-66. · 0.79 Impact Factor
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    ABSTRACT: A 44-year-old woman was hospitalized with a 2-day history of cough, sputum, and fever. There was no history of atopic dermatitis or asthma. On admission, the chest X-ray revealed scattered infiltration in the left upper lung fields. Further examination revealed peripheral blood and bronchoalveolar lavage fluid eosinophilia. Transbronchial lung biopsy revealed eosinophilic pneumonia, with eosinophil infiltration of the alveoli, destroyed basal lumina, and connecting intraluminal fibrosis of the alveolar walls. Based on the findings, we made the diagnosis of chronic eosinophilic pneumonia. Treatment with prednisolone at 60 mg/day resulted in dramatic improvement of both the symptoms and the radiologic abnormalities.
    Asian Pacific journal of allergy and immunology / launched by the Allergy and Immunology Society of Thailand 12/2012; 30(4):321-5. · 0.79 Impact Factor
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    ABSTRACT: Pemetrexed inhibits three key folate enzymes: thymidylate synthetase (TYMS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). The relationship between the clinical efficacy of pemetrexed and the expression of folate enzymes in lung cancer cells is unknown. The purpose of this study was to determine whether TYMS, DHFR, and GARFT expression affect the therapeutic efficacy of pemetrexed. Participants (n=50) were patients with advanced non-small cell lung cancer (NSCLC) treated with pemetrexed. Samples were obtained by tumor biopsy before treatment. We isolated cancer cells from formalin-fixed paraffin-embedded tissues using laser microdissection, and mRNA levels were analyzed using real-time reverse transcription polymerase chain reaction. Protein expression was evaluated using immunohistochemistry. We assessed the association between TYMS, DHFR, and GARFT expression and the therapeutic efficacy of pemetrexed. The median age was 66.8 years. Compared to healthy tissues, the relative TYMS mRNA expression ranged from 0.001 to 41.613 (mean 4.638±1.357), and was significantly lower in responders compared to non-responders (1.671±0.844 versus 5.978±1.895, p=0.0142). Progression-free survival was prolonged in patients with lower TYMS mRNA expression compared to those with higher TYMS mRNA expression, but the difference was not statistically significant (18.0 versus 13.3 weeks, p=0.3001). DHFR and GARFT mRNA expression did not correlate with the efficacy of pemetrexed. We specifically analyzed TYMS, DHFR, and GARFT mRNA expression levels in lung cancer cells from biopsy specimens using laser microdissection. TYMS mRNA expression affected the therapeutic efficacy of pemetrexed and could therefore constitute a useful predictive biomarker for NSCLC patients receiving pemetrexed.
    Anticancer research 10/2012; 32(10):4589-96. · 1.71 Impact Factor
  • Tomoko Kobayashi, Shu Hashimoto
    Nippon rinsho. Japanese journal of clinical medicine 08/2012; 70 Suppl 6:543-7.
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    ABSTRACT: Sleep problems in humans have been reported to impact seriously on daily function and to have a close association with well-being. To examine the effects of individual sleep problems on physical and mental health, we conducted a nationwide epidemiological survey and examined the associations between sleep problems and perceived health status. Cross-sectional surveys with a face-to-face interview were conducted in August and September, 2009, as part of the Nihon University Sleep and Mental Health Epidemiology Project (NUSMEP). Data from 2559 people aged 20 years or older were analyzed (response rate 54.0%). Participants completed a questionnaire on perceived physical and mental health statuses, and sleep problems including the presence or absence of insomnia symptoms (i.e., difficulty initiating sleep [DIS], difficulty maintaining sleep [DMS], and early morning awakening [EMA]), excessive daytime sleepiness (EDS), poor sleep quality (PSQ), short sleep duration (SSD), and long sleep duration (LSD). The prevalence of DIS, DMS, and EMA was 14.9%, 26.6%, and 11.7%, respectively, and 32.7% of the sample reported at least one of them. At the complaint level, the prevalence of EDS, PSQ, SSD, and LSD was 1.4%, 21.7%, 4.0%, and 3.2%, respectively. Multiple logistic regression analyses revealed that DMS, PSQ, SSD, and LSD were independently associated with poor perceived physical health status; DIS, EDS, and PSQ were independently associated with poor perceived mental health status. This study has demonstrated that sleep problems have individual significance with regard to perceived physical or mental health status.
    Sleep Medicine 05/2012; 13(7):831-7. · 3.49 Impact Factor
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    ABSTRACT: 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.
    International immunopharmacology 12/2011; 12(2):350-7. · 2.21 Impact Factor
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    ABSTRACT: 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). 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. 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. These results indicate that HRG activation of ErbB2/ErbB3 heterodimers is essential for regulation of the permeability barrier in AECs.
    Experimental Cell Research 08/2011; 317(13):1947-53. · 3.56 Impact Factor
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    ABSTRACT: Aerosolized cyclosporine A (CsA) increases the local concentration of CsA in lung tissue and has proven to be an effective therapy for refractory rejection in lung transplant patients. However, the safety of high concentrations of CsA on tumour progression remains controversial. Human lung adenocarcinoma A549 cells were cultured with or without 1-3 μg/ml of CsA. The percentage of apoptotic cells was evaluated by Annexin V staining. The expressions of caspase-3, -9, -8 and cytochrome c were determined by Western blotting. CsA therapy suppressed the growth of human lung cancer cells and increased the percentage of apoptotic cells compared with control cells. Western blot analysis revealed that CsA increased the levels of cytosolic cytochrome c and cleaved caspase-3 and -9, but not of cleaved caspase-8 in the lung cancer cells, suggesting that CsA-induced apoptosis is associated with the activation of caspase-3 and -9. Our findings indicate that a high concentration of CsA has cytocidal effects through the caspase-3- and -9-dependent apoptotic pathway. This result shows that local administration of CsA does not increase the risk of secondary lung cancer.
    Anticancer research 06/2011; 31(6):2129-34. · 1.71 Impact Factor
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    ABSTRACT: Airflow obstruction is the most important pathophysiologic factor in chronic obstructive pulmonary disease (COPD). Although the prevalence of airflow obstruction has been increasing worldwide, airflow obstruction is often under-recognized in clinical practice because of insufficient use of spirometry. The aim of the present study was to identify unrecognized airflow obstruction in cases with lifestyle-related diseases using a data mining system that we have developed for use with electronic medical records. Clinical, spirometric data on 27,111 patients aged 40 years or older treated during the period from January 1999 to December 2008 was retrospectively collected from the electronic medical records of the Nihon University School of Medicine clinical data warehouse. Airflow obstruction was defined according to the criteria established by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Of the 27,111 patients, 6,098 (22.5%) showed airflow obstruction. Airflow obstruction was significantly more frequent in males, the elderly and smokers. The prevalence of airflow obstruction in patients with atherosclerosis (29.3%) was greater than that in patients with dyslipidemia (24.3%), diabetes mellitus (23.1%) or hypertension (27.1%). Only 14% of patients with airflow obstruction had a previous diagnosis of COPD. Latent COPD patients with airflow obstruction are highly prevalent, not only in those over 70 years of age with lifestyle-related diseases, but also in middle-aged patients. Spirometry should be widely used for patients with lifestyle-related diseases and a history of smoking, to effectively detect undiagnosed COPD.
    Rinsho byori. The Japanese journal of clinical pathology 02/2011; 59(2):128-33.
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    ABSTRACT: A growing body of evidence indicates that neutrophils may play an important role in the pathogenesis of asthma. However, the involvement of the house dust mite (HDM) in neutrophil activation associated with the pathogenesis of asthma is not fully understood yet. To address this situation, we harvested neutrophils isolated from 15 HDM-sensitized asthmatic subjects and 18 HDM-sensitized nonasthmatic subjects and measured the amounts of neutrophil reactive oxygen species (ROS) production in response to the major HDM allergens Der-f and Der-f1. Der-f and Der-f1 significantly increased ROS production in neutrophils isolated from asthmatic subjects versus nonasthmatic subjects. To assess the involvement of Der-f-specific IgE antibodies binding to their receptors in HDM allergen-induced ROS production, we examined whether neutrophils produce ROS by cross-linking of cell-bound IgE antibodies with anti-IgE. Treatment with anti-IgE antibodies did not induce ROS production by neutrophils isolated from 6 asthmatic subjects. On the other hand, pretreatment of Der-f with E-64, a cysteine protease inhibitor, eliminated Der-f-induced ROS production. These results suggest that HDM-allergen exposure may result in greater production of ROS in asthmatic patients and may be involved in the pathogenesis of asthma.
    International Archives of Allergy and Immunology 01/2011; 155 Suppl 1:104-9. · 2.25 Impact Factor
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    ABSTRACT: 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.
    Internal Medicine 01/2011; 50(18):1997-2002. · 0.97 Impact Factor
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    ABSTRACT: Mast cell is one of the central effectors in inflammatory responses. Recent studies suggest that a promising therapeutic approach for various inflammatory immune diseases, including rheumatoid arthritis, multiple sclerosis, and type I allergies, is to inhibit mast cell growth and/or survival. Studies also indicate that a balanced lipid metabolism is crucial for regulating the life span of cells. Oxysterol is a well-known regulator of lipid metabolism and has diverse functions, such as inhibition of the mevalonate isoprenoid pathway, efflux of free cholesterols, and synthesis of cholesterol esters. Here, we show that 24(S),25-epoxycholesterol, a representative endogenous oxysterol, induces apoptosis in bone marrow-derived murine mast cells. Furthermore, we have revealed, for the first time, that the accumulation of neutral lipids catalyzed by acyl-CoA:cholesterol acyltransferase in the cells was involved in induction of mast cell apoptosis. Our present findings confer new insights into the roles of lipid metabolism during oxysterol-mediated mast cell apoptosis.
    Experimental Cell Research 11/2010; 316(19):3272-81. · 3.56 Impact Factor
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    ABSTRACT: 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.
    Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 10/2010; 48(10):734-8.
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    ABSTRACT: Several features of OSA syndrome suggest that it is a manifestation of the metabolic syndrome (MS). In this study, we investigated the prevalence of the MS among male Japanese patients with OSA, as well as the relationship between OSA in non-obese patients and components of the MS other than obesity (hypertension, dyslipidaemia and glucose intolerance). The study included 416 Japanese men who were diagnosed as having OSA by polysomnography. Among these, 101 non-obese patients were selected and the severity of OSA, as well as the prevalence of hypertension, dyslipidaemia and glucose intolerance, was assessed. The MS was associated with OSA in 218/416 patients (52.4%). A significant increase in the prevalence of the MS was associated with increased severity of OSA, as categorized according to AHI. In the non-obese patients with OSA (mean age 57.6 years, BMI 22.7 kg/m(2), AHI 34.3 events/h), hypertension, dyslipidaemia and glucose intolerance were identified in 70 (69.3%), 43 (42.6%) and 20 patients (19.8%), respectively. At least two of these factors were identified in 40 patients (39.6%). Non-obese patients with severe OSA had a significantly higher prevalence of two or more of these factors (33/59 patients, 55.9%). Although Asians are generally less obese than Caucasians, the prevalence of the MS was high among Japanese patients with OSA, and even among non-obese patients, OSA was associated with risk factors for the MS.
    Respirology 10/2010; 15(7):1122-6. · 2.78 Impact Factor
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    ABSTRACT: 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.
    AJP Lung Cellular and Molecular Physiology 10/2010; 300(1):L56-63. · 3.52 Impact Factor