This study aimed to identify predictive factors associated with prognostic benefits of gefitinib. A total of 221 Japanese patients who received gefitinib (250 mg day À1 ) were examined retrospectively and potential predictive factors analysed. Overall response rate (ORR) was 24.4% and median survival time (MST) was 8.0 months. In a log-rank test, survival was significantly better in females, patients with adenocarcinoma, never-smokers, favourable performance status (PS) and patients with epidermal growth factor receptor (EGFR) mutation. The lower the smoking exposure (Brinkman Index (BI) ¼ cigarettes per day  years smoked), the better the MST (BI 0: 14.5 months, BI o500: 9.5 months, BI 500 to o1000: 6.9 months, BI X1000: 4.0 months). Positive-EGFR mutation status and PS 0 -1 were independent predictors of favourable prognosis by multivariate analysis. Prognosis was significantly different according to EGFR mutation status (with the same smoking status), but not according to smoking status (with the same EGFR mutation status). EGFR mutation status is the most important independent predictor of survival benefit with gefitinib treatment. Although differences in prognosis were observed according to relative smoking status and smoking exposure, the results suggested that smoking is not a direct predictor of prognosis, yet is a surrogate marker of EGFR mutation status.

Inhalation of urokinase-type plasminogen activator reduces airway remodeling in a murine asthma model. Am J Physiol Lung Cell Mol Physiol 296: L337-L346, 2009. First published December 19, 2008 doi:10.1152/ajplung.90434.2008.-The airway remodeling that occurs in asthma is characterized by an excess of extracellular matrix deposition in the submucosa, hyperplasia/hypertrophy of smooth muscle, goblet cell metaplasia, and accumulation of fibroblasts/myofibroblasts. The urokinase-type plasminogen activator (uPA)/plasmin system participates in pericellular proteolysis and is capable of directly degrading matrix components, activating latent proteinases, and activating growth factors. In a mouse ovalbumin (OVA) asthma model, we increased plasminogen activator activity in the lung by administering exogenous uPA or by using mice genetically deficient in the uPA inhibitor plasminogen activator inhibitor-1 (PAI-1) to assess the role of this system in asthma pathogenesis. After intraperitoneal OVA sensitization, mice inhaled OVA plus uPA (500 IU/ mouse) or saline by ultrasonic nebulization for 3 wk. When studied 24 h after the final exposure, the groups with upregulated plasmin activity had significantly reduced subepithelial fibrosis within the airway walls and had decreased airway hyperresponsiveness (AHR) to methacholine. Morphometric analysis showed that subepithelial wall thickening of the bronchi (subepithelial area ratio) was also reduced, as were collagen and ␣-smooth muscle actin. Upregulation of plasmin activity also increased the level of hepatocyte growth factor activity in bronchoalveolar lavage fluid, whereas the release of transforming growth factor-␤ was decreased. The administration of uPA 1 wk after the last OVA inhalation also significantly reduced lung hydroxyproline content and AHR. These results show that enhancing uPA/ plasmin activity lessens the airway remodeling in a murine asthma model.

No abstract

Asthma is a chronic inflammatory airway disease characterized by airway hyperreactivity, increased mucus production, and reversible airway contraction. Asthma is a complex genetic trait caused by environmental factors in genetically predisposed individuals. The transportation of maternal antigen-specific IgG via amniotic fluid, placenta and breast milk plays an important role in passive immunity. First, to examine whether maternal passive immunity by the transportation of antigen-specific IgG via FcRn regulates allergic airway inflammation, ovalbumin-immunized FcRn+/− female mice were bred with FcRn−/− male mice to evaluate the degree of ovalbumin-induced allergic airway inflammation of FcRn−/− offspring. Maternal passive immunity regulated allergic airway inflammation in an FcRn-dependent manner. Second, to examine the role of maternal antigen-specific IgG1 injection into mothers, we intravenously injected ovalbumin-specific IgG1 into wild-type or FcRn+/− mice immediately after they gave birth. The offspring were sensitized and challenged with ovalbumin. Antigen-specific IgG1 administered to lactating mice reduced allergic airway inflammation in their offspring in an FcRn-dependent manner. Last, to exclude the factor of maternal passive immunity other than ovalbumin-specific IgG1, we administered ovalbumin-specific IgG1 orally to offspring after birth. Oral administration of ovalbu-min-specific IgG1 to offspring during the lactating period prevented the development of allergic airway inflammation in an FcRn-dependent manner. These data show that the transfer of maternal antigen-specific IgG regulates the development of allergic airway inflammation early in life in an FcRn-dependent manner.

Our previous report showed that inhibition of sphingosine kinase (SphK) ameliorates eosinophilic inflammation and mucin production in a mouse asthmatic model. To clarify the role of SphK in airway mucin production, we utilized the mouse asthmatic model and found that both SphK and MUC5AC expression were increased and co-localized in airway epithelium. Next we cultured normal human bronchial epithelial cells in an air-liquid interface and treated with IL-13 to induce their differentiation into goblet cells. We found that SphK1 and MUC5AC expression was increased by IL-13 treatment at both protein and mRNA levels, whereas SphK2 expression was not changed. N,N-dimethylsphingosine (DMS), a potent SphK inhibitor, decreased MUC5AC expression up-regulated by IL-13 treatment. Furthermore, DMS inhibited IL-13-induced ERK1/2 phosphorylation but neither p38 MAPK nor STAT6 phosphorylation. These results suggest that SphK1 is involved in MUC5AC production induced by IL-13 upstream of ERK1/2 phosphorylation, and independent of STAT6 phosphorylation.

Airway remodeling is one of the most important features of bronchial asthma. However, there are few studies that have used repeated antigen exposure in murine models. We designed a murine chronic antigen exposure model necessary for studying airway remodeling. Two different strains of mice, BALB/c mice and C57BL/6 mice, were sensitized and challenged for 3-7 weeks with ovalbumin (OVA). Bronchoalveolar lavage (BAL) and histology study were conducted in each phase. Morphometry was performed, and the epithelial area ratio (Ae ratio) and subepithelial area ratio (As ratio) were calculated. The Ae ratio and As ratio of BALB/c mice were significantly increased in sensitized mice compared with non-sensitized mice at 3 and 5 weeks, but not at 7 weeks. In C57BL/6 mice, the Ae ratio showed no significant changes, whereas the As ratio maintained high from 3 to 7 weeks. This thickening of the subepithelial layer consisted of collagen fibers with elastica van-Gieson (EVG) stain. Lymphocytes of the BAL showed a significant increase at 3 and 7 weeks in C57BL/6 mice, but not in BALB/c mice. A murine chronic OVA exposure model in C57BL/6 mice revealed subepithelial layer thickening consisting of collagen fibers and increased lymphocytes until 7 weeks. C57BL/6 mice are useful to elucidate the mechanism of airway remodeling.

Background: Some patients develop asthmatic symptoms such as wheezing and dyspnea during the course of cough variant asthma (CVA), which are considered precursors of classical asthma. Objectives: To identify the characteristics of such patients, we investigated the nature of CVA patients with or without developing bronchial asthma in the longitudinal study. Methods: In 28 CVA patients whom we could observe over 5 years, duration of coughing, physical examination findings, pulmonary function and bronchial hyperresponsiveness to inhaled methacholine were retrospectively assessed. Results: Of these patients with CVA, 10 developed the asthmatic symptoms of wheezing and dyspnea (precursors of classical asthma) over 5 years. All these 10 patients showed marked bronchial hyperresponsiveness; however, there were no significant differences in the bronchial responsiveness to methacholine between patients with precursors of classical asthma and pure CVA patients who did not wheeze. The duration of coughing had a significant relationship with precursors of classical asthma. Seven patients with precursors of classical asthma developed wheezing in the first year and 1 patient each in the second, third and fourth year. Conclusions: These findings of a 5-year observation suggest that longer duration of coughing may be an important factor that develops precursors of classical asthma in patients with CVA.

We report the case of a 70-year-old Japanese male diagnosed with advanced lung adenocarcinoma harboring the echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene. As soon as crizotinib was administered, tumor shrank immediately. On Day 25, he developed interstitial lung disease. Bronchoalveolar lavage fluid analysis demonstrated elevated lymphocytes fractionation. A drug lymphocyte stimulating test for crizotinib with the bronchoalveolar lavage lymphocytes was negative. Crizotinib administration was discontinued, but a life-threatening flare of tumor growth occurred. Since there was no alternative treatment for the lung cancer, we restarted crizotinib in combination with prednisolone. The patient experienced neither disease progression nor recurrence of interstitial lung disease at 6 months. In cases in which no alternate treatment is known, crizotinib retreatment combined with steroid therapy after crizotinib-induced interstitial lung disease could be considered after a careful consideration of the potential risks and benefits.