Tenascin C (TN-C) is an extracellular matrix glycoprotein whose expression is increased in several inflammatory diseases of the lung, including bronchial asthma. However, the exact function of TN-C in the pathogenesis of lung inflammation remains unclear. In the present study, we compared the degree of bronchial asthma in wild-type and TN-C-deficient (-/-) BALB/c mice. Bronchial asthma was induced by sensitization and challenge with ovalbumin. Littermates treated with saline were used as controls. Cytokines in bronchoalveolar lavage fluid and plasma were measured by enzyme immunoassays. The number of eosinophils in the lung was significantly increased in wild-type mice compared with TN-C-knockout mice. Airway hyperreactivity, NF-kappaB activation and concentrations of monocyte chemoattractant protein-1, IL-5, IL-13, metalloproteinase-9 and immunoglobulin-E in the bronchoalveolar lavage fluid were significantly decreased in ovalbumin-sensitized/challenged TN-C-knockout mice compared with their wild-type counterparts. In vitro experiments disclosed that TN-C significantly stimulates the secretion of IL-5, IL-13, IFN-gamma and immunoglobulin-E from spleen lymphocytes. These observations suggest that TN-C is involved in the pathogenesis of bronchial asthma.
The expression of aquaporin-5, the major water channel expressed in alveolar, tracheal, and upper bronchial epithelium, is significantly down-regulated during acute lung injury. In the present study, the expression of aquaporin-5 in two different mouse models of lung fibrosis was evaluated. Lung fibrosis was induced by intratracheal and by subcutaneous infusion of bleomycin. The expression of aquaporin-5 was investigated by immunohistochemical studies and by polymerase chain reaction. There were many cells with loss of aquaporin-5 immunoreactivity in type I alveolar epithelial cells in the mouse models of lung fibrosis. Immunohistochemistry of lung tissue in aquaporin-5 knockout mice revealed a fibrotic phenotype with increased deposition of extracellular collagen type I in thickened alveolar walls. Semiquantitative analysis of aquaporin-5 mRNA expression showed more abundant content of aquaporin-5 in the lung of the normal mouse compared to the mouse with lung fibrosis. The results of this study showed, for the first time, that chronic lung injury and lung fibrosis is associated with decreased protein and mRNA expression of aquaporin-5 in the lung.
Pemetrexed, a multitargeted antifolate, is eliminated by tubular secretion via human organic anion transporter 3 (hOAT3). Although proton pump inhibitors (PPIs) are frequently used in cancer patients, the drug interaction between PPIs and pemetrexed remains to be clarified. In this study, we examined the drug interaction between pemetrexed and PPIs in hOAT3-expressing cultured cells, and retrospectively analyzed the impact of PPIs on the development of hematologic toxicity in 108 patients who received pemetrexed and carboplatin treatment of nonsquamous non-small cell lung cancer for the first time between January 2011 and June 2015. We established that pemetrexed was transported via hOAT3 (K m = 68.3 6 11.1 mM). Lansoprazole, rabeprazole, pantoprazole, esomeprazole, omeprazole, and vonoprazan inhibited hOAT3-mediated uptake of pemetrexed in a concentration-dependent manner. The inhibitory effect of lansoprazole was much greater than those of other PPIs and the apparent IC 50 value of lansoprazole against pemetrexed transport via hOAT3 was 0.57 6 0.17 mM. The inhibitory type of lansoprazole was competitive. In a retrospective study, multivariate analysis revealed that coadministration of lansoprazole, but not other PPIs, with pemetrexed and carboplatin was an independent risk factor significantly contributing to the development of hematologic toxicity (odds ratio: 10.004, P = 0.005). These findings demonstrated that coadministration of lansoprazole could exacerbate the hematologic toxicity associated with pemetrexed, at least in part, by competitive inhibition of hOAT3. Our results would aid clinicians to make decisions of coadministration drugs to avoid drug interactioninduced side effects for achievement of safe and appropriate chemotherapy with pemetrexed.
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