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Background: BRP-39/YKL-40 is a chitinase-like protein that plays a critical role in IL-13-induced inflammation. It correlates positively with asthma severity and airway remodeling ( 1 ) via binding to IL-13 receptor α2 chain (IL-13Rα2). Because the relationship of IL-13Rα2 to human asthma has never been evaluated previously, we sought to determine the relationship between IL-13Rα2, YKL-40, and asthma., Methods: We evaluated 112 patients (69% women) with a mean age of 46.7 years. Subjects completed an asthma phenotyping protocol that included analysis of sputum gene expression by Affymetrix 1.0 ST gene array (Affymetrix, Santa Clara, CA) and YKL-40 protein levels., Measurements and Main Results: IL-13Rα2 gene expression was readily detectable in the sputum and correlated negatively with prebronchodilator (BD) FEV1 (rs = -0.282, P < 0.01), post-BD FEV1 (rs = -0.268, P < 0.01), pre-BD FEV1/FVC ratio (rs = -0.228, P < 0.05), and post-BD FEV1/FVC ratio (rs = -0.242, P < 0.01). IL-13Rα2 gene expression correlated positively with gene expression of IL-13 (rs = 0.484, P < 0.001), IL-5 (rs = 0.237, P < 0.05), and IL-8 (rs = 0.218, P < 0.05). Regression analysis showed that the post-BD FEV1/FVC ratio is significantly associated with IL-13Rα2 expression and CHI3L1 expression in sputum after controlling for IL-4, IL-5, IL-13, and transforming growth factor-β1 gene expression (all P < 0.01). Sputum YKL-40 gene expression positively correlated with IL-8 expression (rs = 0.357, P < 0.001) and negatively correlated with pre- and post-BD FEV1/FVC ratios (rs = -0.299, P < 0.001 and rs = -0.305, P < 0.01, respectively). Sputum and serum YKL-40 protein levels were not associated with IL-13Rα2 expression., Conclusions: This analysis demonstrates that IL-13Rα2 is associated with reduced lung function, helper T-cell type 2 gene expression, and airflow obstruction in the airway of individuals with asthma, which might in turn be driven by airway remodeling. Future studies will be required to define the proinflammatory and remodeling effects of this receptor that up to now has been considered solely a modulator of IL-13-induced inflammation.

Unlabelled: The purpose of this study was to investigate the effect of gimeracil (CDHP), a reversible dihydropyrimidine dehydrogenase (DPD) inhibitor, on the pharmacokinetics of 5-fluorouracil (5-FU) and other related metabolites by comparing the pharmacokinetic (PK) profile of S-1 (tegafur [FT] + CDHP + oteracil potassium [Oxo]) to that of FT alone., Patients and Methods: Patients with advanced solid tumors received single oral doses of S-1 (50 mg) and FT (800 mg) on days 1 and 8 in a randomized crossover fashion. Plasma samples were collected on days 1, 2, 3, 8, 9 and 10. Single-dose PK parameters were determined for FT, 5-FU and α-fluoro-β-alanine (FBAL). Following the single-dose crossover period, patients entered an extension phase and received treatment with S-1 b.i.d. for 14 days followed by a 7-day rest, repeated every 3 weeks., Results: A total of 12 patients were enrolled; median age was 59 years and mean body surface area was 1.94 m(2). Following S-1 administration, 5-FU exposure was significantly greater (approximately 3-fold) compared to FT alone (p ≤ 0.0007 for AUC0-inf, AUC0-last, and C(max) of 5-FU) despite the 16-fold higher dose of FT administered alone compared to S-1, while plasma concentrations of FT and FBAL were significantly lower with S-1 (p < 0.0001 for all comparisons). Following both single- and multiple-dose administration of S-1, the average maximum DPD inhibition was observed at 4 h post-dose. The extent of inhibition was similar following single and multiple dosing. Following single- and multiple-dose administration of S-1, plasma concentrations of uracil returned to baseline levels within approximately 48 h of dosing, indicating reversibility of DPD inhibition by CDHP., Conclusion: Despite the differences in the FT dose administered, exposure to 5-FU was significantly greater following S-1 administration compared to FT administration. Conversely, exposure to FT and FBAL were significantly less following S-1 administration compared to FT administration. Thus, the DPD inhibitory action of CDHP contributes to a decrease in 5-FU catabolism and to significantly higher blood levels of 5-FU compared to FT alone.