To assess the manifestation and location of airway inflammation in smokers with chronic bronchitis (CB) or chronic obstructive pulmonary disease (COPD), we lavaged the airways of 12 smokers with CB and 11 smokers with COPD and coexisting CB (OCB). For comparison, the airways of 5 asymptomatic smokers (AS) and 10 healthy nonsmokers (HNS) were lavaged. In all cases, the first lavage aliquot, labeled "bronchial lavage" (BL), was processed separately from the four subsequent aliquots, which were combined and labeled "bronchoalveolar lavage" (BAL). The composition of BL and BAL fluids indicate an ongoing inflammatory process in the airways of all three groups of smokers. CB patients with obstruction had significantly lower concentrations of inflammatory cells in the BL and BAL fluids compared with subjects with nonobstructed CB. Furthermore, airway obstruction, indicated by a reduced FEV1, was significantly correlated with the concentrations of glutathione (p < 0.001), myeloperoxidase (MPO; p < 0.01), and eosinophil cationic protein (ECP; p < 0.01) in BAL fluids. Taken together, these findings suggest that the manifestations of inflammation present in the airways of smokers with CB are different in those who have developed obstruction compared with those who have not.

A high-throughput method for rapid screening of in vitro drug-brain homogenate binding is presented. The method is based on a straightforward sample pooling approach combining equilibrium dialysis with liquid chromatography mass spectrometry (LCMS). A strong correlation of fraction unbound in brain (fu) between single compound measurements and 25-pooled compounds (R2 = 0.906) was obtained for a selection of structurally diverse CNS compounds with a wide range of fractions unbound. Effects of brain homogenate dilution and dialysis time were investigated. To the best of our knowledge, it was the first time that we have demonstrated consistent fraction unbound in mouse and rat brain homogenate, revealing the drug-tissue partitioning mechanism predominated by hydrophobic interaction. On the basis of this finding, a generic approach to estimate drug binding to various tissues is proposed. A robust and interpretable QSAR for fu prediction is also presented by statistical modeling.

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The total concentration of the atherogenic aminothiol acid homocysteine in plasma of healthy volunteers was decreased after oral administration of N-acetylcysteine (NAC), whereas the reduced and free (non-protein bound) fractions of homocysteine were increased. The decrease of the total fraction varied between 20 and 50% and was dose-related. Cysteinylglycine was also decreased after the administration of NAC, whereas cysteine did not change. Administration of high amounts of NAC probably displaces homocysteine and cysteinylglycine from their protein binding sites by disulfide interchange reactions. This leads to the formation of mixed low molecular-weight cysteine and NAC disulfides with high renal clearance and possibly also increased metabolic bio-availability, thereby eliminating homocysteine and cysteinylglycine from plasma. Since only a small amount of additional urinary homocysteine was recovered it is likely that this aminothiol acid is taken up by the tubular cells and further metabolized.

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Cigarette smoking results in variable degrees of inflammation in the lower respiratory tract. Furthermore, smoking produces oxidant-mediated changes in the lung, important to the pathogenesis of emphysema. Since glutathione can neutralize reactive oxygen species and prevent peroxidation of unsaturated lipids, it may constitute an important component of the lung's defense against oxidant and inflammatory injury. In the present study, broncholaveolar lavage (BAL) was performed in 27 smokers, and the concentrations of total glutathione as well as the cellular and humoral markers of inflammatory activity were studied. There were significant correlations between total glutathione and neutrophils; two neutrophil granule components, myeloperoxidase and elastase; and chemotactic activity for neutrophils. Moreover, the total glutathione correlated with the eosinophil cationic protein (ECP), a granule constituent of the eosinophil, with two locally produced antiproteases, secretory leukocyte protease inhibitor (SLPI) and antichymotrypsin (ACHY), but not with an alpha 1-protease inhibitor and albumin. These data suggest that the total glutathione levels in BAL fluid may reflect a degree of oxidative and inflammatory stress caused by cigarette smoke, and they are therefore likely to contribute to the protection against this stress.

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