The effects of ketolides on bioactive phospholipid-induced injury to human respiratory epithelium in vitro

The potential of the novel ketolide antimicrobial agents, HMR 3004 and HMR 3647, to antagonize the injurious effects of the bioactive phospholipids (PL), platelet-activating factor (PAF), lyso-PAF, and lysophosphatidylcholine (LPC) on the ciliary beat frequency and structural integrity of human ciliated respiratory epithelium in vitro was investigated, in the presence or absence of polymorphonuclear leukocytes (PMNL). The ciliary beat frequency of human nasal respiratory epithelium, obtained by nasal brushing of healthy volunteers, was measured using a photo-transistor technique, while superoxide generation by activated human PMNL and membrane-stabilizing activity were measured by lucigenin-enhanced chemiluminescence and haemolytic procedures, respectively. All three PL, at concentrations of 2.5 mu g.mL(-1), caused significant (p<0.005) ciliary slowing and epithelial damage, while treatment of the epithelial strips with the ketolides, in particular HMR 3004, caused dose-related attenuation of these direct adverse effects of the PL on ciliated epithelium, apparently by a membrane-stabilizing mechanism. When epithelial strips were exposed to the combination of PMNL (1 x 10(6) cells.mL(-1)) and PAF (1 mu g.mL(-1)), significant ciliary dysfunction and epithelial damage were also observed, which were mediated predominantly by neutrophil-derived oxidants. These injurious effects of PAF were antagonized by preincubation of the epithelial strips or the PMNL with HMR 3004 (10 mu g.mL(-1)). The ketolide antimicrobial agents, in particular HMR 3004, antagonize the direct and polymorphonuclear leukocyte-mediated injurious effects of phospholipids on human ciliated epithelium and may have beneficial effects in inflammatory disorders of the airways, such as asthma, chronic bronchitis, diffuse panbronchiolitis and bronchiectasis.