The effects of ketolides on bioactive phospholipid-induced injury to humanrespiratory 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 (P L), platelet-activating factor (PAF), lyso-PAF, and lysophosphatidylcholine (LPC) on the ciliary beat frequency and structural integrity of human cili ated respiratory epithelium in vitro was investigated, in the presence or a bsence 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-transis tor technique, while superoxide generation by activated human PMNL and memb rane-stabilizing activity were measured by lucigenin-enhanced chemiluminesc ence 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 epithel ial strips with the ketolides, in particular HMR 3004, caused dose-related attenuation of these direct adverse effects of the PL on ciliated epitheliu m, apparently by a membrane-stabilizing mechanism. When epithelial strips w ere 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 al so observed, which were mediated predominantly by neutrophil-derived oxidan ts. 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 d irect and polymorphonuclear leukocyte-mediated injurious effects of phospho lipids on human ciliated epithelium and may have beneficial effects in infl ammatory disorders of the airways, such as asthma, chronic bronchitis, diff use panbronchiolitis and bronchiectasis.