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

被引:14
作者
Feldman, C
Anderson, R
Theron, A
Mokgobu, I
Cole, PJ
Wilson, R
机构
[1] Univ Witwatersrand, Sch Med, Dept Med, ZA-2193 Johannesburg, South Africa
[2] Johannesburg Hosp, Dept Med, Div Pulm, Johannesburg, South Africa
[3] Univ Pretoria, MRC, Unit Inflammat & Immun, Dept Immunol, ZA-0002 Pretoria, South Africa
[4] Univ London Sch Pharm, Host Def Unit, Natl Heart & Lung Inst, London, England
关键词
asthma; bioactive phospholipids; ciliary beat frequency; epithelial damage; ketolides; polymorphonuclear leukocytes;
D O I
10.1034/j.1399-3003.1999.13e15.x
中图分类号
R56 [呼吸系及胸部疾病];
学科分类号
摘要
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.
引用
收藏
页码:1022 / 1028
页数:7
相关论文
共 35 条
  • [1] The effect of roxithromycin on the generation of reactive oxygen species in vitro
    Akamatsu, H
    Nishijima, S
    Akamatsu, M
    Kurokawa, I
    Sasaki, H
    Asada, Y
    [J]. JOURNAL OF INTERNATIONAL MEDICAL RESEARCH, 1996, 24 (01) : 27 - 32
  • [3] Membrane-stabilizing, anti-inflammatory interactions of macrolides with human neutrophils
    Anderson, R
    Theron, AJ
    Feldman, C
    [J]. INFLAMMATION, 1996, 20 (06) : 693 - 705
  • [4] AUBIER M, 1997, EUR RESPIR REV, V7, P321
  • [5] BARNES PJ, 1988, PHARMACOL REV, V40, P49
  • [6] NEW CONCEPTS IN THE PATHOGENESIS OF BRONCHIAL HYPERRESPONSIVENESS AND ASTHMA
    BARNES, PJ
    [J]. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 1989, 83 (06) : 1013 - 1026
  • [7] BLACK PN, 1996, EUR RESPIR REV, V6, P240
  • [8] CHELTON FH, 1996, J EXP MED, V183, P2235
  • [9] Platelet activating factor revisited
    Chung, KF
    [J]. THORAX, 1997, 52 (12) : 1019 - 1020
  • [10] MUCOSAL INFLAMMATION IN ASTHMA
    DJUKANOVIC, R
    ROCHE, WR
    WILSON, JW
    BEASLEY, CRW
    TWENTYMAN, OP
    HOWARTH, PH
    HOLGATE, ST
    [J]. AMERICAN REVIEW OF RESPIRATORY DISEASE, 1990, 142 (02): : 434 - 457