Lawrence R, Sorrell T
Centre for Infectious Diseases and Microbiology, University of Sydney, Westmead Hospital, New South Wales, Australia.
Lancet. 1993 Aug 21;342(8869):465-9. doi: 10.1016/0140-6736(93)91594-c.
Much of the lung damage that limits the life of young adults with cystic fibrosis is due to proteases and oxygen metabolites generated by neutrophils, which are recruited into the airway by the interaction between Pseudomonas aeruginosa and pulmonary macrophages. Leukotriene B4 (LTB4) has been proposed as a local mediator of this process; its production is susceptible to specific modulation with dietary eicosapentaenoic acid (EPA). We carried out a placebo-controlled trial of EPA (2.7 g daily for 6 weeks) to assess its effects on markers of clinical state, peripheral neutrophil function, and lung inflammation in sixteen patients with cystic fibrosis colonised with P aeruginosa. EPA was well tolerated and resulted in a significant reduction in sputum volume (median change with EPA -10 mL/day, placebo 0; p = 0.015), and improvements in Schwachman score (EPA 5%, placebo 0; p = 0.034), forced expiratory volume in 1 s (EPA 0.25 L, placebo -0.1 L; p = 0.006), and vital capacity (EPA 0.6 L, placebo 0; p = 0.011). Relative chemotaxis of circulating neutrophils to LTB4 increased from a subnormal baseline of 4 (median; range 0-10) microns/30 min before treatment, to a near normal value of 11 (5-18) microns/30 min after EPA. Relative chemotaxis to LTB4 of patients taking placebo did not change: the difference in response was highly significant (p = 0.001). Specific reduction of neutrophil chemotaxis to LTB4 is a sensitive assay of chronic in-vivo exposure to LTB4. Our results suggest that LTB4 has a pathogenetic role in the lung damage of cystic fibrosis. Longer-term clinical trials of EPA are warranted in a larger number of cystic fibrosis patients.
许多限制囊性纤维化青年患者寿命的肺部损伤是由中性粒细胞产生的蛋白酶和氧代谢产物所致，这些中性粒细胞是通过铜绿假单胞菌与肺巨噬细胞之间的相互作用而被招募到气道中的。白三烯B4（LTB4）被认为是这一过程的局部介质；其产生易受膳食中二十碳五烯酸（EPA）的特异性调节。我们进行了一项EPA（每日2.7克，持续6周）的安慰剂对照试验，以评估其对16例定植有铜绿假单胞菌的囊性纤维化患者的临床状态指标、外周中性粒细胞功能和肺部炎症的影响。EPA耐受性良好，可使痰量显著减少（EPA组中位变化为-10毫升/天，安慰剂组为0；p = 0.015），Schwachman评分得到改善（EPA组为5%，安慰剂组为0；p = 0.034），1秒用力呼气量增加（EPA组为0.25升，安慰剂组为-0.1升；p = 0.006），肺活量增加（EPA组为0.6升，安慰剂组为0；p = 0.011）。循环中性粒细胞对LTB4的相对趋化性从治疗前低于正常水平的基线值4（中位值；范围0 - 10）微米/30分钟增加到EPA治疗后接近正常的11（5 - 18）微米/30分钟。服用安慰剂患者对LTB4的相对趋化性未改变：反应差异非常显著（p = 0.001）。中性粒细胞对LTB4趋化性的特异性降低是慢性体内暴露于LTB4的敏感检测方法。我们的结果表明，LTB4在囊性纤维化的肺部损伤中具有致病作用。有必要在更多囊性纤维化患者中进行EPA的长期临床试验。
