Cole Alexander M, Waring Alan J
Department of Medicine, Division of Pulmonary and Critical Care Medicine,UCLA School of Medicine, Los Angeles, California 90095, USA.
Am J Respir Med. 2002;1(4):249-59. doi: 10.1007/BF03256616.
Innate host defence, involving both cellular and humoral mediators, is a prominent function of the human airways. Cellular mediators of innate immunity include dendritic cells, natural killer cells, cytotoxic T cells, macrophages and neutrophils, while humoral mediators of innate immunity consist of components of the epithelial lining fluid (ELF) covering the airways. Microbicidal substances in the ELF can selectively disrupt bacterial cell walls and membranes, sequester microbial nutrients or act as decoys for microbial attachment. Antimicrobial components of airway secretions include lysozymes, lactoferrin, secretory leukoprotease inhibitor, defensins and cathelicidins. Defensins are the most widely studied family of antimicrobial peptides present in airway fluid. Humans produce at least 10 different defensin molecules, six alpha-defensins and four beta-defensins similar in structure and function. Direct evidence that defensins have central roles in host defense has only recently become available. Some defensins and defensin-like molecules could serve as templates for the development of pulmonary pharmaceuticals. As potential therapeutics, they possess several desirable properties, including the ability to kill a broad spectrum of micro-organisms while permitting little development of microbial resistance. Many peptides can also neutralize effects of lipopolysaccharide on macrophages and other host defense cells and decrease the release of proinflammatory cytokines thereby giving protection against septic shock. Protegrin-1 is a minidefensin isolated from pig leukocytes and has proved to be an attractive template for large-scale development of antibacterials. One such protegrin analog, iseganan is in phase III clinical trials for the treatment of oral mucositis secondary to systemic chemotherapy. Other prospective uses of iseganan include control of respiratory pathogens in patients with cystic fibrosis and reduction of oral bacteria to prevent ventilator-associated pneumonia. However, in order to advance the production and clinical testing of peptide-based therapeutics, technical hurdles of synthesizing large quantities of complexly folded peptides must be first overcome. Strategies to develop potent peptide-based microbicides are promising in the struggle against increasingly resistant pathogens.
涉及细胞和体液介质的先天性宿主防御是人类气道的一项重要功能。先天性免疫的细胞介质包括树突状细胞、自然杀伤细胞、细胞毒性T细胞、巨噬细胞和中性粒细胞，而先天性免疫的体液介质则由覆盖气道的上皮衬液（ELF）成分组成。ELF中的杀菌物质可选择性破坏细菌细胞壁和细胞膜、隔离微生物营养物质或作为微生物附着的诱饵。气道分泌物的抗菌成分包括溶菌酶、乳铁蛋白、分泌型白细胞蛋白酶抑制剂、防御素和cathelicidin。防御素是气道液中研究最广泛的抗菌肽家族。人类至少产生10种不同的防御素分子，6种α-防御素和4种β-防御素，它们在结构和功能上相似。直到最近才有直接证据表明防御素在宿主防御中起核心作用。一些防御素和防御素样分子可作为肺部药物开发的模板。作为潜在的治疗剂，它们具有几个理想的特性，包括能够杀死广谱微生物，同时几乎不会产生微生物耐药性。许多肽还可以中和脂多糖对巨噬细胞和其他宿主防御细胞的作用，并减少促炎细胞因子的释放，从而预防败血症性休克。Protegrin-1是一种从小猪白细胞中分离出的微型防御素，已被证明是大规模开发抗菌药物的一个有吸引力的模板。一种这样的protegrin类似物iseganan正在进行III期临床试验，用于治疗全身化疗继发的口腔粘膜炎。iseganan的其他潜在用途包括控制囊性纤维化患者的呼吸道病原体以及减少口腔细菌以预防呼吸机相关性肺炎。然而，为了推进基于肽的治疗剂的生产和临床试验，必须首先克服合成大量复杂折叠肽的技术障碍。开发有效的基于肽的杀菌剂的策略在对抗日益耐药的病原体的斗争中很有前景。
