{"title":"气道生物膜:对呼吸道感染的发病机制和治疗的意义。","authors":"Hiroyuki Kobayashi","doi":"10.2165/00151829-200504040-00003","DOIUrl":null,"url":null,"abstract":"<p><p>The differentiation of bacterial biofilms in the airway environment, the pathogenesis of airway biofilm, and possible therapeutic methods are discussed. Biofilm diseases that characteristically involve the respiratory system include cystic fibrosis (CF), diffuse panbronchiolitis (DPB), and bronchiectasia with Pseudomonas aeruginosa (P. aeruginosa) infection. There is evidence to suggest that almost all strains of P. aeruginosa have the genetic capacity to synthesize alginate, a main matrix of biofilms, when ecological conditions are unfavorable for their survival. The bacteria inside the mature biofilm show increased resistance to both antibacterials and phagocytic cells, express fewer virulence factors because of their stationary state of growth, and are less stimulatory to the mucosa because of the 'sandwich binding'. These factors facilitate both the colonization of bacteria and their extended survival even under unfavorable conditions. Since the biofilm limits colonization to a latent form, the clinical symptoms in this situation are unremarkable. However, the clinical progression of both CF and DPB proceeds in two characteristic directions. The first is an acute exacerbation caused by planktonic bacteria that have germinated from the biofilm. The second is a slow progression of disease that is induced by harmful immune reactions. The harmful reactions are mediated by alginate, which induces antigen antibody reactions around the airways, as well as formation of circulating immune complexes that are deposited on lung tissue. Furthermore, the highest titer of bacterial permeability increasing anti-neutrophil cytoplasmic autoantibodies (BPI-ANCA) is observed in association with highly impaired pulmonary function in patients with CF and DPB, as well as in patients with a lengthy period of colonization with P. aeruginosa. BPI-ANCA subsequently makes chronic airway infection even more intractable. The long-term use of 14- or 15-ring membered macrolides results in a favorable clinical outcome for patients with DPB and in some patients with CF. In the last 10 years, an increasing number of studies have reported secondary actions of macrolides that include effects on both airway and phagocytic cells, as well as an anti-biofilm activity. The 14- or 15-ring membered macrolides inhibit: (i) the alginate production from P. aeruginosa; (ii) the antibody reaction to alginate, which leads to a decrease in the immune complex formation; and (iii) the activation of the autoinducer 3-O-C12-homoserine lactone and subsequent expression of lasI and rhlI in quorum sensing systems in P. aeruginosa. These anti-biofilm actions of macrolides may represent their basic mechanisms of action on airway biofilm disease.</p>","PeriodicalId":87162,"journal":{"name":"Treatments in respiratory medicine","volume":"4 4","pages":"241-53"},"PeriodicalIF":0.0000,"publicationDate":"2005-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2165/00151829-200504040-00003","citationCount":"26","resultStr":"{\"title\":\"Airway biofilms: implications for pathogenesis and therapy of respiratory tract infections.\",\"authors\":\"Hiroyuki Kobayashi\",\"doi\":\"10.2165/00151829-200504040-00003\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The differentiation of bacterial biofilms in the airway environment, the pathogenesis of airway biofilm, and possible therapeutic methods are discussed. Biofilm diseases that characteristically involve the respiratory system include cystic fibrosis (CF), diffuse panbronchiolitis (DPB), and bronchiectasia with Pseudomonas aeruginosa (P. aeruginosa) infection. There is evidence to suggest that almost all strains of P. aeruginosa have the genetic capacity to synthesize alginate, a main matrix of biofilms, when ecological conditions are unfavorable for their survival. The bacteria inside the mature biofilm show increased resistance to both antibacterials and phagocytic cells, express fewer virulence factors because of their stationary state of growth, and are less stimulatory to the mucosa because of the 'sandwich binding'. These factors facilitate both the colonization of bacteria and their extended survival even under unfavorable conditions. Since the biofilm limits colonization to a latent form, the clinical symptoms in this situation are unremarkable. However, the clinical progression of both CF and DPB proceeds in two characteristic directions. The first is an acute exacerbation caused by planktonic bacteria that have germinated from the biofilm. The second is a slow progression of disease that is induced by harmful immune reactions. The harmful reactions are mediated by alginate, which induces antigen antibody reactions around the airways, as well as formation of circulating immune complexes that are deposited on lung tissue. Furthermore, the highest titer of bacterial permeability increasing anti-neutrophil cytoplasmic autoantibodies (BPI-ANCA) is observed in association with highly impaired pulmonary function in patients with CF and DPB, as well as in patients with a lengthy period of colonization with P. aeruginosa. BPI-ANCA subsequently makes chronic airway infection even more intractable. The long-term use of 14- or 15-ring membered macrolides results in a favorable clinical outcome for patients with DPB and in some patients with CF. In the last 10 years, an increasing number of studies have reported secondary actions of macrolides that include effects on both airway and phagocytic cells, as well as an anti-biofilm activity. The 14- or 15-ring membered macrolides inhibit: (i) the alginate production from P. aeruginosa; (ii) the antibody reaction to alginate, which leads to a decrease in the immune complex formation; and (iii) the activation of the autoinducer 3-O-C12-homoserine lactone and subsequent expression of lasI and rhlI in quorum sensing systems in P. aeruginosa. 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引用次数: 26
摘要
本文讨论了气道环境中细菌生物膜的分化、气道生物膜的发病机制以及可能的治疗方法。典型的涉及呼吸系统的生物膜疾病包括囊性纤维化(CF)、弥漫性泛细支气管炎(DPB)和铜绿假单胞菌(P. aeruginosa)感染的支气管扩张。有证据表明,几乎所有的P. aeruginosa菌株在生态条件不利时都具有合成海藻酸盐(生物膜的主要基质)的遗传能力。成熟生物膜内的细菌对抗菌药和吞噬细胞的抵抗力增强,由于其生长的静止状态而表达的毒力因子较少,并且由于“三明治结合”而对粘膜的刺激较少。这些因素既有利于细菌的定植,也有利于细菌在不利条件下的延长生存。由于生物膜将定植限制在潜伏形式,这种情况下的临床症状并不明显。然而,CF和DPB的临床进展都有两个特征方向。第一种是由从生物膜中萌发的浮游细菌引起的急性恶化。第二种是由有害免疫反应引起的疾病缓慢发展。有害反应是由海藻酸盐介导的,海藻酸盐诱导气道周围的抗原抗体反应,并形成循环免疫复合物,沉积在肺组织上。此外,在CF和DPB患者以及铜绿假单胞菌长时间定植的患者中,观察到细菌渗透性增加的抗中性粒细胞胞质自身抗体(BPI-ANCA)滴度最高的与肺功能高度受损相关。BPI-ANCA随后使慢性气道感染更加难治。长期使用14环或15环成员大环内酯类药物对DPB患者和一些CF患者有良好的临床结果。在过去的10年里,越来越多的研究报道了大环内酯类药物的继发性作用,包括对气道和吞噬细胞的影响,以及抗生物膜活性。14环或15环环内酯类抑制:(i)铜绿假单胞菌海藻酸盐的生产;(ii)对海藻酸盐的抗体反应,导致免疫复合物的形成减少;(iii)铜绿假单胞菌群体感应系统中自诱导剂3- o - c12 -同丝氨酸内酯的激活以及随后lasI和rhlI的表达。大环内酯类药物的这些抗生物膜作用可能代表了其作用于气道生物膜疾病的基本机制。
Airway biofilms: implications for pathogenesis and therapy of respiratory tract infections.
The differentiation of bacterial biofilms in the airway environment, the pathogenesis of airway biofilm, and possible therapeutic methods are discussed. Biofilm diseases that characteristically involve the respiratory system include cystic fibrosis (CF), diffuse panbronchiolitis (DPB), and bronchiectasia with Pseudomonas aeruginosa (P. aeruginosa) infection. There is evidence to suggest that almost all strains of P. aeruginosa have the genetic capacity to synthesize alginate, a main matrix of biofilms, when ecological conditions are unfavorable for their survival. The bacteria inside the mature biofilm show increased resistance to both antibacterials and phagocytic cells, express fewer virulence factors because of their stationary state of growth, and are less stimulatory to the mucosa because of the 'sandwich binding'. These factors facilitate both the colonization of bacteria and their extended survival even under unfavorable conditions. Since the biofilm limits colonization to a latent form, the clinical symptoms in this situation are unremarkable. However, the clinical progression of both CF and DPB proceeds in two characteristic directions. The first is an acute exacerbation caused by planktonic bacteria that have germinated from the biofilm. The second is a slow progression of disease that is induced by harmful immune reactions. The harmful reactions are mediated by alginate, which induces antigen antibody reactions around the airways, as well as formation of circulating immune complexes that are deposited on lung tissue. Furthermore, the highest titer of bacterial permeability increasing anti-neutrophil cytoplasmic autoantibodies (BPI-ANCA) is observed in association with highly impaired pulmonary function in patients with CF and DPB, as well as in patients with a lengthy period of colonization with P. aeruginosa. BPI-ANCA subsequently makes chronic airway infection even more intractable. The long-term use of 14- or 15-ring membered macrolides results in a favorable clinical outcome for patients with DPB and in some patients with CF. In the last 10 years, an increasing number of studies have reported secondary actions of macrolides that include effects on both airway and phagocytic cells, as well as an anti-biofilm activity. The 14- or 15-ring membered macrolides inhibit: (i) the alginate production from P. aeruginosa; (ii) the antibody reaction to alginate, which leads to a decrease in the immune complex formation; and (iii) the activation of the autoinducer 3-O-C12-homoserine lactone and subsequent expression of lasI and rhlI in quorum sensing systems in P. aeruginosa. These anti-biofilm actions of macrolides may represent their basic mechanisms of action on airway biofilm disease.