Physiology and Experimental Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
Respir Res. 2010 Nov 30;11(1):166. doi: 10.1186/1465-9921-11-166.
Among patients with cystic fibrosis (CF), females have worse pulmonary function and survival than males, primarily due to chronic lung inflammation and infection with Pseudomonas aeruginosa (P. aeruginosa). A role for gender hormones in the causation of the CF "gender gap" has been proposed. The female gender hormone 17β-estradiol (E2) plays a complex immunomodulatory role in humans and in animal models of disease, suppressing inflammation in some situations while enhancing it in others. Helper T-cells were long thought to belong exclusively to either T helper type 1 (Th1) or type 2 (Th2) lineages. However, a distinct lineage named Th17 is now recognized that is induced by interleukin (IL)-23 to produce IL-17 and other pro-inflammatory Th17 effector molecules. Recent evidence suggests a central role for the IL-23/IL-17 pathway in the pathogenesis of CF lung inflammation. We used a mouse model to test the hypothesis that E2 aggravates the CF lung inflammation that occurs in response to airway infection with P. aeruginosa by a Th17-mediated mechanism.
Exogenous E2 caused adult male CF mice with pneumonia due to a mucoid CF clinical isolate, the P. aeruginosa strain PA508 (PA508), to develop more severe manifestations of inflammation in both lung tissue and in bronchial alveolar lavage (BAL) fluid, with increased total white blood cell counts and differential and absolute cell counts of polymorphonuclear leukocytes (neutrophils). Inflammatory infiltrates and mucin production were increased on histology. Increased lung tissue mRNA levels for IL-23 and IL-17 were accompanied by elevated protein levels of Th17-associated pro-inflammatory mediators in BAL fluid. The burden of PA508 bacteria was increased in lung tissue homogenate and in BAL fluid, and there was a virtual elimination in lung tissue of mRNA for lactoferrin, an antimicrobial peptide active against P. aeruginosa in vitro.
Our data show that E2 increases the severity of PA508 pneumonia in adult CF male mice, and suggest two potential mechanisms: enhancement of Th17-regulated inflammation and suppression of innate antibacterial defences. Although this animal model does not recapitulate all aspects of human CF lung disease, our present findings argue for further investigation of the effects of E2 on inflammation and infection with P. aeruginosa in the CF lung.
在囊性纤维化 (CF) 患者中，女性的肺功能和存活率比男性差，主要是由于慢性肺部炎症和铜绿假单胞菌 (P. aeruginosa) 的感染。有人提出，性别激素在 CF“性别差距”的发生中起作用。女性性别激素 17β-雌二醇 (E2) 在人类和疾病动物模型中发挥着复杂的免疫调节作用，在某些情况下抑制炎症，而在其他情况下增强炎症。辅助性 T 细胞长期以来被认为仅属于辅助性 T 细胞 1 (Th1) 或 2 (Th2) 谱系。然而，现在已经认识到一种名为 Th17 的独特谱系，它由白细胞介素 (IL)-23 诱导产生 IL-17 和其他促炎 Th17 效应分子。最近的证据表明，IL-23/IL-17 途径在 CF 肺部炎症的发病机制中起核心作用。我们使用一种小鼠模型来检验这样一个假设，即 E2 通过 Th17 介导的机制加重 CF 肺部炎症，这种炎症是由气道感染铜绿假单胞菌引起的。
外源性 E2 导致患有肺炎的成年雄性 CF 小鼠，其肺炎由粘液化 CF 临床分离株铜绿假单胞菌菌株 PA508 (PA508) 引起，在肺部组织和支气管肺泡灌洗液 (BAL) 中表现出更严重的炎症，总白细胞计数和多形核白细胞 (中性粒细胞) 的差异和绝对计数增加。组织学上炎症浸润和粘蛋白产生增加。肺组织中 IL-23 和 IL-17 的 mRNA 水平升高，BAL 液中 Th17 相关促炎介质的蛋白水平升高。肺组织匀浆和 BAL 液中 PA508 细菌负荷增加，体外对抗铜绿假单胞菌的抗菌肽乳铁蛋白的肺组织 mRNA 几乎消除。
我们的数据表明，E2 增加了成年 CF 雄性小鼠 PA508 肺炎的严重程度，并提出了两种潜在的机制：增强 Th17 调节的炎症和抑制先天抗菌防御。尽管这种动物模型不能重现人类 CF 肺部疾病的所有方面，但我们目前的研究结果表明，需要进一步研究 E2 对 CF 肺部铜绿假单胞菌感染和感染的影响。
