Hypoxia, receptor for advanced glycation end products, and cystic fibrosis: a pathway to chronic inflammation?
Hypoxia, receptor for advanced glycation end products, and cystic fibrosis: a pathway to chronic inflammation?
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缺氧、晚期糖基化终产物受体和囊性纤维化：慢性炎症的途径？
DOI：
10.1164/rccm.201310-1908ed
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发表时间：
2013
影响因子：
24.7
通讯作者：
McGuire,JohnK
中科院分区：
文献类型：
--
作者：
McGuire,JohnK
囊性纤维化（CF）肺病的病理生理学是多因素的。CF跨膜电导调节因子（CFTR）的突变导致肺上皮离子和液体转运缺陷，导致粘液分泌物粘稠。粘膜纤毛清除功能受损以及分泌物和物质（包括病原体）滞留在空气中，导致气道阻塞、感染和慢性炎症的循环（1）。因此，治疗通常通过粘液溶解和气道清除策略、抗生素方案和/或抗氧化剂治疗来靶向这些病理机制中的一种或多种，并且最近，通过CFTR“校正剂”如ivacaftor（Kalydeco）来靶向氯离子通道缺陷本身（2）。患者队列的遗传研究已经确定了几种导致CF肺病表型的修饰基因（3）。这些基因发现可能揭示CF病理生理学的新见解，并确定新的治疗靶点。这些基因中有AGER，它编码晚期糖基化终末产物（AGEs）的受体，AGER是一种损伤相关分子模式的传感器。在肺中高度表达，可调节肺损伤、哮喘和慢性阻塞性肺疾病中的病理性炎症（4，5）。在本期杂志中，Iannitti和他的同事（pp. 1338-1350）评价了在CF转基因小鼠和培养的人CF支气管上皮细胞的急性肺感染的小鼠模型中，低氧血症在CF肺部炎症中的潜在作用以及低氧血症和缺氧之间的相互作用（6）。然而，低氧血症的常见临床参数，脉搏血氧饱和度低或动脉血气分析PaO 2低，并没有揭示细胞水平缺氧的重要后果。低组织氧水平诱导低氧诱导因子（HIF）的表达，HIF是一种由氧调节的HIF 1-a和组成型表达的HIF-1b组成的核蛋白（7）。HIF 1-a是连续合成的，但在常氧条件下是泛素化和蛋白酶体降解的目标。相反，在缺氧条件下，HIF 1-a稳定，与HIF 1-B二聚化，结合缺氧反应元件的共激活因子，并调节缺氧调节基因的转录（8）。在生理上，HIF在发育、血管发生、伤口愈合和干细胞维持中是重要的。然而，HIF反应也与病理状况相关，如肿瘤发生、肺动脉高压和失调的炎症（7）。作者使用急性烟曲霉感染模型以及铜绿假单胞菌琼脂糖珠肺部感染模型中关键发现的验证性研究，发现CF小鼠（双转基因肠道校正Cftr J/J小鼠[9]）表达的Ager mRNA和Agr蛋白水平以及Agr配体S100 B水平高于野生型C57 BL/6小鼠（6）。令人感兴趣的是，β-淀粉样蛋白同种型的表达模式也不同，CF小鼠显示出显著较低水平的可溶性β-淀粉样蛋白（saponin）同种型，其可能作为β-淀粉样蛋白配体诱饵受体发挥作用以抑制β-淀粉样蛋白激活（10）。尽管CF患者通常不受急性曲霉菌肺炎的影响，CF小鼠铜绿假单胞菌模型也不重现人类CF的慢性感染，但这些发现提出了关于肺中CFTR功能缺陷如何与正常肺不同地调节肺功能的有趣问题。
The pathophysiology of cystic fibrosis (CF) lung disease is multifactorial. Mutations in the CF transmembrane conductance regulator (CFTR) lead to defective lung epithelial ion and fluid transport, resulting in thick mucous secretions. Impaired mucociliary clearance and the trapping of secretions and material in the airspaces (including pathogens) contribute to a cycle of airway obstruction, infection, and chronic inflammation (1). Thus, treatment generally targets one or more of these pathological mechanisms with mucolytic and airway clearance strategies, antibiotic regimens, and/or antiinflammatory therapies and, more recently, targets the chloride channel defect itself with CFTR “correctors” such as ivacaftor (Kalydeco)(2). Genetic studies of patient cohorts have identified several modifier genes that contribute to CF lung disease phenotypes (3). These genetic discoveries may reveal new insights into CF pathophysiology and identify new therapeutic targets. Among these genes is AGER, which codes for the receptor for advanced glycation end products (RAGE), a sensor of damageassociated molecular patterns. RAGE is highly expressed in the lung and may regulate pathologic inflammation in lung injury, asthma, and chronic obstructive pulmonary disease (4, 5). In this issue of the Journal, Iannitti and colleagues (pp. 1338–1350) evaluate a potential role for RAGE in CF lung inflammation and an interaction between RAGE and hypoxia in mouse models of acute lung infection in CF transgenic mice and in cultured human CF bronchial epithelial cells (6).Though not a typically a factor in early CF lung disease, hypoxemia is common in advanced disease. However, the usual clinical parameters of hypoxemia, low oxygen saturations on pulse oximetry or low PaO2 on arterial blood gas analysis, do not reveal the important consequences of hypoxia at the cellular level. Low tissue oxygen levels induce expression of hypoxia-inducible factor (HIF), a nucleoprotein consisting of the oxygen-regulated HIF1-a and the constitutively expressed HIF-1b (7). HIF1-a is continuously synthesized, but under normoxic conditions is targeted for ubiquitination and proteasomal degradation. In contrast, under hypoxic conditions, HIF1-a is stabilized, dimerizes with HIF1-b, binds coactivators of hypoxia response elements, and regulates transcription of hypoxia-regulated genes (8). Physiologically, HIF is important in development, vasculogenesis, wound healing, and stem cell maintenance. However, the HIF response is also associated with pathological conditions such as tumorigenesis, pulmonary hypertension, and dysregulated inflammation (7). Using an acute Aspergillus fumigatus infection model with confirmatory studies of key findings in a Pseudomonas aeruginosa agarose bead lung infection model, the authors found that CF mice (bitransgenic gut-corrected Cftr J/J mice [9]) express higher levels of Ager mRNA and RAGE protein and higher levels of the RAGE ligand S100B than wild-type C57BL/6 mice (6). Interestingly, the pattern of RAGE isoforms expression also differed, with CF mice showing significantly lower levels of the soluble RAGE (sRAGE) isoform, which may function as a RAGE ligand decoy receptor to inhibit RAGE activation (10). Although patients with CF are not typically affected by acute Aspergillus pneumonia and CF mouse P. aeruginosa models do not recapitulate the chronic infection of human CF, these findings raise interesting questions as to how CFTR functional deficiency in the lung regulates RAGE differently from normal lung.