Morbini Patrizia, Villa Chiara, Campo Ilaria, Zorzetto Michele, Inghilleri Simona, Luisetti Maurizio
Dipartimento di Anatomia ed Istologia Patologica, IRCCS Policlinico San Matteo, Università di Pavia, Pavia, Italy.
Mod Pathol. 2006 Nov;19(11):1437-45. doi: 10.1038/modpathol.3800661. Epub 2006 Aug 25.
The binding of the receptor for advanced glycation end products (RAGE) with its ligands begins a sustained period of cellular activation and inflammatory signal amplification in different tissues and diseases. This binding could represent an as yet uninvestigated pathway of inflammatory reaction in the lung, where the presence of the receptor has been largely documented and advanced glycation end products (AGEs) are produced by nonenzymatic glycation and oxidation of proteins and lipids, driven by smoke and pollutants exposure or inflammatory stress. We immunohistochemically assessed the expression of RAGE and of its major proinflammatory ligands, N-epsilon-carboxy-methyl-lysine, S100B and S-100A12 in normal lung and in non-neoplastic lung disorders including smoke-related airway disease, granulomatous inflammation, postobstructive damage and usual interstitial pneumonia. In normal lung low expression of the receptor was observed in bronchiolar epithelia, type II pneumocytes, macrophages and some endothelia. S100A12 and S100B were expressed, respectively, in granulocytes and in dendritic cells. Carboxy-methyl-lysine was present in bronchiolar epithelia and macrophages. In all pathological conditions associated with inflammation and lung damage overexpression of both the receptor and of AGEs was observed in bronchiolar epithelia, type II alveolar pneumocytes, alveolar macrophages and endothelia. RAGE overexpression was more evident in epithelia associated with inflammatory cell aggregates. Fibroblasts in usual interstitial pneumonia expressed both the receptor and AGEs. The number of S100A12 and S100B immunoreactive inflammatory cells was variable. S100A12 was also expressed in mononuclear inflammatory cells and in activated epithelia. The activation of the inflammatory pathway controlled by the RAGE is not specific of a single lung disease, however, it may be relevant as a nonspecific pathway of sustained inflammation in lung tissue, and on this basis therapeutic approaches based on receptor blockage can be envisaged.
晚期糖基化终末产物受体（RAGE）与其配体的结合会在不同组织和疾病中引发一段持续的细胞活化和炎症信号放大期。这种结合可能代表了肺中一条尚未被研究的炎症反应途径，在肺中该受体的存在已被大量记录，并且晚期糖基化终末产物（AGEs）是由蛋白质和脂质的非酶糖基化和氧化产生的，由接触烟雾和污染物或炎症应激驱动。我们采用免疫组织化学方法评估了RAGE及其主要促炎配体N-ε-羧甲基赖氨酸、S100B和S-100A12在正常肺组织以及包括烟雾相关气道疾病、肉芽肿性炎症、阻塞后损伤和寻常型间质性肺炎在内的非肿瘤性肺疾病中的表达。在正常肺组织中，在细支气管上皮细胞、II型肺泡上皮细胞、巨噬细胞和一些内皮细胞中观察到该受体的低表达。S100A12和S100B分别在粒细胞和树突状细胞中表达。羧甲基赖氨酸存在于细支气管上皮细胞和巨噬细胞中。在所有与炎症和肺损伤相关的病理状况下，在细支气管上皮细胞、II型肺泡上皮细胞、肺泡巨噬细胞和内皮细胞中均观察到该受体和AGEs的过表达。RAGE的过表达在与炎症细胞聚集相关的上皮细胞中更为明显。寻常型间质性肺炎中的成纤维细胞同时表达该受体和AGEs。S100A12和S100B免疫反应性炎症细胞的数量各不相同。S100A12也在单核炎症细胞和活化的上皮细胞中表达。由RAGE控制的炎症途径的激活并非单一肺部疾病所特有，然而，它可能作为肺组织中持续炎症的非特异性途径具有相关性，基于此可以设想基于受体阻断的治疗方法。
