The receptor for advanced glycation end products and its ligands: a new inflammatory pathway in lung disease?

Abstract

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-e-carboxy-methyl-lysine, S100B and S-100A12 in normal lung and in nonneoplastic 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.

Phagocyte-specific S100 proteins in the local response to theEchinococcus granulosuslarva

“…In other systems, S100A12 is known to be expressed in granulocytes but not in monocytes or resident macrophages (Vogl et al 1999a;Pietzsch and Hoppmann, 2009). S100A12 expression in granuloma macrophages, including epithelioid cells and MGC specifically, has been reported, in human systems, in the last few years (Kim et al 2006;Morbini et al 2006;Campo et al 2007); the expression of S100A9 and S100A8 was not analysed in these works. Other works have reported widely different observations on the expression of S100A9 and S100A8 in these cell types; these observations include co-expression of both, expression of only S100A9, and lack of expression of either (Zwadlo et al 1988;Delabie et al 1990;Aguiar-Passeti et al 1997;Arai et al 1999;Sunderkotter et al 2004;Kurata et al 2005;Terasaki et al 2007).…”

Lack of an Endogenous Anti-inflammatory Protein in Mice Enhances Colonization of B16F10 Melanoma Cells in the Lungs

“…new pathway for pulmonary inflammation (35). The S100 protein family, especially S100A8 (29) and S100A9 (27), are cytoplasmic EF-hand Ca 2ϩ -binding proteins (36), which are some of the ligands that have been linked to human inflammatory and neoplastic diseases (37).…”

The Role of Receptor for Advanced Glycation Endproducts (RAGE) in Infection

“…Knowledge of the expression and role of RAGE in host defense during pneumonia is limited. Morbini et al observed increased RAGE expression in patients with interstitial and postobstructive pneumonia [32]; this report left unanswered whether patients with bacterial pneumonia were included in the analysis. Notably, two other studies showed that constitutively present RAGE was not upregulated during pulmonary infl ammation associated with ALI or acute respiratory distress syndrome (ARDS): First, rats with ALI induced by intratracheally administered LPS displayed no change in the distribution of RAGEexpressing cells [29]; and second, patients with ARDS did not have increased pulmonary expression of RAGE [26].…”

“…In particular, although the kidney is dramatically aff ected by microangiopathy and fi brosiswhich is substantially attributed to RAGE -in patients with diabetes, the lungs, with a signifi cantly higher baseline RAGE expression than the kidney, remain unaff ected. In addition, RAGE has been found to be specifi cally localized near the basal cell membrane within alveolar pneumocytes [32,35,36]. Th ese two observa tions raise the question as to whether RAGE has a function in normal healthy lungs.…”

“…Physiologically, RAGE is expressed at high basal levels in the lungs relative to other tissues [26,[29][30][31][32][33][34], suggesting that RAGE may have lung-specifi c functions distinct from the role of RAGE in other adult tissues. In particular, although the kidney is dramatically aff ected by microangiopathy and fi brosiswhich is substantially attributed to RAGE -in patients with diabetes, the lungs, with a signifi cantly higher baseline RAGE expression than the kidney, remain unaff ected.…”