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Implication of receptor for advanced glycation end product (RAGE) in pulmonary health and pathophysiology

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Abstract

Receptor for advanced glycation end products (RAGE) is a membrane bound receptor and member of the immunoglobulin super family and is normally present in a highly abundant basal level expression in lung. This high expression of RAGE in lung alveolar epithelial type I (ATI) cells is presumably involved in the proliferation and differentiation of pulmonary epithelial cells. However, typically higher than basal level expression of RAGE may indicate the existence of severe pathophysiological condition in lung, e.g. acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). During pulmonary tissue injury an endogenous secretory isoform of RAGE called EsRAGE is noticed at high levels in broncho-alveolar lavage (BAL) and plasma. Recently, a soluble form of RAGE (sRAGE) produced by recombinant gene technology was shown to exhibit a therapeutic potential in experimental animal models. Detailed study of RAGE in the pulmonary tissues will facilitate the understanding of the importance of RAGE signaling in the pulmonary health and pathophysiology.

Introduction

The receptor for advanced glycation end products (RAGE) is defined as the receptor for advanced glycation end product (AGE) and is a member of the immunoglobulin (Ig) super family of the cell surface receptors (Neeper et al., 1992). RAGE is a single membrane spanning receptor, consisting of a very short cytosolic domain of approximately 40 residues and a large extra cellular region containing 3 Ig-like domains (V, C1 and C2 domains) (Dattilo et al., 2007). The V and C1 domains are not independent domains, but rather form an integrated structural unit. In contrast, C2 domain is attached to VC1 by a flexible linker and is fully independent. These three domains coordinately interact and bind with several unrelated ligands namely AGE (Neeper et al., 1992), amphoterins (commonly known as high mobility group box chromosomal protein, i.e. HMGB1) (Hori et al., 1995), S100/calgranulins (Hofmann et al., 1999), amyloid beta peptide and beta fibrils (Yan et al., 1996) and Mac-1 (Chavakis et al., 2003). Thus, the molecule RAGE is termed as a multiligand receptor. Besides binding RAGE and influencing its activities each of these ligands may have their own physiological and/or pathophysiological functions. The multiligand receptor RAGE is naturally found in low basal level expression in most of the healthy adult tissues. In the contrary, even in the normal physiological condition the pulmonary tissues display a relatively high and quite abundant basal level expression of RAGE (Brett et al., 1993). Under some conditions the large extracellular region of RAGE is endogenously secreted in the lung and other organs to form a soluble isoform of RAGE called EsRAGE (Yonekura et al., 2003). Increasing number of evidences indicate that human EsRAGE may be a product of alternative mRNA splicing (Yonekura et al., 2003). In contrast, in some studies the murine EsRAGE is illustrated as a product of alternative mRNA splicing (Harashima et al., 2006), while others demonstrate it as a product of carboxy terminal truncation (Hanford et al., 2004). Based on the splicing, human EsRAGE contains unique amino acids that are not present in the typical V, C1, C2 domains present in membrane anchored RAGE. Recently, a soluble form of RAGE called sRAGE has been produced by recombinant gene technology (Hanford et al., 2004, Park et al., 1998). Of note, EsRAGE contains typical amino acid sequence that may not be found in sRAGE. In several studies administration of sRAGE was shown to exhibit a therapeutic potential in experimental animal models by blocking the action of RAGE (Park et al., 1998). Again, RAGE acts as an important progression factor amplifying the immune and inflammatory responses in several pathophysiological conditions (Schmidt et al., 2001). Therefore, sRAGE might serve as a decoy receptor by attenuating the immune and inflammatory reactions mediated by RAGE (Fig. 1, Fig. 2).

Section snippets

Distribution of RAGE in pulmonary tissues

In the lung, the cell-restricted expression of RAGE has remained so far a controversial issue. Initially, Neeper et al. (1992) showed RAGE mRNA transcript was very high in lung. During the first comparative study on the source of RAGE in healthy tissues, although RAGE was found to be located in multiple tissues, a moderately high level occurrence of RAGE transcript was initially found in the in vitro cultured bovine pulmonary artery endothelial cells (Brett et al., 1993). Similarly, in situ

Ligands of RAGE in pulmonary tissues

RAGE binds to a group of structurally similar but seemingly unrelated ligands including AGE (Neeper et al., 1992), HMGB1 (Hori et al., 1995), S100/calgranulins (Hofmann et al., 1999), amyloidal beta peptides and beta fibrils (Yan et al., 1996) and Mac-1 (Chavakis et al., 2003). It has been suggested that most of the known RAGE ligands (e.g. S100, HMGB1, etc.) fulfill intra and extracellular functions independent of RAGE (Schraml et al., 1997, Donato et al., 2003). The ligands of RAGE were

Significance of RAGE in normal pulmonary health and physiology

The presence of a relatively high basal level expression of RAGE in the normal pulmonary tissues suggests that RAGE may have a significant role in the lung homeostasis, particularly cell spreading and growth. No work on lung tissues available that directly indicate the involvement of RAGE in normal pulmonary health and physiology. Regarding work on other tissues, one study showed HMGB1-mediated regulation of RAGE might contribute to promotion of neurite growth and spreading (Li et al., 1998).

Acute lung injury and acute respiratory distress syndrome

In one of the initial studies, McElroy and Kasper (2004) used alveolar epithelial type 1 cell-selective markers to investigate lung injury and repair. Based on the experimental studies in rats as well as in patients with acute lung injury (ALI) another research group established the idea of RAGE as a potential marker of ATI epithelial cell injury (Uchida et al., 2006). Thus, damage to the ATI cells is an important feature of both ALI and acute respiratory distress syndrome (ARDS). This study

Involvement of RAGE in cell signaling

A good number of studies suggest the mechanism of action of RAGE in evoking vascular inflammatory responses in various systems. However, no studies have yet been completed that addresses RAGE-dependent signaling pathways specifically for the pulmonary system. Extensive studies have been reported showing the diversity of RAGE-dependent signaling pathways that depend on the specificity of the cell types. For example, while MAP kinase and p21(ras) mediated nuclear factor-kappa B (NF-κB) signaling

Possible anti-RAGE therapy: use of soluble RAGE in clinical perspective

Since higher than basal level expression of RAGE is linked to a number of both pulmonary and non-pulmonary inflammatory disorders it is necessary to control the expression and activity of RAGE in the lung tissue. Treatment of RAGE mediated pro-inflammatory damage mainly includes the prevention of the RAGE ligand interaction by blocking either the receptor or ligand. Blocking the receptor RAGE is usually performed by administration of the anti-RAGE antibody, which itself occupies the

Conclusion and future perspective

RAGE is a novel pleiotropic factor which is needed for the proliferation, differentiation and survival of normal pulmonary cells and presumably its prevention against the NSCLC. However, extremely high level of RAGE has pathophysiological consequences during the pro-inflammatory conditions. During lung injury, depending on the intensity of the level of injury, EsRAGE may be secreted to the BAL or even to the plasma. The amount of EsRAGE in BAL or plasma may thus act as a potential marker of

Acknowledgement

The National Institute of Health grant HL67281 supported this work.

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