Advanced glycation end products (AGEs), first described by Louis-Camille Maillard in 1912, are the end products of irreversible molecular adducts formed through non-enzymatic reactions between reducing sugars such as fructose and glucose with proteins or lipids (Gkogkolou and Böhm, 2012, Singh et al., 2001). A comprehensive evaluation of the diverse precursors and intricate mechanisms involved in the heterogeneous pathways leading to the chemical synthesis of AGEs has already been published (Ahmed et al., 1986, Gkogkolou and Böhm, 2012, Henning and Glomb, 2016, Vistoli et al., 2013). Over 20 different types of AGEs have been detected in human tissues and blood, including carboxymethyl-lysine (CML), carboxyethyl-lysine, pyrraline, pentosidine and methylglyoxal-lysine dimer. Despite having varying chemical structures, these AGEs share the common feature of containing a lysine residue within their molecular makeup (Perrone, Giovino, Benny, & Martinelli, 2020). AGEs damage human tissues through two distinct mechanisms: first, they alter the structures of proteins through chemical cross-linking, and second, they activate various receptors, thereby stimulating several intracellular pathways that lead to an increase in the production of pro-inflammatory cytokines and reactive oxygen species (ROS) (Ott et al., 2014). These include scavenger receptors, such as CD36 (Horiuchi et al., 1996), as well as receptors that are predominantly found on macrophages, such as galectin-3 (Pricci et al., 2000), OST-48 (Y. M. Li et al., 1996), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) (X. Chen, Zhang, & Du, 2008), and the receptor of advanced glycation end products (RAGE), which is the most extensively researched and best-known receptor for AGEs (Schmidt et al., 1992). RAGE, a 35 kDa protein belonging to the immunoglobulin superfamily, is encoded by the AGER gene located near major histocompatibility complex III on chromosome 6 (Bierhaus et al., 2005, Fleming et al., 2011, Gkogkolou and Böhm, 2012). Genetic variations within the AGER gene, such as single nucleotide polymorphisms (SNPs) and mutations, can significantly influence its expression and function, ultimately affecting the progression of lung disease. One key aspect of RAGE’s role of RAGE in lung diseases is its involvement in the regulation of inflammation. When RAGE binds to ligands such as AGEs or high-mobility group box 1 (HMGB1), it activates pro-inflammatory signaling pathways, including the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). This activation leads to the production of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-8, interferon-γ, and monocyte chemoattractant protein-1 (MCP-1) (Wang et al., 2019). Excessive inflammation is a common feature in conditions such as acute respiratory distress syndrome (ARDS) and asthma, and genetic variants that enhance RAGE-mediated inflammation can worsen disease severity (Jones et al., 2020, Niu et al., 2019). RAGE signaling is also associated with lung tissue damage. When activated, RAGE can induce oxidative stress and stimulate the release of proinflammatory molecules, leading to the breakdown of lung tissue and impairment of lung function (Sanders et al., 2019). Genetic factors that increase RAGE expression or ligand-binding can amplify these damaging effects. In diseases characterized by fibrosis, such as idiopathic pulmonary fibrosis (IPF), RAGE activation plays a critical role in promoting fibroblast differentiation and collagen production, thereby contributing to the fibrotic process (Perkins and Oury, 2021, Yamaguchi et al., 2022). Genetic variations that enhance RAGE-mediated fibrotic pathways may accelerate IPF progression (Kinjo et al., 2020). Furthermore, RAGE signaling can lead to the generation of ROS within lung tissue, contributing to oxidative stress. Oxidative stress can damage lung cells and exacerbate conditions, such as chronic obstructive pulmonary disease (COPD) (Taniguchi, Tsuge, Miyahara, & Tsukahara, 2021) or pulmonary hypertension (Prasad, 2019). Genetic factors that promote RAGE-mediated oxidative stress may aggravate oxidative damage in lungs (Malik, Hoidal, & Mukherjee, 2021). Understanding the intricate relationship between AGER genetics and lung disease is crucial for tailoring treatments and improving patient outcomes. Genetic profiling of individuals with lung diseases can potentially identify those who are more likely to respond to therapies targeting RAGE or its downstream pathways, such as RAGE-blocking drugs, sRAGE, or small-molecule inhibitors. Ongoing research is essential to identify specific genetic markers and their functional consequences in various lung diseases, enabling the development of more precise and effective therapeutic interventions.

RAGE can be found in the body in two forms: membrane-bound RAGE (mRAGE) and soluble RAGE (sRAGE). Three domains comprise membrane-bound RAGE: an extracellular domain that identifies and attaches RAGE ligands, a hydrophobic transmembrane domain, and a charged cytoplasmic domain that participates in intracellular signaling (Oczypok, Perkins, & Oury, 2017). RAGE is strongly expressed in many tissues of the developing embryo, but as the organism matures, it loses its expression in all tissues but the lung (Bierhaus et al., 2005). mRAGE functions as a pattern recognition receptor that can bind to various molecules, including AGEs, S-100/calgranulins, HMGB1, β-amyloid peptides, and β-sheet fibrils (Bierhaus et al., 2005, Fleming et al., 2011, Gkogkolou and Böhm, 2012). Increasing evidence suggests that RAGE activation triggers inflammatory reactions and oxidative stress (Lubitz et al., 2016, Sharma et al., 2021). When ligands bind to RAGE, they trigger several signaling pathways, such as mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinases (ERK) 1 and 2, phosphatidyl-inositol 3 kinase (PI3K), p21Ras, stress-activated protein kinase/c-Jun-N-terminal kinase (SAPK/JNK), and Janus kinase (JAK). This stimulation of RAGE leads to the activation of NF-κB and subsequent transcription of multiple pro-inflammatory genes (Bierhaus et al., 2005, Fleming et al., 2011, Gkogkolou and Böhm, 2012). In addition to its pro-inflammatory character, RAGE activation can also induce oxidative stress through both direct and indirect mechanisms. It can directly activate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and lower the activity of superoxide dismutase (SOD), catalase, and other pathways. RAGE activation can directly diminish cellular antioxidant defenses such as glutathione (GSH) and ascorbic acid (Bierhaus et al., 2005, Gkogkolou and Böhm, 2012, Loughlin and Artlett, 2010, Ramasamy et al., 2005). sRAGE is incapable of triggering cellular signaling owing to the absence of intracellular domains. sRAGE exists in two distinct isoforms, namely cleaved RAGE (cRAGE) and endogenous secretory RAGE (esRAGE), although the mechanisms regulating these isoforms remain unclear. cRAGE production is mediated by proteases, including matrix metalloproteinases (MMP), disintegrin, and ADAM metalloproteinase domain-containing protein 10 (ADAM10), which act on the cell surface. The RAGE gene uses alternative splicing to generate the second isoform, esRAGE (Libby et al., 2011, Park et al., 2004, Pinto et al., 2022, Yonekura et al., 2003).

Chronic pulmonary diseases, such as COPD, asthma, and pulmonary fibrosis, are the third leading cause of death worldwide and are increasing in prevalence over time (Somayaji & Chalmers, 2022). According to the World Health Organization (WHO), chronic respiratory disease causes 4.6 million premature deaths annually, accounting for over 5% of all global fatalities. Notably, almost 90% of these fatalities occur in low-income and middle-income nations (Byrne et al., 2015, Racanelli et al., 2018). The pathogenesis of chronic pulmonary illnesses is characterized by persistent respiratory tract inflammation. Genetic predisposition and environmental factors, such as exposure to bacteria, atmospheric particles, irritants, pollutants, allergens, and toxic molecules, may contribute to persistent lung inflammation (Racanelli et al., 2018). RAGE is a pro-inflammatory mediator, and numerous studies have identified RAGE as a key component of numerous pulmonary illnesses, including lung cancer, COPD, asthma, pulmonary fibrosis, cystic fibrosis (CF), and acute lung injury (Oczypok et al., 2017). Lung diseases are characterized by matrix remodeling, such as elastosis and fibrosis (Ito et al., 2019), in which RAGE plays a significant role (Oczypok et al., 2017). Elastosis, characterized by the abnormal accumulation of elastic fibers in the lung tissue, is one of the processes influenced by RAGE. RAGE activation triggers signaling pathways that lead to the production and activation of MMPs (Hergrueter, Nguyen, & Owen, 2011). These MMPs, notably elastase-type MMPs such as MMP-2 and MMP-9, are enzymes responsible for degrading elastin, a crucial component of elastic fibers within the lung (Corbel, Belleguic, Boichot, & Lagente, 2002). Consequently, MMP-mediated elastin degradation contributes to the disruption of the elastic recoil properties of the lungs, resulting in reduced lung compliance and impaired respiratory function. On the other hand, fibrosis, a hallmark of several lung diseases, involves the excessive deposition of collagen and other extracellular matrix components in lung tissue (Todd, Luzina, & Atamas, 2012). RAGE signaling has also been implicated in this process (Perkins & Oury, 2021). RAGE activation stimulates fibroblast activation, prompting these cells to transition into myofibroblasts, which possess enhanced contractile properties and increased capacity for collagen production. RAGE-mediated signaling activates intracellular pathways, including the MAPK and NF-κB pathways, which when triggered by RAGE, promote the transcriptional upregulation of genes associated with collagen synthesis (Thakur et al., 2022, Tian et al., 2019). This results in the accumulation of collagen, which contributes to the stiffening of lung tissue and disruption of normal lung architecture. These fibrotic changes lead to a decreased oxygen exchange and impaired lung function. This review highlights the current understanding of the role of AGEs and (s)RAGE in pulmonary diseases and its potential as a biomarker and therapeutic target for preventing and treating these diseases.