A Role for the Receptor for Advanced Glycation End Products in Idiopathic Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a severely debilitating disease associated with a dismal prognosis. There are currently no effective therapies for IPF, thus the identification of novel therapeutic targets is greatly needed. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface receptors whose activation has been linked to various pathologies. In healthy adult animals, RAGE is expressed at the highest levels in the lung compared to other tissues. To investigate the hypothesis that RAGE is involved in IPF pathogenesis, we have examined its expression in two mouse models of pulmonary fibrosis and in human tissue from IPF patients. In each instance we observed a depletion of membrane RAGE and its soluble (decoy) isoform, sRAGE, in fibrotic lungs. In contrast to other diseases in which RAGE signaling promotes pathology, immunohistochemical and hydroxyproline quantification studies on aged RAGEnull mice indicate that these mice spontaneously develop pulmonary fibrosis-like alterations. Furthermore, when subjected to a model of pulmonary fibrosis, RAGE-null mice developed more severe fibrosis, as measured by hydroxyproline assay and histological scoring, than wild-type controls. Combined with data from other studies on mouse models of pulmonary fibrosis and human IPF tissues indicate that loss of RAGE contributes to IPF pathogenesis. Idiopathic pulmonary fibrosis (IPF) is a debilitating disease with a dismal prognosis. Mean survival time after biopsy-confirmed diagnosis is 3 to 5 years.1,2 Traditional therapy involves the use of corticosteroids as nonspecific anti-inflammatory agents. This treatment produces an objective response in only 10 to 20% of patients and has a minimal effect on the fatal course of IPF.2-4 Thus, the need for new therapeutic modalities is evident.The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin super family of cell surface receptors. 5 In most healthy adult animal tissues, RAGE is expressed at low to undetectable levels.6,7 Activation of membrane-bound RAGE (mRAGE) by its ligands (including advanced glycation end products, HMGB1/amphoterin, S100/calgranulins, and amyloid-␤ peptide) often leads to proinflammatory signaling as well as up-regulation of RAGE itself.8 This signaling by mRAGE is believed to play an important role in disease progression for several nonpulmonary diseases, including various diabetic complications, chronic inflammation, and Alzheimer's disease, among others. 9,10 In contrast to other healthy adult tissues, RAGE mRNA and sRAGE protein are highly expressed in normal adult lungs. 6,7,11 Most recently it has been suggested that RAGE is a marker of type I alveolar epithelial cells 12 and type II alveolar epithelial cell transdifferentiation, a component of pulmonary re-epithelialization and repair.

HMGB1 blockade attenuates experimental autoimmune myocarditis and suppresses Th17‐cell expansion

“…It remains unclear whether HMGB1 directly or indirectly led to the cardiac fibrosis. However, some reports indicate that HMGB1 contributes to pulmonary fibrosis [32] and hepatic fibrosis [33]. Our results show that HMGB1 could directly lead to cardiac fibrosis; in addition, IL-17 secreted by Th17 cells also could directly lead to cardiac fibrosis (our unpublished data).…”

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

“…Lung injury induced by either bleomycin or hyperoxia is diminished in RAGE -/-mice [37,38], suggesting a deteriorating attribution of RAGE. In contrast, Englert et al showed that RAGE -/-mice developed more severe lung fi brosis after asbestos adminis tration as measured by histological scoring and total lung hydroxyproline quantifi cation [31]. Of note, in all these studies, the mice were much younger at the time of sacrifi ce than the aged (19-24 month-old) RAGE -/-mice that developed pulmonary fi brosis spontaneously in the experiment by Englert et al [31].…”

“…Of note, in all these studies, the mice were much younger at the time of sacrifi ce than the aged (19-24 month-old) RAGE -/-mice that developed pulmonary fi brosis spontaneously in the experiment by Englert et al [31]. Interestingly, lung homogenates and bronchoalveolar lavage (BAL) fl uid from patients suff ering from idiopathic pulmonary fi brosis reveal reduced membrane bound (and soluble) RAGE protein levels compared to healthy donor samples [31,34]. …”

“…Th ese two observa tions raise the question as to whether RAGE has a function in normal healthy lungs. Indeed, Englert et al documented that aged RAGE -/-mice develop pulmonary fi brosis-like alterations spontaneously; lungs from 19 to 24 month-old RAGE -/-mice showed increased collagen staining and displayed increased levels of hydroxyproline relative to wild type mice [31]. RAGE knockdown in pulmonary fi broblasts increased their proliferation and migration in vitro, suggesting an important protective function of RAGE in the lungs and that loss of RAGE may be related to functional changes of pulmonary cell types resulting in fi brotic disease [34].…”

“…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.…”