The role of the receptor for advanced glycation end-products in lung fibrosis

Abstract

The pathogenesis of pulmonary fibrosis remains unclear. The receptor for advanced glycation end-products (RAGE) is a multi-ligand receptor known to be involved in the process of fibrotic change in several organs, such as peritoneal fibrosis and kidney fibrosis. The aim of this study was to examine the contribution of RAGE during the acute inflammation and chronic fibrotic phases of lung injury induced by intratracheal instillation of bleomycin in mice. Bleomycin-induced lung fibrosis was evaluated in wild-type and RAGE-deficient (RAGE-/-) mice. Bleomycin administration to wild-type mice caused an initial pneumonitis that evolved into fibrosis. While RAGE-/- mice developed a similar early inflammatory response, the mice were largely protected from the late fibrotic effects of bleomycin. The protection afforded by RAGE deficiency was accompanied by reduced pulmonary levels of the potent RAGE-inducible profibrotic cytokines transforming growth factor (TGF)-beta and PDGF. In addition, bleomycin administration induced high mobility group box 1 (HMGB-1) production, one of the ligands of RAGE, from inflammatory cells that accumulated within the air space. Coculture with HMGB-1 induced epithelial-mesenchymal transition (EMT) in alveolar type II epithelial cells from wild-type mice. However, alveolar type II epithelial cells derived from RAGE-/- mice did not respond to HMGB-1 treatment, such that the RAGE/HMGB-1 axis may play an important role in EMT. Also, bleomycin administration induced profibrotic cytokines TGF-beta and PDGF only in wild-type mouse lungs. Our results suggested that RAGE contributes to bleomycin-induced lung fibrosis through EMT and profibrotic cytokine production. Thus, RAGE may be a new therapeutic target for pulmonary fibrosis.

Inhibitory effect of receptor for advanced glycation end products (RAGE) on the TGF-β-induced alveolar epithelial to mesenchymal transition

“…A separate study showed the significant down-regulation of RAGE in lung homogenates and ATII cells from patients with IPF, as well as in bleomycin-treated mice (Queisser et al, 2008). These findings conflict with results from previous papers showing that RAGE contributes to bleomycin-induced lung fibrosis (He at al., 2007;Hamada et al, 2008).…”

“…RAGE also contributes to bleomycin-induced lung fibrosis (He et al, 2007;Hamada et al, 2008). RAGE over-expression is evident in areas of active fibrosis, including fibroblastic foci (Morbini et al, 2006).…”

The Receptor for Advanced Glycation End Products Impairs Host Defense in Pneumococcal Pneumonia

“…This is in line with other reports in which inhibition of the interaction of RAGE with its ligands led to a reduced inflammation in models of hepatic injury (19 -21), diabetic atherosclerosis (22, 23), delayed-type hypersensitivity (24, 25), type II collagen-induced arthritis (25), and sepsis (24). In addition, in a recent study, RAGE was found to be important for the development of lung fibrosis upon intratracheal administration of bleomycin (42). Because activation of RAGE triggers multiple intracellular signaling pathways, including NF-B, resulting in the transcription of proinflammatory factors (43,44), these findings could at least in part be attributed to the blockade of RAGE interaction with its ligands via diminished activation of NF-B, resulting in attenuated tissue injury/damage and/or inflammation (24,45).…”

Combined effects of maternal inflammation and neonatal hyperoxia on lung fibrosis and RAGE expression in newborn rats

“…Previous studies revealed that RAGE expression produces paradoxical responses in different models of pulmonary fibrosis (33)(34)(35). The effect of hyperoxia on RAGE expression has been shown to differ between adult mouse and neonatal rat models (12,13).…”