The Role of the Receptor for Advanced Glycation End-Products in a Murine Model of Silicosis

Abstract

BackgroundThe role of the receptor for advanced glycation end-products (RAGE) has been shown to differ in two different mouse models of asbestos and bleomycin induced pulmonary fibrosis. RAGE knockout (KO) mice get worse fibrosis when challenged with asbestos, whereas in the bleomycin model they are largely protected against fibrosis. In the current study the role of RAGE in a mouse model of silica induced pulmonary fibrosis was investigated.Methodology/Principal FindingsWild type (WT) and RAGE KO mice received a single intratracheal (i.t.) instillation of silica in saline or saline alone as vehicle control. Fourteen days after treatment mice were subjected to a lung mechanistic study and the lungs were lavaged and inflammatory cells, protein and TGF-β levels in lavage fluid determined. Lungs were subsequently either fixed for histology or excised for biochemical assessment of fibrosis and determination of RAGE protein- and mRNA levels. There was no difference in the inflammatory response or degree of fibrosis (hydroxyproline levels) in the lungs between WT and RAGE KO mice after silica injury. However, histologically the fibrotic lesions in the RAGE KO mice had a more diffuse alveolar septal fibrosis compared to the nodular fibrosis in WT mice. Furthermore, RAGE KO mice had a significantly higher histologic score, a measure of affected areas of the lung, compared to WT silica treated mice. A lung mechanistic study revealed a significant decrease in lung function after silica compared to control, but no difference between WT and RAGE KO. While a dose response study showed similar degrees of fibrosis after silica treatment in the two strains, the RAGE KO mice had some differences in the inflammatory response compared to WT mice.Conclusions/SignificanceAside from the difference in the fibrotic pattern, these studies showed no indicators of RAGE having an effect on the severity of pulmonary fibrosis following silica injury.

The receptor for advanced glycation end-products supports lung tissue biomechanics

“…The mouse airway resistance was reduced with advanced age as also observed by Huang et al (20,21), but this reduction is not significantly influenced by RAGE. Our findings are in contrast to previous observations of Ramsgaard et al (38), who did not find RAGE-dependent differences in the respiratory function. One reason for this discrepancy might be the young age of the mice (younger than 3 mo) used in their study (38) because RAGE expression might reach its maximal level first when lung development is nearly completed [earliest with 4 mo (31)].…”

“…Our findings are in contrast to previous observations of Ramsgaard et al (38), who did not find RAGE-dependent differences in the respiratory function. One reason for this discrepancy might be the young age of the mice (younger than 3 mo) used in their study (38) because RAGE expression might reach its maximal level first when lung development is nearly completed [earliest with 4 mo (31)]. Our additional studies investigating 3-mo-old mice, which did not show an effect of RAGE on lung physiological parameters, confirmed this assumption.…”

RAGE processing in chronic airway conditions: Involvement of Staphylococcus aureus and ECP

“…9 However, RAGE knockout mice were also described to be protected against bleomycin-induced pulmonary fibrosis, 14,15 while RAGE does not seem to be implicated in the fibrotic process of silica-induced pulmonary fibrosis. 16 A similar ambiguity can be found in the literature on human lower airways where on the one hand an elevation in the overall levels of RAGE was reported in the lung tissue of patients with chronic obstructive pulmonary disease (COPD), 17 while decreased levels of mRAGE and cRAGE but not sRAGE were observed in another study assessing lung tissues of patients with COPD. 18 Interestingly, Sukkar et al 19 reported reduced levels of lung sRAGE in neutrophilic asthma and COPD while levels of sRAGE in asthma and COPD without neutrophilia were not different from control levels.…”

The Receptor For Advanced Glycation End-Products Is A Central Mediator Of Asthma Pathogenesis

“…Founder RAGE knockout (RAGE KO) mice were provided by Dr. A. Bierhaus (University of Heidelberg), and from these mice a breeding colony was initiated. 6,11,17 These mice are congenic with the C57BL/6 background. RAGE KO mice were age-and sexmatched to WT mice for each experiment.…”