Abstract
BackgroundAdvanced glycation end products (AGEs) have been proposed to be involved in pulmonary fibrosis, but its role in this process has not been fully understood. To investigate the role of AGE formation in pulmonary fibrosis, we used a bleomycin (BLM)-stimulated rat model treated with aminoguanidine (AG), a crosslink inhibitor of AGE formation.MethodsRats were intratracheally instilled with BLM (5 mg/kg) and orally administered with AG (40, 80, 120 mg/kg) once daily for two weeks. AGEs level in lung tissue was determined by ELISA and pulmonary fibrosis was evaluated by Ashcroft score and hydroxyproline assay. The expression of heat shock protein 47 (HSP47), a collagen specific molecular chaperone, was measured with RT-PCR and Western blot. Moreover, TGFβ1 and its downstream Smad proteins were analyzed by Western blot.ResultsAGEs level in rat lungs, as well as lung hydroxyproline content and Ashcroft score, was significantly enhanced by BLM stimulation, which was abrogated by AG treatment. BLM significantly increased the expression of HSP47 mRNA and protein in lung tissues, and AG treatment markedly decreased BLM-induced HSP47 expression in a dose-dependent manner (p < 0.05). In addition, AG dose-dependently downregulated BLM-stimulated overexpressions of TGFβ1, phosphorylated (p)-Smad2 and p-Smad3 protein in lung tissues.ConclusionThese findings suggest AGE formation may participate in the process of BLM-induced pulmonary fibrosis, and blockade of AGE formation by AG treatment attenuates BLM-induced pulmonary fibrosis in rats, which is implicated in inhibition of HSP47 expression and TGFβ/Smads signaling.
Highlights
Advanced glycation end products (AGEs) have been proposed to be involved in pulmonary fibrosis, but its role in this process has not been fully understood
AGEs level as well as bleomycin-induced pulmonary fibrosis is attenuated by AG treatment Bleomycin instillation significantly induced pulmonary fibrosis (Figure 2A)
Compared with the SA group, AGEs level in lung tissues was markedly increased in the BLM group (p < 0.01; Figure 2B), and was dose-dependently decreased with AG treatment, similar to the changes of Ashcroft score and lung hydroxyproline content (Figure 2C, D), which were used for assessing the degree of pulmonary fibrosis
Summary
Advanced glycation end products (AGEs) have been proposed to be involved in pulmonary fibrosis, but its role in this process has not been fully understood. The underlying molecular mechanisms of pulmonary fibrosis remain not fully understood, increased synthesis and deposition of extracellular matrix (ECM) is confirmed to be an important pathological feature of pulmonary fibrosis [1]. Advanced glycation end products (AGEs), the irreversible products of nonenzymatic glycation of proteins, nucleic acids and lipids, are increased in situations with hyperglycemia and oxidative stress, which involves a series of complex biochemical events with oxidative and nonoxidative molecular rearrangements [2,3]. Previous studies have suggested that AGEs have multiple potential effects on various disorders [2-4]. T Matsuse et al reported AGE modified proteins accumulated in alveolar macrophages in patients with idiopathic pulmonary fibrosis [5], which suggests for the first time that AGEs probably contribute to the pathogenesis of pulmonary fibrosis. Its role in pulmonary fibrosis has not been well-elucidated
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