Research

Blockade of advanced glycation end product formation attenuates bleomycin-induced pulmonary fibrosis in rats

Lei Chen^1,2* , Tao Wang^1,2* , Xun Wang^1,2 , Bei-Bei Sun^1,2 , Ji-Qiong Li^1,2 , Dai-Shun Liu^1,2 , Shang-Fu Zhang³ , Lin Liu^2,4 , Dan Xu^1,2 , Ya-Juan Chen^1,2 and Fu-Qiang Wen^1,2

¹  Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China

²  Department of Respiratory Medicine, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China

³  Department of Pathology, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China

⁴  Department of Respiratory Medicine, the Third People's Hospital of Mianyang, Mianyang, Sichuan 621000, PR China

author email corresponding author email* Contributed equally

Respiratory Research 2009, 10:55doi:10.1186/1465-9921-10-55

Published:	24 June 2009

Abstract

Background

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. 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.

Methods

Rats 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.

Results

AGEs 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.

Conclusion

These 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.