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Published ahead of print on September 1, 2005, doi:10.1165/rcmb.2005-0184OC

Am. J. Respir. Cell Mol. Biol., Volume 34, Number 1, January 2006, 65-72

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Submitted on May 15, 2005
Revised on September 1, 2005

Lipoxin A4 Inhibits Proliferation of Human Lung Fibroblasts Induced by CTGF

Sheng-Hua Wu1, Xiang-Hua Wu1*, Chao Lu1, Ling Dong2, and Zi-Qing Chen3

1 Department of Pediatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China, 2 Central Laboratory, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China, 3 Nanjing University of Technology, Nanjing, Jiangsu, China

* To whom correspondence should be addressed. E-mail: littlea9917{at}sina.com.

Connective tissue growth factor (CTGF) plays an important role in pathways leading to lung fibrosis via the mitogenic action of CTGF on fibroblasts. Studies have shown that lipoxin A4 (LXA4) inhibits proliferation of renal mesangial cells induced by leukotriene D4 or platelet-derived growth factor. The present study investigates the regulatory role of LXA4 on proliferation of human lung fibroblasts (HLFs) induced by CTGF and mechanisms of LXA4 action. CTGF induced HLF proliferation, enhanced the expression of cyclin D1, phosphorylated extracellular signal-regulated kinase (ERK)1/2, phosphoinositide 3-kinase (PI3-K) and protein kinase B (PKB), and DNA-binding activity of signal transducers and activators of transcription-3 (STAT3), and inhibited expression of p27kip1. LXA4 downregulated the CTGF-stimulated HLF proliferation and expression of cyclin D1, phosphorylated ERK1/2, PI3-K and PKB, and DNA-binding activity of STAT3. CTGF-induced decrement in expression of p27kip1 was ameliorated by LXA4. PI3-K or STAT blockade but not ERK1/2 blockade partially inhibited the CTGF-activated proliferation of HLFs. Transfection of human LXA4 receptor (ALXR) gene into HLFs intensified the inhibition of LXA4 on CTGF-induced cell proliferation. These results demonstrate that CTGF induces proliferation of HLFs via upregulation of PI3-K/PKB, STAT3 and cyclin D1, and downregulation of p27kip1. LXA4 inhibits the above effects of CTGF on HLFs.




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