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Published ahead of print on September 1, 2005, doi:10.1165/rcmb.2005-0184OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 34, pp. 65-72, 2006
© 2006 American Thoracic Society
DOI: 10.1165/rcmb.2005-0184OC

Lipoxin A4 Inhibits Proliferation of Human Lung Fibroblasts Induced by Connective TissueGrowth Factor

Sheng-Hua Wu, Xiang-Hua Wu, Chao Lu, Ling Dong and Zi-Qing Chen

Department of Pediatrics, Central Laboratory, the First Affiliated Hospital of Nanjing Medical University, Nanjing University of Technology, Nanjing, Jiangsu, People's Republic of China

Correspondence and requests for reprints should be addressed to Sheng-Hua Wu, M.D., Department of Pediatrics, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, People's Republic of China. E-mail: kad-yc{at}163.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. This study investigates the regulatory role of LXA4 on proliferation of human lung fibroblasts (HLF) 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), 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; and phosphorylated ERK1/2, PI3-K, 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 HLF. Transfection of the human LXA4 receptor gene into HLF intensified the inhibition of LXA4 on CTGF-induced cell proliferation. These results demonstrate that CTGF induces proliferation of HLF via upregulation of PI3-K/PKB, STAT3, and cyclin D1, and downregulation of p27kip1. LXA4 inhibits these effects of CTGF on HLF.

Key Words: lipoxin A4 • connective tissue growth factor • fibroblasts • lung • proliferation




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