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

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 p27^kip1. 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 p27^kip1 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 p27^kip1. LXA₄ inhibits these effects of CTGF on HLF.

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

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