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

Abstract

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.

CTGF Mediates Smad-Dependent Transforming Growth Factor β Signaling To Regulate Mesenchymal Cell Proliferation during Palate Development

“…CTGF has been implicated in complex biological processes such as angiogenesis, chondrogenesis, and osteogenesis, as well as fibrosis and tumorigenesis (22,54). Specifically, CTGF induces proliferation in diverse cell types, including chondrocytes (56,57), osteoblasts (51), human bone marrow stromal cells (58), lung fibroblasts (59), and beta cells (60), among others.…”

Aspirin-Triggered Lipoxins Override the Apoptosis-Delaying Action of Serum Amyloid A in Human Neutrophils: A Novel Mechanism for Resolution of Inflammation

“…LXA 4 /15-epi-LXA 4 attenuates peroxynitrite signaling (25) via the regulation of presqualene diphosphate accumulation in human PMN (52). LXA 4 /15-epi-LXA 4 through inhibition of PI3K antagonized proliferation of renal mesangial cells (53,54) and human lung fibroblasts (55). In mesangial cells, LXA 4 stimulated phosphorylation of ERK and p38 MAPK (53).…”

ATLa, an Aspirin-Triggered Lipoxin A4 Synthetic Analog, Prevents the Inflammatory and Fibrotic Effects of Bleomycin-Induced Pulmonary Fibrosis

“…LXA 4 inhibits the TGF-␤-stimulated proliferation of NIH 3T3 fibroblasts and the proliferation of human lung fibroblasts induced by connective tissue growth factor (54,63). Mesangial cell proliferation that is induced by platelet-derived growth factor, leukotriene D 4 or TNF-␣ is also inhibited by LXA 4 or its analogs (64 -66).…”