Lipoxin A4 Attenuates Constitutive and TGF-β1-Dependent Profibrotic Activity in Human Lung Myofibroblasts

Idiopathic pulmonary fibrosis (IPF) is a common, progressive, and invariably lethal interstitial lung disease with no effective therapy. The key cell driving the development of fibrosis is the myofibroblast. Lipoxin A(4) (LXA(4)) is an anti-inflammatory lipid, important in the resolution of inflammation, and it has potential antifibrotic activity. However, the effects of LXA(4) on primary human lung myofibroblasts (HLMFs) have not previously been investigated. Therefore, the aim of this study was to examine the effects of LXA(4) on TGF-beta 1-dependent responses in IPF- and nonfibrotic control (NFC)-derived HLMFs. HLMFs were isolated from IPF and NFC patients and grown in vitro. The effects of LXA(4) on HLMF proliferation, collagen secretion, alpha-smooth muscle actin (alpha SMA) expression, and Smad2/3 activation were examined constitutively and following TGF-beta 1 stimulation. The LXA(4) receptor (ALXR) was expressed in both NFC- and IPF-derived HLMFs. LXA(4) (10(-10) and 10(-8) mol) reduced constitutive alpha SMA expression, actin stress fiber formation, contraction, and nuclear Smad2/3, indicating regression from a myofibroblast to fibroblast phenotype. LXA(4) also significantly inhibited FBS-dependent proliferation and TGF-beta 1-dependent collagen secretion, alpha SMA expression, and Smad2/3 nuclear translocation in IPF- derived HLMFs. LXA(4) did not inhibit Smad2/3 phosphorylation. In summary, LXA(4) attenuated profibrotic HLMF activity and promoted HLMF regression to a quiescent fibroblast phenotype. LXA(4) or its stable analogs delivered by aerosol may offer a novel approach to the treatment of IPF.