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

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journal contribution
posted on 2015-09-02, 10:54 authored by Katy M. Roach, C. A. Feghali-Bostwick, Yassine Amrani, Peter Bradding
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[subscript: 4] (LXA[subscript: 4]) is an anti-inflammatory lipid, important in the resolution of inflammation, and it has potential antifibrotic activity. However, the effects of LXA[subscript: 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[subscript: 4] on TGF-β1-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[subscript: 4] on HLMF proliferation, collagen secretion, α-smooth muscle actin (αSMA) expression, and Smad2/3 activation were examined constitutively and following TGF-β1 stimulation. The LXA[subscript: 4] receptor (ALXR) was expressed in both NFC- and IPF-derived HLMFs. LXA[subscript: 4] (10[superscript: -10] and 10[superscript: -8] mol) reduced constitutive αSMA expression, actin stress fiber formation, contraction, and nuclear Smad2/3, indicating regression from a myofibroblast to fibroblast phenotype. LXA[subscript: 4] also significantly inhibited FBS-dependent proliferation and TGF-β1-dependent collagen secretion, αSMA expression, and Smad2/3 nuclear translocation in IPF-derived HLMFs. LXA[subscript: 4] did not inhibit Smad2/3 phosphorylation. In summary, LXA[subscript: 4] attenuated profibrotic HLMF activity and promoted HLMF regression to a quiescent fibroblast phenotype. LXA[subscript: 4] or its stable analogs delivered by aerosol may offer a novel approach to the treatment of IPF.



Journal of Immunology, 2015, 195 (6), pp. 2852-2860

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/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Infection, Immunity and Inflammation


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