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 A4 (LXA4) is an anti-inflammatory lipid, important in the resolution of inflammation, and it has potential antifibrotic activity. However, the effects of LXA4 on primary human lung myofibroblasts (HLMFs) have not previously been investigated. Therefore, the aim of this study was to examine the effects of LXA4 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 LXA4 on HLMF proliferation, collagen secretion, α-smooth muscle actin (αSMA) expression, and Smad2/3 activation were examined constitutively and following TGF-β1 stimulation. The LXA4 receptor (ALXR) was expressed in both NFC- and IPF-derived HLMFs. LXA4 (10(-10) and 10(-8) mol) reduced constitutive αSMA expression, actin stress fiber formation, contraction, and nuclear Smad2/3, indicating regression from a myofibroblast to fibroblast phenotype. LXA4 also significantly inhibited FBS-dependent proliferation and TGF-β1-dependent collagen secretion, αSMA expression, and Smad2/3 nuclear translocation in IPF-derived HLMFs. LXA4 did not inhibit Smad2/3 phosphorylation. In summary, LXA4 attenuated profibrotic HLMF activity and promoted HLMF regression to a quiescent fibroblast phenotype. LXA4 or its stable analogs delivered by aerosol may offer a novel approach to the treatment of IPF.
Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Leicester LE1 7RH, United Kingdom; and kmr11@le.ac.uk.
Katy M
KM
Roach
Division of Rheumatology and Immunology, Department of Medicine, University of South Carolina, Columbia, SC 29208.
Carol A
CA
Feghali-Bostwick
Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Leicester LE1 7RH, United Kingdom; and.
Yassine
Y
Amrani
Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Leicester LE1 7RH, United Kingdom; and.
Peter
P
Bradding
D000199:Actins / Q000096:biosynthesis; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000276:immunology / Q000473:pathology*; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D044045:Lipoxins / Q000494:pharmacology*; D008168:Lung / Q000166:cytology / Q000473:pathology; D058628:Myofibroblasts / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D044042:Receptors, Formyl Peptide / Q000096:biosynthesis*; D044067:Receptors, Lipoxin / Q000096:biosynthesis*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
C541116:ACTA2 protein, human; D000199:Actins; C105101:FPR2 protein, human; D044045:Lipoxins; D012333:RNA, Messenger; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; C040527:lipoxin A4; D003094:Collagen