WNT5A is a regulator of fibroblast proliferation and resistance to apoptosis.
Usual interstitial pneumonia (UIP) is a specific histopathologic pattern of interstitial lung fibrosis that may be idiopathic or secondary to autoimmune diseases and environmental exposures. In this study, we compared gene expression patterns in primary fibroblasts isolated from lung tissues with UIP histology and fibroblasts isolated from lung tissues with normal histology using expression microarrays. We found that WNT5A was significantly increased in fibroblasts obtained from UIP lung tissues compared with normal lung fibroblasts, an observation verified by quantitative real-time RT-PCR and Western blot. Because the role of WNT5A in UIP is unknown, we treated normal lung fibroblasts or UIP lung fibroblasts with WNT5A, and found that WNT5A increased proliferation as well as relative resistance to H2O2-induced apoptosis. This effect was not mediated through the canonical WNT/beta-catenin pathway, as WNT5A induced a decrease in beta-catenin levels in the same cells. In addition, WNT5A induced increases in fibronectin and alpha(5)-integrin in normal lung fibroblasts. Collectively, our data suggest that WNT5A may play a role in fibroblast expansion and survival characteristics of idiopathic pulmonary fibrosis and other fibrotic interstitial lung diseases that exhibit UIP histological patterns.
Vuga
Louis J
LJ
Dorothy P. and Richard P. Simmons Center for Interstitial Lung Diseases, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Ben-Yehudah
Ahmi
A
Kovkarova-Naumovski
Elizabetha
E
Oriss
Timothy
T
Gibson
Kevin F
KF
Feghali-Bostwick
Carol
C
Kaminski
Naftali
N
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D016022:Case-Control Studies; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D039482:Integrin alpha5 / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D015854:Up-Regulation; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000378:metabolism
C495267:CTNNB1 protein, mouse; D005353:Fibronectins; D039482:Integrin alpha5; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D051176:beta Catenin; D006861:Hydrogen Peroxide; C505409:Casp3 protein, mouse; D053148:Caspase 3