FIZZ1 stimulation of myofibroblast differentiation.
Bleomycin-induced pulmonary fibrosis is characterized by inflammation, emergence of myofibroblasts, and deposition of extracellular matrix. In an attempt to identify genes that may be involved in fibrosis, we used a 10,000 element (10 K) rat cDNA microarray to analyze the lung gene expression profiles in this model in the rat. Cluster analysis showed 628 genes were more than or equal to twofold up- or down-regulated, many of which were known to be involved in fibrosis. However, the most dramatic increase was observed with FIZZ1 (found in inflammatory zone; also known as RELM-alpha or resistin-like molecule-alpha), which was induced 17-fold to approximately 25-fold at the peak of expression. In situ hybridization analysis revealed FIZZ1 expression to localize primarily to alveolar and airway epithelium, which was confirmed in vitro by analysis of isolated type II alveolar epithelial cells. However FIZZ1 expression was not detected in isolated lung fibroblasts. Co-culture of FIZZ1-expressing type II cells with fibroblasts stimulated alpha-smooth muscle actin and type I collagen expression independent of transforming growth factor-beta. Transfection of a FIZZ1-expressing plasmid into fibroblasts or treatment with glutathione S-transferase-FIZZ1 fusion protein stimulated alpha-smooth muscle actin and collagen I production. These results suggest a novel role for FIZZ1 in myofibroblast differentiation in pulmonary fibrosis.
Liu
Tianju
T
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. tianliu@umich.edu
Dhanasekaran
Saravana M
SM
Jin
Hong
H
Hu
Biao
B
Tomlins
Scott A
SA
Chinnaiyan
Arul M
AM
Phan
Sem H
SH
D000199:Actins / Q000096:biosynthesis; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D024042:Collagen Type I / Q000096:biosynthesis; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology*; D017403:In Situ Hybridization; D009130:Muscle, Smooth / Q000378:metabolism; D020932:Nerve Growth Factor / Q000096:biosynthesis*; D020411:Oligonucleotide Array Sequence Analysis; D011650:Pulmonary Alveoli / Q000166:cytology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D000199:Actins; D000964:Antimetabolites, Antineoplastic; D024042:Collagen Type I; D012333:RNA, Messenger; D011994:Recombinant Proteins; D001761:Bleomycin; D020932:Nerve Growth Factor