Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans.
Pulmonary fibrosis is a progressive and largely untreatable group of disorders that affects up to 100,000 people on any given day in the United States. To elucidate the molecular mechanisms that lead to end-stage human pulmonary fibrosis we analyzed samples from patients with histologically proven pulmonary fibrosis (usual interstitial pneumonia) by using oligonucleotide microarrays. Gene expression patterns clearly distinguished normal from fibrotic lungs. Many of the genes that were significantly increased in fibrotic lungs encoded proteins associated with extracellular matrix formation and degradation and proteins expressed in smooth muscle. Using a combined set of scoring systems we determined that matrilysin (matrix metalloproteinase 7), a metalloprotease not previously associated with pulmonary fibrosis, was the most informative increased gene in our data set. Immunohistochemisry demonstrated increased expression of matrilysin protein in fibrotic lungs. Furthermore, matrilysin knockout mice were dramatically protected from pulmonary fibrosis in response to intratracheal bleomycin. Our results identify matrilysin as a mediator of pulmonary fibrosis and a potential therapeutic target. They also illustrate the power of global gene expression analysis of human tissue samples to identify molecular pathways involved in clinical disease.
Zuo
Fengrong
F
Roche Bioscience, Palo Alto, CA 94304; Functional Genomics, and Institute of Respiratory Medicine, Sheba Medical Center, Tel Hashomer, 52621 Israel.
Kaminski
Naftali
N
Eugui
Elsie
E
Allard
John
J
Yakhini
Zohar
Z
Ben-Dor
Amir
A
Lollini
Lance
L
Morris
David
D
Kim
Yong
Y
DeLustro
Barbara
B
Sheppard
Dean
D
Pardo
Annie
A
Selman
Moises
M
Heller
Renu A
RA
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology; D018925:Chemokines / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D006801:Humans; D006909:Hydroxyproline / Q000494:pharmacology; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000166:cytology; D020411:Oligonucleotide Array Sequence Analysis; D011658:Pulmonary Fibrosis / Q000378:metabolism*; D018075:RNA, Complementary / Q000378:metabolism; D015854:Up-Regulation
D000900:Anti-Bacterial Agents; D018925:Chemokines; D018075:RNA, Complementary; D001761:Bleomycin; D020783:Matrix Metalloproteinase 7; D006909:Hydroxyproline