Mononuclear phagocytes and airway epithelial cells: novel sources of matrix metalloproteinase-8 (MMP-8) in patients with idiopathic pulmonary fibrosis.
OBJECTIVE
Matrix metalloproteinase-8 (MMP-8) promotes lung fibrotic responses to bleomycin in mice. Although prior studies reported that MMP-8 levels are increased in plasma and bronchoalveolar lavage fluid (BALF) samples from IPF patients, neither the bioactive forms nor the cellular sources of MMP-8 in idiopathic pulmonary fibrosis (IPF) patients have been identified. It is not known whether MMP-8 expression is dys-regulated in IPF leukocytes or whether MMP-8 plasma levels correlate with IPF outcomes. Our goal was to address these knowledge gaps.


METHODS
We measured MMP-8 levels and forms in blood and lung samples from IPF patients versus controls using ELISAs, western blotting, and qPCR, and assessed whether MMP-8 plasma levels in 73 IPF patients correlate with rate of lung function decline and mortality. We used immunostaining to localize MMP-8 expression in IPF lungs. We quantified MMP-8 levels and forms in blood leukocytes from IPF patients versus controls.


RESULTS
IPF patients have increased BALF, whole lung, and plasma levels of soluble MMP-8 protein. Active MMP-8 is the main form elevated in IPF lungs. MMP-8 mRNA levels are increased in monocytes from IPF patients, but IPF patients and controls have similar levels of MMP-8 in PMNs. Surprisingly, macrophages and airway epithelial cells are the main cells expressing MMP-8 in IPF lungs. Plasma and BALF MMP-8 levels do not correlate with decline in lung function and/or mortality in IPF patients.


CONCLUSIONS
Blood and lung MMP-8 levels are increased in IPF patients. Active MMP-8 is the main form elevated in IPF lungs. Surprisingly, blood monocytes, lung macrophages, and airway epithelial cells are the main cells in which MMP-8 is upregulated in IPF patients. Plasma and BALF MMP-8 levels are unlikely to serve as a prognostic biomarker for IPF patients. These results provide new information about the expression patterns of MMP-8 in IPF patients.
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Vanessa J
VJ
Craig
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy; Pulmonary Fibrosis Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, United States of America.
Francesca
F
Polverino
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Maria E
ME
Laucho-Contreras
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Pulmonary Fibrosis Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, United States of America.
Yuanyuan
Y
Shi
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Pulmonary Fibrosis Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, United States of America.
Yushi
Y
Liu
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Juan C
JC
Osorio
Chronic Obstructive Pulmonary Disease Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, United States of America.
Yohannes
Y
Tesfaigzi
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Victor
V
Pinto-Plata
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Bernadette R
BR
Gochuico
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Pulmonary Fibrosis Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, United States of America.
Ivan O
IO
Rosas
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Pulmonary Fibrosis Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, United States of America; Chronic Obstructive Pulmonary Disease Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, United States of America.
Caroline A
CA
Owen
D000368:Aged; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000097:blood / Q000378:metabolism*; D008875:Middle Aged; D012157:Mononuclear Phagocyte System / Q000378:metabolism*
D020784:Matrix Metalloproteinase 8