Elevated gelatinase activity in pulmonary alveolar proteinosis: role of macrophage-colony stimulating factor.
Pulmonary alveolar proteinosis (PAP) is an anti-granulocyte macrophage-colony stimulating factor (GM-CSF) autoimmune disease resulting in the accumulation of phospholipids in the alveoli. GM-CSF knockout (KO) mice exhibit a strikingly similar lung pathology to patients with PAP. The lack of functionally active GM-CSF correlates with highly elevated concentrations of M-CSF in the lungs of PAP patients and GM-CSF KO mice. M-CSF has been associated with alternative macrophage activation, and in models of pulmonary fibrosis, M-CSF also contributes to tissue resorption and fibrosis. Matrix metalloproteinase-2 (MMP-2) and MMP-9 have been implicated in extracellular matrix degradation in animal models of fibrosis and asthma. We show for the first time that the lungs of PAP patients contain highly elevated levels of MMP-2 and MMP-9. PAP broncholaveolar lavage (BAL) cells but not bronchial epithelial cells expressed increased MMP-2 and MMP-9 mRNA relative to healthy controls. Both MMPs were detectable as pro and active proteins by gelatin zymography; and by fluorometric global assay, PAP-MMP activity was elevated. BAL cells/fluids from GM-CSF KO mice also demonstrated significantly elevated MMP-2 and MMP-9 gene expression, protein, and activity. Finally, PAP patients undergoing GM-CSF therapy exhibited significantly reduced MMPs and M-CSF. These data suggest that in the absence of GM-CSF, excess M-CSF in PAP may redirect alveolar macrophage activation, thus potentially contributing to elevated MMP expression in the lung.
Bonfield
Tracey L
TL
Department of Pulmonary, Allergy and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195-5038, USA. bonfiet@ccf.org
Swaisgood
Carmen M
CM
Barna
Barbara P
BP
Farver
Carol F
CF
Kavuru
Mani S
MS
Thomassen
Mary Jane
MJ
D000818:Animals; D018893:Bronchoalveolar Lavage; D004847:Epithelial Cells / Q000201:enzymology / Q000276:immunology; D018093:Gelatinases; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000172:deficiency / Q000276:immunology / Q000627:therapeutic use; D006801:Humans; D008168:Lung / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology*; D016173:Macrophage Colony-Stimulating Factor / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D020782:Matrix Metalloproteinases; D051379:Mice; D018345:Mice, Knockout; D011649:Pulmonary Alveolar Proteinosis / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology
D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D018093:Gelatinases; D020782:Matrix Metalloproteinases