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Summary Idiopathic pulmonary fibrosis (IPF) is a form of progressive interstitial lung disease with unknown etiology. Due to a lack of effective treatment, IPF is associated with a high mortality rate. The hallmark feature of this disease is the accumulation of activated myofibroblasts that excessively deposit extracellular matrix proteins, thus compromising lung architecture and function and hindering gas exchange. Here we investigated the origin of activated myofibroblasts and the molecular mechanisms governing fibrosis formation and resolution. Genetic engineering in mice enables the time-controlled labeling and monitoring of lipogenic or myogenic populations of lung fibroblasts during fibrosis formation and resolution. Our data demonstrate a lipogenic-to-myogenic switch in fibroblastic phenotype during fibrosis formation. Conversely, we observed a myogenic-to-lipogenic switch during fibrosis resolution. Analysis of human lung tissues and primary human lung fibroblasts indicates that this fate switching is involved in IPF pathogenesis, opening potential therapeutic avenues to treat patients.

Cell surface-associated proteolysis plays a crucial role in the migration of mononuclear phagocytes to sites of inflammation. The glycolytic enzyme enolase-1 (ENO-1) binds plasminogen at the cell surface, enhancing local plasmin production. This study addressed the role played by ENO-1 in lipopolysaccharide (LPS)-driven chemokine-directed monocyte migration and matrix invasion in vitro, as well as recruitment of monocytes to the alveolar compartment in vivo. LPS rapidly up-regulated ENO-1 cell-surface expression on human blood monocytes and U937 cells due to protein translocation from cytosolic pools, which increased plasmin generation, enhanced monocyte migration through epithelial monolayers, and promoted matrix degradation. These effects were abrogated by antibodies directed against the plasminogen binding site of ENO-1. Overexpression of ENO-1 in U937 cells increased their migratory and matrix-penetrating capacity, which was suppressed by overexpression of a truncated ENO-1 variant lacking the plasminogen binding site (ENO-1⌬PLG). In vivo, intratracheal LPS application in mice promoted alveolar recruitment of monocytic cells that overexpressed ENO-1, but not of cells overexpressing ENO-1⌬PLG. Consistent with these data, pneumoniapatients exhibited increased ENO-1 cellsurface expression on blood monocytes and intense ENO-1 staining of mononuclear cells in the alveolar space. These data suggest an important mechanism of inflammatory cell invasion mediated by increased cell-surface expression of ENO-1. (Blood. 2009;113:5588-5598) IntroductionMonocytes are circulating mononuclear phagocytes with a broad spectrum of activities and functions. In pathologic conditions associated with acute or chronic inflammation, monocytes migrate into the affected tissues and differentiate into tissue macrophages. 1,2 Thus, monocytes and tissue macrophages are critical cellular components of the host defense system against infectious diseases, including forms of pneumonia, and have important functions in both native and acquired immunity. They are responsible for the phagocytosis and clearance of invading microorganisms, regulate antimicrobial programs of gene expression, are a potent source of inflammatory cytokines, and interact with T cells through cell-cell or cytokine-mediated mechanisms, thereby facilitating acquired immunity to specific pathogens. [1][2][3][4][5][6][7] In atherosclerosis, monocytes infiltrate atherosclerotic plaques, accumulate lipidrich material, and differentiate into macrophage-type foam cells. 8 Moreover, tumor-infiltrating monocytes may play a role in tumor progression and metastasis by different mechanisms, including regulation of angiogenesis. 9 Many of these activities depend upon the ability of monocytes to localize and regulate cell surfaceassociated proteolytic activity.The enzymes of the fibrinolytic system represent one of the most broadly distributed cell surface-associated protease systems. The accumulation of plasminogen (PLG) and its activators, namely urokinase (u-PA) and tissue-plasminog...