Idiopathic pulmonary fibrosis (IPF) is a progressive and usually lethal interstitial lung disease of unknown etiology characterized by aberrant activation of epithelial cells that induce the migration, proliferation and activation of fibroblasts. The resulting distinctive fibroblastic/ myofibroblastic foci are responsible for the excessive extracellular matrix (ECM) production and abnormal lung remodeling. We have recently found that matrix metalloproteinase 19 (MMP-19)-deficient (Mmp19Ϫ/Ϫ) mice develop an exaggerated bleomycin-induced lung fibrosis, but the mechanisms are unclear. In this study, we explored the effect of MMP-19 deficiency on fibroblast gene expression and cell behavior. Microarray analysis of Mmp19Ϫ/Ϫ lung fibroblasts revealed the dysregulation of several profibrotic pathways, including ECM formation, migration, proliferation, and autophagy. Functional studies confirmed these findings. Compared with wild-type mice, Mmp19Ϫ/Ϫ lung fibroblasts showed increased ␣1 (I) collagen gene and collagen protein production at baseline and after transforming growth factor-␤ treatment and increased smooth muscle-␣ actin expression (P Ͻ 0.05). Likewise, Mmp19-deficient lung fibroblasts showed a significant increase in proliferation (P Ͻ 0.01) and in transmigration and locomotion over Boyden chambers coated with type I collagen or with Matrigel (P Ͻ 0.05). These findings suggest that, in lung fibroblasts, MMP-19 has strong regulatory effects on the synthesis of key ECM components, on fibroblast to myofibroblast differentiation, and in migration and proliferation. lung fibrosis; matrix metalloproteinase; fibroblasts; collagen IDIOPATHIC PULMONARY FIBROSIS (IPF) is a progressive and usually lethal lung disease of unknown etiology and without current effective therapy (15). It is characterized by injury and aberrant activation of the alveolar epithelium, which induces, through the release of a variety of growth factors, cytokines, and matrix metalloproteinases (MMPs), a flow of dysregulated epithelial-fibroblast crosstalk (20). Activated epithelial cells provoke the migration, proliferation, and activation of mesenchymal cells, with the formation of fibroblast and myofibroblast foci, whereas activated myofibroblasts secrete exaggerated amounts of extracellular matrix (ECM) molecules culminating in the destruction of the lung parenchyma (5). However, the molecular mechanisms involved in IPF development and progression are uncertain. Studies in our group and others have shown that some MMPs such as MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, and MMP-13 are highly expressed in IPF, playing diverse roles in the fibrotic response; however, the exact mechanisms are not well characterized (4,10,11,21,24,27). Recently, we identified the overexpression of MMP-19 in the hyperplastic alveolar epithelium of IPF lungs and demonstrated that, surprisingly, mice lacking this MMP developed an exacerbated bleomycin-induced lung fibrosis (25). Perturbations of MMP-19 levels in epithelial cells in vivo and in vitro were associated with changes...

Idiopathic pulmonary fibrosis (IPF) is a lethal age-related lung disease whose pathogenesis involves an aberrant response of alveolar epithelial cells (AEC). Activated epithelial cells secrete mediators that participate in the activation of fibroblasts and the excessive deposition of extracellular matrix proteins. Previous studies indicate that matrix metalloproteinase 14 (MMP14) is increased in the lung epithelium in patients with IPF, however, the role of this membrane-type matrix metalloproteinase has not been elucidated. In this study, the role of Mmp14 was explored in experimental lung fibrosis induced with bleomycin in a conditional mouse model of lung epithelial MMP14-specific genetic deletion. Our results show that epithelial Mmp14 deficiency in mice increases the severity and extension of fibrotic injury and affects the resolution of the lesions. Gain-and loss-of-function experiments with human epithelial cell line A549 demonstrated that cells with a deficiency of MMP14 exhibited increased senescence-associated markers. Moreover, conditioned medium from these cells increased fibroblast expression of fibrotic molecules. These findings suggest a new anti-fibrotic mechanism of MMP14 associated with anti-senescent activity, and consequently, its absence results in impaired lung repair. Increased MMP14 in IPF may represent an anti-fibrotic mechanism that is overwhelmed by the strong profibrotic microenvironment that characterizes this disease.

Idiopathic pulmonary fibrosis (IPF) is a progressive and usually lethal interstitial lung disease of unknown etiology characterized by aberrant activation of epitelial cells that induce the migration, proliferation and activation of fibroblast/myofibroblasts. The resulting distinctive fibroblastic foci are responsible of the excessive extracellular matrix production. We have recently found that Mmp19‐/‐ mice develop an exaggerated bleomycin‐induced lung fibrosis but the mechanisms are unclear. In this study we explored the effect of MMP19 deficiency on fibroblast behavior. Compared with wild type mice, Mmp19‐/‐ lung fibroblasts showed a decreased expression of Th1‐1 (p<0.01), and alpha 1 (I) collagen gene and collagen protein production at baseline and after TGF‐β treatment (p< 0.05). Likewise, they showed a significant increase in growth rate (p< 0.01), and in transmigration over Boyden chambers coated with type I collagen or with Matrigel (p< 0.05). Microarray analysis revealed the upregulation of several profibrotic pathways in Mmp19‐/‐ lung fibroblasts. These findings suggest that the absence of MMP19 induces in lung fibroblasts a profibrotic phenotype. Grant Funding Source: CONACyT 177641

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