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Open AccessArticle

Matrix Metalloproteinases Retain Soluble FasL-mediated Resistance to Cell Death in Fibrotic-Lung Myofibroblasts

1
Lung Cellular and Molecular Biology Laboratory, Institute of Pulmonary Medicine, Hadassah Medical Research Center, PO Box 12000, Kiryat Hadassah, Jerusalem 91120, Israel
2
Department of Pathology and Laboratory Medicine, 670 Albany St, 4th Floor, Boston University School of Medicine, Boston, MA 02118, USA
*
Author to whom correspondence should be addressed.
Cells 2020, 9(2), 411; https://doi.org/10.3390/cells9020411
Received: 16 January 2020 / Revised: 4 February 2020 / Accepted: 7 February 2020 / Published: 11 February 2020
A prominent feature of obstructed tissue regeneration following injury in general, and fibrotic lung tissue in particular, is fibroblast proliferation and accumulation. The Fas/FasL apoptotic pathway has been shown to be involved in human idiopathic pulmonary fibrosis (IPF) and bleomycin-induced lung fibrosis in rodents. We previously showed that in normal injury repair, myofibroblasts’ accumulation is followed by their decline by FasL+ T cell-induced cell death. In pathological lung fibrosis, myofibroblasts resist cell death and accumulate. Like other members of the tumor necrosis factor (TNF) family, membrane-bound FasL can be cleaved from the cell surface to generate a soluble form (sFasL). Metalloproteinases (MMPs) are known to convert the membrane-bound form of FasL to sFasL. MMP-7 knockout (KO) mice were shown to be protected from bleomycin (BLM)-induced lung fibrosis. In this study, we detected increased levels of sFasL in their blood serum, as in the lungs of patients with IPF, and IPF-lung myofibroblast culture medium. In this study, using an MMP-inhibitor, we showed that sFasL is decreased in cultures of IPF-lung myofibroblasts and BLM-treated lung myofibroblasts, and in the blood serum of MMP-7KO mice. Moreover, resistant fibrotic-lung myofibroblasts, from the lungs of humans with IPF and of BLM-treated mice, became susceptible to T-cell induced cell death in a co-culture following MMP-inhibition- vs. control-treatment or BLM-treated MMP-7KO vs. wild-type mice, respectively. sFasL may be an unrecognized mechanism for MMP-7-mediated decreased tissue regeneration following injury and the evolution of lung fibrosis.
Keywords: pulmonary fibrosis; lung myofibroblasts; matrix metalloproteinase (MMP); soluble FasL (sFasL); cell death pulmonary fibrosis; lung myofibroblasts; matrix metalloproteinase (MMP); soluble FasL (sFasL); cell death
MDPI and ACS Style

Nareznoi, D.; Konikov-Rozenman, J.; Petukhov, D.; Breuer, R.; Wallach-Dayan, S.B. Matrix Metalloproteinases Retain Soluble FasL-mediated Resistance to Cell Death in Fibrotic-Lung Myofibroblasts. Cells 2020, 9, 411.

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