Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 314, Issue 4, Pages 1569-1582Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00565.2016
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Funding
- National Institutes of Health [R01-HL-120908, T32-HL-066988, P30-ES-001247]
- Greg Chandler and Guy F. Solimano Fibrosis Research Fund
- Doran Family Endowment
- C. Jane Davis and C. Robert Davis Professorship
- US Army Medical Department
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In pulmonary fibrosis (PF), fibroblasts and myofibroblasts proliferate and deposit excessive extracellular matrix in the interstitium, impairing normal lung function. Because most forms of PF have a poor prognosis and limited treatment options, PF represents an urgent unmet need for novel, effective therapeutics. Although the role of immune cells in lung fibrosis is unclear, recent studies suggest that T lymphocyte (T cell) activation may be impaired in PF patients. Furthermore, we have previously shown that activated T cells can produce prostaglandins with anti-scarring potential. Here, we test the hypothesis that activated T cells directly inhibit myofibroblast differentiation using a coculture system. Coculture with activated primary blood-derived T cells, from both healthy human donors and PF patients, inhibited transforming growth factor beta-induced myofibroblast differentiation in primary human lung fibroblasts isolated from either normal or PF lung tissue. Coculture supernatants contained anti-fibrotic prostaglandins D-2 and E-2, and the inhibitory effect of coculture on myofibroblast differentiation was largely reversed when prostaglandin production was abrogated either by resting the T cells before coculture or via specific pharmacological inhibitors. Moreover, coculture conditions induced COX-2 in HLFs but not in T cells, suggesting that T cells deliver an activating signal to HLFs, which in turn produce anti-fibrotic prostaglandins. We show for the first time that coculture with activated primary human T lymphocytes strongly inhibits myofibroblast differentiation, revealing a novel cell-to-cell communication network with therapeutic implications for fibrotic lung diseases.
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