期刊
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
卷 185, 期 1, 页码 77-84出版社
AMER THORACIC SOC
DOI: 10.1164/rccm.201105-0834OC
关键词
mesenchymal stem cell; bronchiolitis obliterans syndrome; lung transplant; prostaglandin E2
资金
- NIH [RO1 HL094622, RO1 094311]
- American Thoracic Society
- Scleroderma Research Foundation
- Brian and Mary Campbell and Elizabeth Campbell Carr research gift fund
Rationale: Donor mesenchymal stromal/stem cell (MSC) expansion and fibrotic differentiation is associated with development of bronchiolitis obliterans syndrome (BOS) in human lung allografts. However, the regulators of fibrotic differentiation of these resident mesenchymal cells are not well understood. Objectives: This study examines the role of endogenous and exogenous prostaglandin (PG) E-2 as a modulator of fibrotic differentiation of human lung allograft-derived MSCs. Methods: Effect of PGE(2) on proliferation, collagen secretion, and alpha-smooth muscle actin (alpha-SMA) expression was assessed in lung-resident MSCs (LR-MSCs) derived from patients with and without BOS. The response pathway involved was elucidated by use of specific agonists and antagonists. Measurement and Main Results: PGE(2) treatment of LR-MSCs derived from normal lung allografts significantly inhibited their proliferation, collagen secretion, and alpha-SMA expression. On the basis of pharmacologic and small-interfering RNA approaches, a PGE(2)/E prostanoid (EP)2/adenylate cyclase pathway was implicated in these suppressive effects. Stimulation of endogenous PGE(2) secretion by IL-1 beta was associated with amelioration of their myofibroblast differentiation in vitro, whereas its inhibition by indomethacin augmented alpha-SMA expression. LR-MSCs from patients with BOS secreted significantly less PGE(2) than non-BOSLR-MSCs. Furthermore, BOS LR-MSCs were found to be defective in their ability to induce cyclooxygenase-2, and therefore unable to up-regulate PGE(2) synthesis in response to IL-1 beta. BOS LR-MSCs also demonstrated resistance to the inhibitory actions of PGE(2) in association with a reduction in the EP2/EP1 ratio. Conclusions: These data identify the PGE(2) axis as an important autocrine-paracrine brake on fibrotic differentiation of LR-MSCs, a failure of which is associated with BOS.
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