期刊
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
卷 63, 期 6, 页码 819-830出版社
AMER THORACIC SOC
DOI: 10.1165/rcmb.2020-0227OC
关键词
IPF; stiffness; PGE(2); cPLA(2); PTGES
资金
- Australian Research Council [IC170100016, LP160100635]
- National Health and Medical Research Council (Australia) Centre for Research Excellence in Pulmonary Fibrosis [1116371]
- Ideas grant [1181637]
- CSL Ltd.
Pathological changes in the biomechanical environment are implicated in the progression of idiopathic pulmonary fibrosis (IPF). Stiffened matrix augments fibroblast proliferation and differentiation and activates TGF-beta 1 (transforming growth factor-beta 1). Stiffened matrix impairs the synthesis of the antifibrogenic lipid mediator prostaglandin E-2 (PGE(2)) and reduces the expression of the rate-limiting prostanoid biosynthetic enzyme cyclooxygenase-2 (COX-2). We now show that prostaglandin E synthase (PTGES), the final enzyme in the PGE(2) biosynthetic pathway, is expressed at lower levels in the lungs of patients with IPF. We also show substantial induction of COX-2, PTGES, prostaglandin E receptor 4 (EP4), and cytosolic phospholipase A(2) (cPLA(2)) expression in human lung fibroblasts cultured in soft collagen hydrogels or in spheroids compared with conventional culture on stiff plastic culture plates. Induction of COX-2, cPLA(2), and PTGES expression in spheroid cultures was moderately inhibited by the p38 mitogen-activated protein kinase inhibitor SB203580. The induction of prostanoid biosynthetic enzyme expression was accompanied by an increase in PGE(2) levels only in non-IPF-derived fibroblast spheroids. Our study reveals an extensive dysregulation of prostanoid biosynthesis and signaling pathways in IPF-derived fibroblasts, which are only partially abrogated by culture in soft microenvironments.
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