Matrices of physiologic stiffness potently inactivate idiopathic pulmonary fibrosis fibroblasts

Aleksandar Marinković, Fei Liu, Daniel J. Tschumperlin

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

Fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) have been shown to differ from normal lung fibroblasts in functional behaviors that contribute to the pathogenesis of IPF, including the expression of contractile proteins and proliferation, but how such behaviors vary in matrices with stiffness matched to normal and fibrotic lung tissue remains unknown. Here, we tested whether pathologic changes in matrix stiffness control IPF and normal lung tissue-derived fibroblast functions, and compared the relative efficacy of mechanical cues to an antifibrotic lipid mediator, prostaglandin E2 (PGE2). Fibroblasts were grown on collagen I-coated glass or hydrogel substrates of discrete stiffnesses, spanning the range of normal and fibrotic lung tissue. Traction microscopy was used to quantify contractile function. The CyQuant Cell Proliferation Assay (Invitrogen, Carlsbad,CA)wasusedto assesschangesin cell number, and PGE2 concentrations were measured by ELISA. We confirmed differences in proliferation and PGE2 synthesis between IPF and normal tissue-derived fibroblasts on rigid substrates. However, IPF fibroblasts remained highly responsive to changes in matrix stiffness, and both proliferative and contractile differences between IPF and normal fibroblastswere ablated on physiologically softmatrices.We also confirmed the relative resistance of IPF fibroblasts to PGE2, while demonstrating that decreases inmatrix stiffness and the inhibition of Rho kinase both potently attenuate contractile function in IPF-derived fibroblasts. We conclude that pathologic changes in the mechanical environment control important IPF fibroblast functions. Understanding how mechanical cues control fibroblast functionmay offer newopportunities for targeting these cells, even when they are resistant to antifibrotic pharmacological agents or biologicalmediators.

Original languageEnglish (US)
Pages (from-to)422-430
Number of pages9
JournalAmerican journal of respiratory cell and molecular biology
Volume48
Issue number4
DOIs
StatePublished - Apr 1 2013

Keywords

  • Extracellular matrix
  • Fibroblast contractility
  • Lung
  • Pulmonary fibrosis

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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