title: Computational Modeling Predicts Simultaneous Targeting of Fibroblasts and Epithelial Cells Is Necessary for Treatment of Pulmonary Fibrosis.
abstract: Pulmonary fibrosis is pathologic remodeling of lung tissue that can result in difficulty breathing, reduced quality of life, and a poor prognosis for patients. Fibrosis occurs as a result of insult to lung tissue, though mechanisms of this response are not well-characterized. The disease is driven in part by dysregulation of fibroblast proliferation and differentiation into myofibroblast cells, as well as pro-fibrotic mediator-driven epithelial cell apoptosis. The most well-characterized pro-fibrotic mediator associated with pulmonary fibrosis is TGF-β1. Excessive synthesis of, and sensitivity to, pro-fibrotic mediators as well as insufficient production of and sensitivity to anti-fibrotic mediators has been credited with enabling fibroblast accumulation. Available treatments neither halt nor reverse lung damage. In this study we have two aims: to identify molecular and cellular scale mechanisms driving fibroblast proliferation and differentiation as well as epithelial cell survival in the context of fibrosis, and to predict therapeutic targets and strategies. We combine in vitro studies with a multi-scale hybrid agent-based computational model that describes fibroblasts and epithelial cells in co-culture. Within this model TGF-β1 represents a pro-fibrotic mediator and we include detailed dynamics of TGF-β1 receptor ligand signaling in fibroblasts. PGE2 represents an anti-fibrotic mediator. Using uncertainty and sensitivity analysis we identify TGF-β1 synthesis, TGF-β1 activation, and PGE2 synthesis among the key mechanisms contributing to fibrotic outcomes. We further demonstrate that intervention strategies combining potential therapeutics targeting both fibroblast regulation and epithelial cell survival can promote healthy tissue repair better than individual strategies. Combinations of existing drugs and compounds may provide significant improvements to the current standard of care for pulmonary fibrosis. Thus, a two-hit therapeutic intervention strategy may prove necessary to halt and reverse disease dynamics.
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School Ann Arbor, MI, USA.
authors.forename: Hayley C
authors.initials: HC
authors.lastname: Warsinske
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School Ann Arbor, MI, USA.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Wheaton
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School Ann Arbor, MI, USA.
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Kim
authors.affiliation: Department of Chemical Engineering, University of Michigan Ann Arbor, MI, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Linderman
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical SchoolAnn Arbor, MI, USA; Department of Internal Medicine, University of Michigan Medical SchoolAnn Arbor, MI, USA.
authors.forename: Bethany B
authors.initials: BB
authors.lastname: Moore
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School Ann Arbor, MI, USA.
authors.forename: Denise E
authors.initials: DE
authors.lastname: Kirschner
keywords: IPF; agent-based modeling; epithelial cells; fibroblasts; prostaglandin E2; pulmonary fibrosis; therapeutics for fibrosis; transforming growth factor beta1