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.
Highlights
Pulmonary fibrosis is a pathologic feature associated with many interstitial lung diseases (Buzan and Pop, 2015)
Previous work has demonstrated the roles of TGF-β1 and PGE2 in fibroblast to myofibroblast differentiation (Kolodsick et al, 2003; Thannickal et al, 2003; Epa et al, 2015; Warsinske et al, 2015)
We sought to determine the capacity for TGF-β1 and PGE2 to influence IMR-90 fibroblast proliferation in vitro
Summary
Pulmonary fibrosis is a pathologic feature associated with many interstitial lung diseases (Buzan and Pop, 2015). Myofibroblasts play an important role in the fourth stage of the wound healing process, the remodeling stage They secrete extracellular matrix (ECM) proteins including collagen and fibronectin (Witte and Barbul, 1997; Midwood et al, 2004; Velnar et al, 2009) that are cross-linked to provide a substrate for re-epithelialization of wounded tissue (Midwood et al, 2004). Myofibroblasts are able to adhere to surrounding tissue and contract, collapsing the wound gap (Thannickal et al, 2003; Ibrahim et al, 2015) Dysregulation of this process, through unknown mechanisms, results in excessive ECM protein secretion and tissue remodeling. These actions result in the formation of stiff, scarred tissue that is inflexible, and unproductive for gas exchange (Selman et al, 2004; Jastrzebski et al, 2005)
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