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.

Ginsenoside Rg1 Ameliorates Cigarette Smoke-Induced Airway Fibrosis by Suppressing the TGF-β1/Smad Pathway In Vivo and In Vitro

“…The activated fibroblasts contribute to the deposition of collagen and other ECM components [21, 22], which increase the thickness of small airways and contribute to airflow limitation, leading to pulmonary fibrosis and airway remodeling. CS is a key risk factor in COPD and has been reported to promote the transition of fibroblasts to myofibroblasts [4].…”

Identifying mechanisms driving formation of granuloma-associated fibrosis during Mycobacterium tuberculosis infection

“…Diffusion mechanisms are described by partial differential equations (PDEs) while receptor ligand signaling mechanisms are described by ordinary differential equations (ODEs). Diffusion dynamics have been described previously, as well as strategies that we use for efficient numerical implementation of hybrid multi-scale agent-based models (16, 74, 75). At the cellular scale, GranSim accounts for discrete cellular agents whose actions are governed by model rules.…”

“…Each model scale is linked to the other scales through cytokine concentrations and/or agent behaviors (Figure 2B) as we have done previously (16–19, 70, 74, 76–78). Molecules that are secreted and diffuse at the molecular scale dictate behavior of cells at the cellular scale (eg.…”

“…Fibroblast agents include fine-grained molecular scale TGF-β1 receptor/ligand signaling dynamics (16, 75). Within this updated version of GranSim there are four macrophage states (resting, activated, infected, and chronically infected) and three distinct T-cell types (cytotoxic, regulatory, and IFNγ producing T-cells).…”

“…We combine pro-fibrotic cellular agents, cells known as fibroblasts, that we calibrated in a previously published model of fibrotic regulation (16), with our existing multi-scale model of granuloma formation, GranSim (17–21), that includes molecular scale mechanisms of a pro-fibrotic mediator, TGF-β1 (Warsinske et al JI in review). This next-generation GranSim incorporates fibrotic mechanisms at the molecular, cellular, and tissue scales.…”