ArticleFrontiers in pharmacology2016
Computational Modeling Predicts Simultaneous Targeting of Fibroblasts and Epithelial Cells Is Necessary for Treatment of Pulmonary Fibrosis.
Article in Frontiers in pharmacology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 36 citations in OpenAlex.
- An agent-based model suggests how senescent cell behavior and matrix mechanics drive pulmonary fibrosis in aged mice.bioRxiv : the preprint server for biology · 2026Article
- Bifurcation in the healing or fibrotic response in a network model of fibrosis: role of the initial injury structure.Frontiers in network physiology · 2025Article
- A perfectly imperfect engine: Utilizing the digital twin paradigm in pulmonary hypertension.Pulmonary circulation · 2024Review
- An agent-based modeling approach for lung fibrosis in response to COVID-19.PLoS computational biology · 2023Article
- Differences in Treatment Response in Bronchial Epithelial Cells from Idiopathic Pulmonary Fibrosis (IPF) Patients: A First Step towards Personalized Medicine?Antioxidants (Basel, Switzerland) · 2023Article
- A computational modeling approach for predicting multicell spheroid patterns based on signaling-induced differential adhesion.PLoS computational biology · 2022Article
- Systems biology predicts that fibrosis in tuberculous granulomas may arise through macrophage-to-myofibroblast transformation.PLoS computational biology · 2020Article
- Type I Collagen Signaling Regulates Opposing Fibrotic Pathways through αAmerican journal of respiratory cell and molecular biology · 2020Article
- Multi-scale models of lung fibrosis.Matrix biology : journal of the International Society for Matrix Biology · 2020Review
- Diverse Injury Pathways Induce Alveolar Epithelial Cell CCL2/12, Which Promotes Lung Fibrosis.American journal of respiratory cell and molecular biology · 2020Article
- Agent-based models of inflammation in translational systems biology: A decade later.Wiley interdisciplinary reviews. Systems biology and medicine · 2019Review
- In Vitro Granuloma Models of Tuberculosis: Potential and Challenges.The Journal of infectious diseases · 2019Review
- Multiscale Coupling of an Agent-Based Model of Tissue Fibrosis and a Logic-Based Model of Intracellular Signaling.Frontiers in physiology · 2019Article
- A review of inflammatory mechanism in airway diseases.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2019Review
- Differential effects of Nintedanib and Pirfenidone on lung alveolar epithelial cell function in ex vivo murine and human lung tissue cultures of pulmonary fibrosis.Respiratory research · 2018Article
- Dynamic balance of pro- and anti-inflammatory signals controls disease and limits pathology.Immunological reviews · 2018Review
- Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease.Nature reviews. Drug discovery · 2017Review
- Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease.Nature reviews. Drug discovery · 2017Article
- Identifying mechanisms driving formation of granuloma-associated fibrosis during Mycobacterium tuberculosis infection.Journal of theoretical biology · 2017Article
- Lung epithelial cell focal adhesion kinase signaling inhibits lung injury and fibrosis.American journal of physiology. Lung cellular and molecular physiology · 2017Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
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.
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