Abstract
Understanding the pathophysiology of lung fibrosis is of paramount importance to elaborate targeted and effective therapies. As it onsets, the randomly accumulating extracellular matrix (ECM) breaks the symmetry of the branching lung structure. Interestingly, similar pathways have been reported for both idiopathic pulmonary fibrosis and radiation-induced lung fibrosis (RILF). Individuals suffering from the disease, the worldwide incidence of which is growing, have poor prognosis and a short mean survival time. In this context, mathematical and computational models have the potential to shed light on key underlying pathological mechanisms, shorten the time needed for clinical trials, parallelize hypotheses testing, and improve personalized drug development. Agent-based modeling (ABM) has proven to be a reliable and versatile simulation tool, whose features make it a good candidate for recapitulating emergent behaviors in heterogeneous systems, such as those found at multiple scales in the human body. In this paper, we detail the implementation of a 3D agent-based model of lung fibrosis using a novel simulation platform, namely, BioDynaMo, and prove that it can qualitatively and quantitatively reproduce published results. Furthermore, we provide additional insights on late-fibrosis patterns through ECM density distribution histograms. The model recapitulates key intercellular mechanisms, while cell numbers and types are embodied by alveolar segments that act as agents and are spatially arranged by a custom algorithm. Finally, our model may hold potential for future applications in the context of lung disorders, ranging from RILF (by implementing radiation-induced cell damage mechanisms) to COVID-19 and inflammatory diseases (such as asthma or chronic obstructive pulmonary disease).
Highlights
Lung fibrosis is characterized by the progressive aberrant accumulation of extracellular matrix (ECM) accompanied by the depletion of healthy epithelial tissue, which eventually result in poor gas exchange, increased lung stiffness, and death [1]
For f > 40%, the healthy AEC2 cells are sive decline in the final ECM concentration. This notwithstanding, we show that the loss unable to support the mesenchymal population, whose drop leads to a progressive decline of AEC2 progenitor cells is reflected by a sharp decline in the number of AEC1 cells that in the final ECM concentration. This notwithstanding, we show that the loss of AEC2 has been experimentally detected in lung fibrosis patients as a depletion in epithelial inprogenitor cells is reflected by a sharp decline in the number of AEC1 cells that has been tegrity [9]
We outlined the development of a hybrid 3D Agentbased modeling (ABM) of lung fibrosis
Summary
Lung fibrosis is characterized by the progressive aberrant accumulation of extracellular matrix (ECM) accompanied by the depletion of healthy epithelial tissue, which eventually result in poor gas exchange, increased lung stiffness, and death [1]. Despite having an idiopathic origin in most of the cases (referred to as idiopathic pulmonary fibrosis, IPF), radiation-induced lung fibrosis (RILF) is commonly observed in cancer patients treated with thoracic ionizing radiation, representing the major dose-limiting factor [2]. Fibrosis is thought to originate from the lung parenchyma, where more than 300 million alveoli, functional units responsible for gas exchange, reside [1,4,5]. When damaged AECII are unable to repair properly, they can either undergo apoptosis or activate and adopt a senescent phenotype [11]. If the latter occurs, AECII cells lose their
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