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).
Mechanisms of the alternative activation of macrophages and non-coding RNAs in the development of radiation-induced lung fibrosis