Mathematical Modeling of Impacts of Patient Differences on COVID-19 Lung Fibrosis Outcomes

Introduction:: Patient-specific premorbidity, age, and sex are significant heterogeneous factors that influence the severe manifestation of lung diseases, including COVID-19 fibrosis. The renin-angiotensin system (RAS) plays a prominent role in regulating effects of these factors. Recent evidence suggests that patient-specific alteration of RAS homeostasis with premorbidity and the expression level of angiotensin-converting enzyme 2 (ACE2), depending on age and sex, is correlated with lung fibrosis. However, conflicting evidence suggests decreases, increases, or no changes in RAS after SARS-CoV-2 infection [1]. In addition, detailed mechanisms connecting the patient-specific conditions before infection to infection-induced fibrosis are still unknown.

Materials and Methods:: Here, a mathematical model is developed to quantify the systemic contribution of heterogeneous factors of RAS in the progression of lung fibrosis. Three submodels are connected—a RAS model, an agent-based COVID-19 in-host immune response model (“immune model”), and a fibrosis model—to investigate the effects of patient-group-specific factors in the systemic alteration of RAS and collagen deposition in the lung [2]. The RAS model consists of a set of ODEs to account for patient-specific local and systemic changes in RAS peptides and enzymes. The immune model is developed in an open-source multiscale agent-based framework PhysiCell and simulates a tissue section representing a monolayer of stationary epithelial cells on an alveolar surface of lung tissue [3]. We infect the tissue by placing SARS-CoV-2 viruses in the extracellular space using uniform random and Gaussian distribution. Viral particles diffuse through tissue, bind with unoccupied ACE2 receptors on the epithelial cell surface, internalize via endocytosis, replicate through intracellular viral replication kinetics, and export back to the extracellular domain by exocytosis. We varied the initial unoccupied ACE2 receptors concentration on the cell surface based on the availability of ACE2 receptors for different age-sex groups [4]. The variations of ACE2 before infection and immune response after viral infection alter TGF-b dynamics, leading to recruitment of fibroblasts. The excess collagen deposition by fibroblasts causes fibrosis. The fibrosis model accounts for systemic contribution to fibrosis due to patient-group-specific conditions before infection and infection-induced fibrosis through TGF-b-dependent fibroblasts activation, recruitment, and collagen deposition.


Results, Conclusions, and Discussions:: The model results indicated cell death due to inflammatory response as a major contributor to the reduction of ACE and ACE2, whereas there were no significant changes in ACE2 dynamics due to viral-bound internalization of ACE2. Reduction of ACE reduces the homeostasis of RAS including angiotensin II (ANGII), while the decrease in ACE2 increases ANGII and results in severe lung injury and fibrosis. The model explains possible mechanisms for conflicting evidence of RAS alterations in previously published studies. We also observed longer viral persistence with a lower initial number of ACE2, which is consistent with the severity of SARS-CoV-2 infection in older people (Figure 1A). We simulated cell population and collagen dynamics for different patient-specific groups and calculated collagen area fraction as the ratio of collagen area to the total area of the tissue (Figure 1B-1D). The results show that ACE2 variations with age and sex significantly alter RAS peptides and lead to fibrosis with around 20% additional collagen deposition from systemic RAS with slight variations depending on age and sex. This model may find further applications in patient-specific calibrations of tissue models for acute and chronic lung diseases to develop personalized treatments.


Acknowledgements (Optional): : This work was supported by the National Institutes of Health grant R35GM133763 and the University at Buffalo.

References (Optional): : [1] Kutz, A. et al., Renin-angiotensin-aldosterone system peptide profiles in patients with COVID-19, European Journal of Endocrinology 184 (2021) 543–552


[2] Islam, M. A. and Ford Versypt, A.N., Mathematical modeling of impacts of patient differences on COVID-19 lung fibrosis outcomes, BioRxiv (2022)

[3] Getz, M. et al., Iterative community-driven development of a SARS-CoV-2 tissue simulator, BioRxiv (2021)

[4] Xudong, X. et al., Age-and gender-related difference of ACE2 expression in rat lung, Life sciences 78.19 (2006): 2166-2171