An Agent-Based Model of Radiation-Induced Lung Fibrosis
Early- and late-phase radiation-induced lung injuries, namely pneumonitis and lung fibrosis (RILF), severely constrain the maximum dose and irradiated volume in thoracic radiotherapy. As the most radiosensitive targets, epithelial cells respond to radiation either by undergoing apoptosis or switchin...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/22/13920 |
| _version_ | 1797465167004434432 |
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| author | Nicolò Cogno Roman Bauer Marco Durante |
| author_facet | Nicolò Cogno Roman Bauer Marco Durante |
| author_sort | Nicolò Cogno |
| collection | DOAJ |
| description | Early- and late-phase radiation-induced lung injuries, namely pneumonitis and lung fibrosis (RILF), severely constrain the maximum dose and irradiated volume in thoracic radiotherapy. As the most radiosensitive targets, epithelial cells respond to radiation either by undergoing apoptosis or switching to a senescent phenotype that triggers the immune system and damages surrounding healthy cells. Unresolved inflammation stimulates mesenchymal cells’ proliferation and extracellular matrix (ECM) secretion, which irreversibly stiffens the alveolar walls and leads to respiratory failure. Although a thorough understanding is lacking, RILF and idiopathic pulmonary fibrosis share multiple pathways and would mutually benefit from further insights into disease progression. Furthermore, current normal tissue complication probability (NTCP) models rely on clinical experience to set tolerance doses for organs at risk and leave aside mechanistic interpretations of the undergoing processes. To these aims, we implemented a 3D agent-based model (ABM) of an alveolar duct that simulates cell dynamics and substance diffusion following radiation injury. Emphasis was placed on cell repopulation, senescent clearance, and intra/inter-alveolar bystander senescence while tracking ECM deposition. Our ABM successfully replicates early and late fibrotic response patterns reported in the literature along with the ECM sigmoidal dose-response curve. Moreover, surrogate measures of RILF severity via a custom indicator show qualitative agreement with published fibrosis indices. Finally, our ABM provides a fully mechanistic alveolar survival curve highlighting the need to include bystander damage in lung NTCP models. |
| first_indexed | 2024-03-09T18:17:40Z |
| format | Article |
| id | doaj.art-647a49c3394045d8b723be3d791abbb2 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T18:17:40Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-647a49c3394045d8b723be3d791abbb22023-11-24T08:35:36ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123221392010.3390/ijms232213920An Agent-Based Model of Radiation-Induced Lung FibrosisNicolò Cogno0Roman Bauer1Marco Durante2Biophysics Department, GSI Helmholtzzentrum für Schwerionenforschung GmbH, 64291 Darmstadt, GermanyDepartment of Computer Science, University of Surrey, Guildford GU2 7XH, UKBiophysics Department, GSI Helmholtzzentrum für Schwerionenforschung GmbH, 64291 Darmstadt, GermanyEarly- and late-phase radiation-induced lung injuries, namely pneumonitis and lung fibrosis (RILF), severely constrain the maximum dose and irradiated volume in thoracic radiotherapy. As the most radiosensitive targets, epithelial cells respond to radiation either by undergoing apoptosis or switching to a senescent phenotype that triggers the immune system and damages surrounding healthy cells. Unresolved inflammation stimulates mesenchymal cells’ proliferation and extracellular matrix (ECM) secretion, which irreversibly stiffens the alveolar walls and leads to respiratory failure. Although a thorough understanding is lacking, RILF and idiopathic pulmonary fibrosis share multiple pathways and would mutually benefit from further insights into disease progression. Furthermore, current normal tissue complication probability (NTCP) models rely on clinical experience to set tolerance doses for organs at risk and leave aside mechanistic interpretations of the undergoing processes. To these aims, we implemented a 3D agent-based model (ABM) of an alveolar duct that simulates cell dynamics and substance diffusion following radiation injury. Emphasis was placed on cell repopulation, senescent clearance, and intra/inter-alveolar bystander senescence while tracking ECM deposition. Our ABM successfully replicates early and late fibrotic response patterns reported in the literature along with the ECM sigmoidal dose-response curve. Moreover, surrogate measures of RILF severity via a custom indicator show qualitative agreement with published fibrosis indices. Finally, our ABM provides a fully mechanistic alveolar survival curve highlighting the need to include bystander damage in lung NTCP models.https://www.mdpi.com/1422-0067/23/22/13920agent-based modellingRILFIPFsenescencebystander3D modelling |
| spellingShingle | Nicolò Cogno Roman Bauer Marco Durante An Agent-Based Model of Radiation-Induced Lung Fibrosis International Journal of Molecular Sciences agent-based modelling RILF IPF senescence bystander 3D modelling |
| title | An Agent-Based Model of Radiation-Induced Lung Fibrosis |
| title_full | An Agent-Based Model of Radiation-Induced Lung Fibrosis |
| title_fullStr | An Agent-Based Model of Radiation-Induced Lung Fibrosis |
| title_full_unstemmed | An Agent-Based Model of Radiation-Induced Lung Fibrosis |
| title_short | An Agent-Based Model of Radiation-Induced Lung Fibrosis |
| title_sort | agent based model of radiation induced lung fibrosis |
| topic | agent-based modelling RILF IPF senescence bystander 3D modelling |
| url | https://www.mdpi.com/1422-0067/23/22/13920 |
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