Modeling the Role of Organ Crosstalk and Cellular Adaptation in Multiple Organ Dysfunction Syndrome
Authors: Papadopoulos Stefanos , Parker Robert , Clermont Gilles 
Published: February 2025

Objectives: In the intensive care unit (ICU) 75% of severe sepsis patients develop multiple organ dysfunction syndrome (MODS)1. The dysfunction of a single organ disrupts complex organ interactions leading to the onset of MODS. These interaction mechanisms are not well understood and have limited development of targeted interventions. To overcome this challenge, we extend our model, which integrates a game theoretic approach for cellular adaptation with a physiological model, to include multiple organs and the trafficking of multiple currencies to better elucidate the drivers of MODS.Methods: Our previous lung-centric model was expanded to incorporate liver and kidney interactions2. The lung is responsible for oxygen uptake, while the liver and kidney handle waste clearance. The immune system consists of 6 states: pathogen, pro- and anti-inflammatory responses, and damage to each organ. A pathogen insult triggers inflammation causing damage. This causes a decrease in oxygen availability and waste accumulation. The trafficking of these currencies (oxygen, waste) informs the physio-economic game. Cells have two available strategies: cooperation and defection. Each strategy has a set of reward functions for each currency. Cells transition between strategies to maximize an organ’s reward and adapt to changes in oxygen availability and waste concentration, but significant defection leads to organ dysfunction. The predicted progression of MODS is investigated, while varying immune system parameters and treatment.Results: The model predicts a recovery envelope in two-dimensional inflammatory parameter space (pro- vs anti-inflammatory generation rate), with MODS occurring outside the envelope. In both recovery and failure, initial inflammation causes lung damage, decreasing oxygen delivery and incentivizing cellular defection in the liver and kidney. This conserves oxygen and temporarily stabilizes the system. But if pathogen and inflammation persist, liver and kidney damage occur. Both defection and damage in the liver and kidney cause systemic waste accumulation. These mechanisms produce a positive feedback loop between oxygen, waste and organ dysfunction that overwhelms the recovery mechanisms. To avert collapse, mechanical ventilation is implemented as a logic controller. Supplemental oxygen and positive end expiratory pressure (PEEP–increases lung volume for gas exchange) are used to maintain a target oxygen saturation. The administration of a generic antibiotic is implemented using a one-compartment model. The predicted progression of MODS and the currencies are compared to trends in ICU patient biomarkers and critical care scoring systems.Conclusion: Our novel model framework integrates cell level physio-economics with organ level physiological functions to predict MODS progression. Interindividual differences in inflammatory response (parameter values) capture the organ interdependencies and clinically-observed outcomes of recovery and MODS.Citations: [1] Blanco J, Muriel-Bombín A, Sagredo V, et al. Incidence, organ dysfunction and mortality in severe sepsis: a Spanish multicentre study. Critical Care. 2008 12(6):R158. [2] Papadopoulos S, Clermont G, Parker RS. Modeling Organ Failure Under Hypoxic Stress. IFAC-PapersOnLine. 2022, 55(23):33-4.