Age-dependent ventilator-induced lung injury: Mathematical modeling, experimental data, and statistical analysis

Area of Science:

• Pulmonary Medicine
• Computational Biology
• Immunology

Background:

• Mechanical ventilation is life-saving but can cause ventilator-induced lung injury (VILI).
• Older individuals exhibit increased respiratory distress and altered inflammatory responses.
• Age-related differences in VILI pathogenesis require further investigation.

Purpose of the Study:

• To investigate age-dependent differences in lung injury following mechanical ventilation.
• To develop a mathematical model of the inflammatory response to VILI.
• To identify key parameters and potential interventions for mitigating VILI in older mice.

Main Methods:

• High-pressure mechanical ventilation of young and old mice for 2 hours.
• Analysis of macrophage phenotypes and lung tissue integrity.
• Development of a mathematical model incorporating inflammatory cells, mediators, epithelial cells, and repair mediators.
• Classification and sensitivity analyses to identify influential model parameters.

Main Results:

• Older mice exhibited greater baseline macrophage activation and significant airspace enlargement post-ventilation.
• The mathematical model identified parameters related to epithelial repair/damage and M1 macrophages as influential.
• In-silico interventions showed the most impact on simulated older mice with pre-existing lung conditions.
• M1 macrophage dynamics and pro-inflammatory responses were highlighted as drivers of age-dependent VILI.

Conclusions:

• Age significantly influences the inflammatory response and susceptibility to VILI.
• Mathematical modeling provides insights into VILI mechanisms and identifies potential therapeutic targets.
• M1 macrophages and pro-inflammatory pathways are critical areas for future research in age-related VILI.