Strategies to protect the lung from ventilation-induced injury and fibrosis due to abnormal alveolar micromechanics

• Applicants: Professor Dr. Lars Knudsen; Professor Dr. Ulrich A. Maus; Clemens Ruppert, Ph.D.
• Subject Area: Pneumology, Thoracic Surgery
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 471334884

Mechanical ventilation of an injured lung is a double-edged sword: it saves lives in patients with acute respiratory distress syndrome, but can also worsen existing damage by transmitting mechanical stress to fine lung parenchyma even during protective mechanical ventilation. Injurious stress is supposed to result from abnormal alveolar micromechanics. In a healthy lung the surfactant system stabilizes alveoli and homogenizes alveolar ventilation. Homogeneous ventilation minimizes the mechanical stress that effects the blood-gas barrier. Surfactant is produced and secreted by alveolar epithelial type II cells which are also attacked by lung injury. This leads to surfactant dysfunction and associated abnormalities in alveolar micromechanics: e.g. alveolar collapse (=microatelectases) and related heterogeneous ventilation. In a network of interdependent alveoli, microatelectases have been suggested to act as stress concentrators causing tensile forces on neighboring alveoli. In presence of microatelectases, our computational simulations of alveolar micromechanics demonstrated increased static and dynamic alveolar volume changes during mechanical ventilation and mechanical ventilation unmasked lung injury in our animal experiments characterized by progressive damage of the alveolar epithelial cells linked with increased endoplasmic reticulum (ER) stress. However, our understanding of the spread of lung injury during ventilation and the exact micromechanical mechanisms which are involved is still fragmentary. Hence, we aim to address three objectives that are to be evaluated in our animal models of mechanical ventilation of pre-injured lungs suffering from microatelectases: 1. Testing the hypothesis whether microatelectases operate as germinal centers for the spread of the alveolar epithelial injury, ER-stress, vascular leak and pro-fibrotic remodeling during mechanical ventilation. We will characterize the spatial-temporal spread of lung injury during mechanical ventilation in relation to microatelectases, using i.a. quantitative and correlative imaging. 2. Testing the hypothesis whether early treatment of alveolar collapse by means of aerosolized surfactant prevents the ventilation-induced worsening of lung injury and pro-fibrotic remodeling. 3. Simulation of alveolar micromechanics during mechanical ventilation using computational modelling based on lung mechanical and structural data. These simulations will allow us to infer the dominant micromechanical mechanism (e.g. alveolar stretch, alveolar wall folding/ unfolding, alveolar collapse) responsible for lung injury progression and can also be used to identify optimal ventilation parameters to minimize injury. This project will improve our understanding of the changes in micromechanics and their role in the spread of ventilation-induced lung damage. Moreover, it will help to identify strategies to reduce harmful transmission of stress during mechanical ventilation in clinical lung injury.

• DFG Programme: Research Grants
• International Connection: USA
• Cooperation Partner: Professor Dr. Bradford J. Smith