Variable cell stretching and mechanical ventilation: A comprehensive investigation on the mechanisms and long-term effects of a new ventilatory strategy

• Applicant: Professor Dr. Marcelo Gama de Abreu
• Subject Area: Anaesthesiology
• Term: from 2013 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 234005084

Variable mechanical ventilation improves lung function and damage in experimental lung injury, as compared to conventional mechanical ventilation. Such effects are partially explained by redistribution of aeration and perfusion to dependent lung zones, which may improve ventilation/perfusion matching and reduce regional stress/strain. Theoretically, a differentiated mechanotransduction in alveolar epithelial cells during variable tidal stretching could also contribute to the mechanisms of lung protection during variable ventilation. This project aims at shedding light onto the mechanisms of lung protection of long-term variable ventilation in the micro and macro-structure of lungs (studies A and B, respectively). In study A, alveolar epithelial cells type L2, as well as primary alveolar epithelial cells type II and type I-like from rats, will be submitted to variable and non-variable tidal stretching. The inflammatory response, activation of transcriptional factors and the regulation of cation channels on the cell membrane will be determined. In study B, lung injury will be induced in pigs by a double-hit approach, and animals ventilated for 24 h with either variable, or non-variable volume controlled mechanical ventilation. The regional distribution of the net uptake rate of the intravenous injection of 18F-fluorodeoxyglucose (18F-FDG) will be assessed using positron emission tomography and a multicompartmental model of 18F-FDG kinetics. We hypothesize that variable compared to non-variable tidal cell stretching (study A): 1) decreases the gene expression of the mechano-sensitive cell membrane protein amphiregulin; 2) decreases the activation and release of pro-inflammatory cytokines; 3) decreases the activation of transcriptional factors c-fos, NF-kappa-B and their translocation into the cell nucleus and; 4) under-regulates the opening of cation channels on the cell membrane. We also hypothesize that variable compared to non-variable volume controlled ventilation, in the long-term (study B): a) reduces and redistributes neutrophilic inflammation across the lungs; b) reduces diffuse alveolar damage; c) improves gas exchange and; d) results in more homogeneous distribution of aeration, ventilation and perfusion across the lungs. The results from this project may have impact on the understanding of the micro- and macro-structural mechanisms of protection, as well as on characterization of the long-term effects of variable mechanical ventilation on lung function and damage. Such information will likely motivate clinical investigations on this ventilatory strategy, which may influence the practice of mechanical ventilation in patients suffering from the acute respiratory distress syndrome.

• DFG Programme: Research Grants
• International Connection: Italy, USA
• Participating Institution: Massachusetts General Hospital; Department of Anesthesia, Critical Care and Pain Medicine; Università degli Studi di Genova; Dipartimento di Scienze Chirurgiche e Diagnostiche Integrate; Technische Universität Dresden ; Medizinische Fakultät Carl-Gustav-Carus ; Institut für Anatomie; Universitätsklinikum Aachen, AöR; Institut für Pharmakologie und Toxikologie; Universitätsklinikum Carl Gustav Carus; an der Technischen Universität Dresden; Klinik und Poliklinik für Nuklearmedizin
• Participating Persons: Professor Dr. Michael Kasper; Professor Dr. Jörg Kotzerke; Professor Dr. Paolo Pelosi; Professor Dr. Stefan Uhlig; Professor Dr. Marcos Francisco Vidal Melo