Influence of Cytoskeletal Mechanics and Networks on Lung Injury, Inflammation and Repair

Samir Ghadiali
Biomedical Engineering, The Ohio State University

(March 4, 2010 10:30 AM - 11:18 AM)

Influence of Cytoskeletal Mechanics and Networks on Lung Injury, Inflammation and Repair

Abstract

The ability of cells to sense and respond to mechanical forces, i.e. mechanotransduction, plays an important role in many biological processes and in several disease pathologies. Although the exact mechanisms by which cells sense and respond to mechanical force is not known, force transmission via cytoskeletal networks likely plays a key role. Our laboratory is specifically investigating how cytoskeletal mechanics and networks influence the injury, inflammation and repair of lung epithelial cells during the acute respiratory distress syndrome (ARDS). ARDS is a devastating disorder in which bacterial/viral infections (e.g. pneumonia or H1N1 flu) cause cellular damage, lung inflammation and multisystem organ failure. Although mechanical ventilation is required for survival, these ventilators often exacerbate the existing lung injury leading to high mortality rates (~30%). One source of injury during ventilation is the microbubble flows generated during cyclic airway closure and reopening. In addition to causing cell necrosis and barrier disruption, the mechanical forces generated by microbubbles also result in the up-regulation of inflammatory pathways. Since preventing microbubbles in a clinical setting is difficult, we are investigating an alternative approach to preventing injury in which changes in cytoskeletal mechanics/structure are used to mitigate the mechanotransduction processes responsible for inflammatory signaling. We are particularly interested in how changes in cytoskeletal networks may be used to mitigate the activation of Nf-kB pathways, secretion of pro-inflammatory cytokines and expression of microRNAs that regulate inflammation. In addition to in-vitro experiments, we have also developed a novel multi-scale mathematical model of force transmission and cell deformation to identify how specific changes in cytoskeletal structure influence injury patterns. Our combined computational-experimental approach has lead to a better understanding about how changes in cytoskeletal structure may be used to mitigate the mechanotransduction processes responsible for lung injury and inflammation during ARDS.