The Acute Respiratory Distress Syndrome (ARDS) is significantly heterogeneous in both severity and response to treatment. While some treatments (PEEP, prone position) are more beneficial in severe cases, severity alone is insufficient to fully identify patient subgroups. Statistical analysis of clinical trial data has identified hyper-inflammatory and non-inflammatory endotypes with the former being associated with worse outcomes. However, such statistical approaches do not provide direct insight into mechanism. Here we propose to use a novel in vitro force microscopy platform to establish a mechanistic link between hyper inflammatory ARDS, endothelial disruption, and intercellular mechanical stress. We hypothesize that constellations of biomarkers impact the clinical phenotype by altering the mechanical state of the endothelium. Moreover, our preliminary data suggests that endothelial disruption results not from a disruption of a localized balance of forces at cell-cell junctions, but rather from a global reorganization of stress transmission within the endothelial layer. This mechanical reorganization moves the endothelium from an elastic phase, characterized by short- range forces and tolerant of large deformations prior to yielding, to a rigid phase, characterized by longer ranged forces and vulnerable to fracture. We further hypothesize that (i) endothelial mechanical states differ in their response to exogenous forces such as stretch or shear flow (ii) that the endothelial mechanical state may be defined in vitro by the set of cell-generated forces and the endothelial permeability and (iii) specific endothelial mechanical endotypes may be mapped to specific constellations of inflammatory biomarkers. In sum, we hypothesize that endothelial mechanical state may provide a causal link between measurable biomarkers and patient outcomes. The non-inflammatory endotype is characterized by an endothelium tolerant of physiologic levels of stretch and hyper inflammatory ARDS is characterized by an endothelium in which even low magnitude exogenous forces result in increased permeability.
The Acute Respiratory Distress Syndrome (ARDS) is a common illness defined by pathologic leaking of plasma and cells from the blood vessels into the air spaces of the lung. Despite years of research, no specific therapy exists. Research aimed at developing such therapies is complicated by the fact that ARDS is significantly heterogeneous in both severity and response to treatment. Attempts have been made to define subtypes of ARDS to better individualize treatments. As helpful as these efforts have been, however, they have so far been limited to classification by variables such as levels of inflammatory markers that have been tracked in existing clinical trials. This project is built on newly developed technologies that enable us to measure mechanical forces at the cellular level and the effect of those forces on blood vessel integrity. By mapping the cell level mechanical events that are directly responsible for vascular leak to the actions of inflammatory markers (those that have been followed in clinical trials and those for which such data does not yet exist) we hope to classify patients based on the fundamental mechanisms of the disease. Such pathophysiologic typing can lead to more precise clinical trials and better-individualized treatments to improve outcome for individual patients.
| Hardin, C Corey; Chattoraj, Joyjit; Manomohan, Greeshma et al. (2018) Long-range stress transmission guides endothelial gap formation. Biochem Biophys Res Commun 495:749-754 |
