Acute Respiratory Distress Syndrome (ARDS) is a devastating illness with an annual incidence of 200,000 and a mortality of 40%. Sepsis is a major cause of ARDS, contributing up to ~80% of ARDS cases. Endothelial barrier dysfunction is critical for the pathogenesis of vascular permeability and the resulting tissue edema and profound hypoxia seen in ARDS. Endothelial barrier dysfunction in sepsis is a complex phenomenon involving cytoskeletal changes in response to pro-inflammatory mediators, where the actin cytoskeleton plays a pivotal role in mediating endothelial barrier function and permeability. Interestingly, the same stimuli that lead to cytoskeletal changes within the endothelium, e.g. activation of toll-like receptor 4, fas-ligand and stress activated kinases, can also precipitate endothelial cell apoptosis. While cytoskeletal changes are reversible and are eventually followed by recovery of the endothelial barrier, endothelial cell apoptosis represents a final cellular fate and may be an irreversible determinant of endothelial barrier disruption. In fact, after apoptotic-endothelial injury, restoration of barrier function requires endothelial cell proliferation, migration and/or endothelial progenitor cell seeding implying an irreversibility to apoptotic endothelial barrier disruption. These two mechanisms of vascular permeability, bring about the possibility of a transition point linking reversal (cytoskeletal) and irreversible (apoptotic) modes of endothelial barrier disruption that if identified, could be exploited for therapeutic intervention. Many models used for understanding the pathophysiology of endothelial barrier dysfunction have focused on the initiation phase of endothelial barrier disruption. Recently new insights have started to emerge regarding the resolution of ARDS. Understanding of both phases of ARDS has significant merit towards the development of therapeutic targets. Importantly, molecular targets that integrate and lie at the intersection of these two phases of ARDS could not only attenuate injury but concomitantly accelerate recovery. This proposal will provide new insight into concurrent attenuation of endothelial barrier disruption and promotion of endothelial barrier recovery by elucidating the molecular mechanisms by which caspase 3 influences cytoskeletal de-remodeling and apoptotic-endothelial injury.

Public Health Relevance

Endothelial barrier disruption is the pathophysiological hallmark of sepsis-induced acute respiratory distress syndrome (ARDS). We have identified previously unrecognized dual and divergent, location-specific roles for cleaved caspase 3 (generally thought to be involved mostly in the execution of apoptosis), with cytosolic caspase 3 opposing and nuclear caspase 3 promoting endothelial barrier disruption. Combining the scientific team's expertise in endothelial biology, apoptosis, MAP kinase signaling and murine models of vascular dysfunction, this project will utilize a multidisciplinary approach reliant on molecular biological tools, phospho-proteomic analyses and animal models of sepsis to determine the mechanisms by which MK2 facilitates the transition of active caspase 3 from barrier protective to injurious. i

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Zhou, Guofei
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Suresh, Karthik; Servinsky, Laura; Jiang, Haiyang et al. (2018) Reactive oxygen species induced Ca2+ influx via TRPV4 and microvascular endothelial dysfunction in the SU5416/hypoxia model of pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 314:L893-L907
Magruder, J Trent; Grimm, Joshua C; Crawford, Todd C et al. (2018) Imatinib Is Protective Against Ischemia-Reperfusion Injury in an Ex Vivo Rabbit Model of Lung Injury. Ann Thorac Surg 105:950-956
Damarla, Mahendra; Johnston, Laura F; Liu, Gigi et al. (2017) XOR inhibition with febuxostat accelerates pulmonary endothelial barrier recovery and improves survival in lipopolysaccharide-induced murine sepsis. Physiol Rep 5: