The Pulmonary/Critical Care Research Laboratory at the Providence VA Medical Center is focussed on understanding the mechanism(s) of vascular endothelial cell injury which result in increased vascular permeability and the clinical syndromes of Acute Respiratory Distress Syndrome (ARDS) and Multisystem Organ Dysfunction Syndrome (MODS). Despite significant improvements in supportive care, the mortality of ARDS and MODS remains unacceptably high. Better understanding of the pathogenesis of these injuries will result in improved methods of treatment and prevention.

Our laboratory has studied mechanisms of endothelial cell injury, including injury caused by activated neutrophils. We have defined the effects of extracellular nucleotides on neutrophil adhesion to endothelial cells (1,2) and to tracheobronchial epithelial cells (3).

One form of endothelial cell injury is apoptosis, or programmed cell death. Apoptosis occurs in acute vascular injuries and also is important in limiting angiogenesis during the repair phase of injury. We have described a novel model of endothelial cell apoptosis which is caused by extracellular ATP and adenosine (4). The effects of adenosine require uptake into cells and are exacerbated by excess homocysteine. This model of apoptosis appears to be caused by inhibition of S-adenosylhomocysteine hydrolase activity and by inhibition of protein carboxyl methyl transferase activity (5). More recent studies have focussed on cell signaling mechanisms and on disruption of focal adhesion complexes in this model of endothelial cell apoptosis.

Future investigations will focus on defining the mechanism of disruption of focal adhesion complexes in adenosine/homocysteine-induced apoptosis. We will also determine the link between methyltransferase inhibition and focal adhesion complex disruption. These studies are funded by VA Merit Review, a collaborative research grant from the VA and the Department of Defense, and the NHLBI.