Elucidation of the Mechanisms of Transcellular and Paracellular Endothelial Permeability -- Towards its Therapeutic Manipulation

Every blood vessel in the body is lined on its luminal aspect with a single layer of interconnected cells, known as endothelial cells. Together, these cells form a tissue known as the endothelium, a tightly regulated system that physically segregates the fluid in the blood from the peripheral tissues, and orchestrates the passage of nutrients, xenobiotics, immune cells, and fluids between distinct compartments in the body. In healthy, quiescent vasculature, passage of compounds across the vasculature occurs by two separate, yet equally important mechanisms. In the paracellular route, compounds that are small enough to pass between endothelial cell junctions freely diffuse down their concentration gradient, reaching equilibrium between the blood and sub-endothelial compartments. In contrast, transcytosis involves the regulated transit of compounds through endothelial cells by endocytosis, subcellular trafficking, and exocytosis, and in doing so, allows for the transport of larger compounds through the use of a number of specialized proteins. Under normal circumstances, these two mechanisms of endothelial permeability work in concert to maintain homeostasis. However it has recently become apparent that dysregulated endothelial permeability is the cause of a number of pathological conditions. Increased paracellular permeability of the lung endothelium leads to the acute respiratory distress syndrome (ARDS), a potentially fatal condition involving acute lung edema, respiratory failure, and death. Endothelial transcytosis of low-density lipoprotein (LDL) leads to the accumulation of LDL in the subendothelial intima, the initiating event in atherosclerotic lesion development. Although dysregulated endothelial permeability is central to the pathophysiology of these diseases, the paucity of literature on the subject highlights the need for a detailed, mechanistic investigation. In this thesis I present a body of work that uncovers several novel mechanisms that regulate endothelial permeability in the pathological contexts of pathogen-induced ARDS and LDL transcytosis as a precursor to atherosclerotic lesion development. Results from these studies suggest that targeting endothelial permeability is novel and viable therapeutic strategy for management of these common diseases.Ph.D