Thursday, May 9, 2024
5/9/2024
PROJECT SUMMARY Acute respiratory distress syndrome (ARDS) is a life-threatening inflammatory lung disease that has high morbidity and mortality rates, with 40% of patients dying making it a significant public health concern. In the healthy human lung, the fluid in the airspace is balanced by two complementary processes: sodium-driven fluid clearance and paracellular diffusion of fluid through the junctions between epithelial cells. ARDS is due to dysfunction in these two processes, leading to flooding of the tiny air sacs in the lungs (the alveoli). In the impaired lung, paracellular diffusion increases due to increased leak, but the lung compensates by increasing sodium-driven fluid clearance. This leaves the lung functional but impaired, priming it for ARDS. The damaged lung barrier combined with a second injury such as pneumonia, sepsis, or ventilator-induced injury can cause severe airspace flooding, pulmonary edema, that cannot be mediated by compensatory fluid clearance. Chronic alcohol abuse exacerbates the severity and likelihood of ARDS, by disrupting a major regulator of the fluid balance in the lungs, tight junctions. Studies have examined factors that affect tight junctions in alveolar epithelial cells, but a lesser studied possible interactor of tight junctions are integrins. Integrins exist as obligate a/ß heterodimer pairs that can form several functionally distinct conformations. The two forms are an inactive bent state and an active extended state that enables high affinity ligand binding. Here we will examine integrin expression, localization, and function in primary alveolar and airway epithelial cells. The effect of specifically targeting integrins on paracellular permeability will be measured, along with determining the molecular mechanisms linking integrins to the regulation of tight junctions. This approach will help evaluate integrins as a target to regulate lung fluid balance through the control of lung epithelial tight junctions.
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