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EB2004 SYMPOSIUM REPORT

Integrated control of lung fluid balance

¹Department of Pharmacology, University of Illinois-Chicago Medical Center, Chicago, Illinois 60612; ²Department of Medicine, Columbia University, New York, New York 10019; and ³Department of Medicine and Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, California 94143

Submitted 18 August 2004 ; accepted in final form 18 August 2004

This review summarizes the highlights of the EB2004 symposium that dealt with the integrated aspects of the lung fluid balance. It is apparent that maintenance of lung fluid balance requires the proper functioning of vascular endothelial and alveolar epithelial barriers. Under physiological conditions, the transcytotic pathway requiring repeated fission-fusion events of the caveolar membrane with other caveolae solely transports albumin. Caveolin-1, which forms caveolae, and albumin-binding proteins play a central role in signaling the transcytosis of albumin. Signals responsible for increasing endothelial permeability in lung microvessels in response to inflammatory mediators were also described. These studies in gene knockout mouse models revealed the importance of Ca²⁺ signaling via store-operated transient receptor channel 4 and the activation of endothelial myosin light chain kinase isoform in mediating the increase in microvessel permeability. Increases in the cytosolic Ca²⁺ in situ in microvessel endothelia can occur by mitochondria-dependent as well as mitochondria-independent pathways (such as the endoplasmic reticulum). Both these pathways, by triggering endothelial cell activation, may result in lung microvascular injury. The resolution of alveolar edema, requiring clearance of fluid from the air space, is another area of intense investigation in animal models. Although -adrenergic agonists can activate alveolar fluid clearance, signaling pathways regulating these events in intact alveoli remain to be established. Development of mouse models in which the function of regulatory proteins (identified in cell culture studies) can be systematically analyzed will provide a better and more integrated picture of lung fluid balance. In vivo veritas!

caveolin-1; albumin binding proteins; intracellular calcium; store-operated transient receptor channel 4; mitochondria; Na⁺-K⁺-ATPase; CFTR; microvessel permeability

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