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TRANSLATIONAL PHYSIOLOGY

Physiological and biochemical markers of alveolar epithelial barrier dysfunction in perfused human lungs

Departments of ¹Medicine and ²Anesthesia, ³Cardiovascular Research Institute, University of California, San Francisco; ⁴San Francisco Veterans Administration Medical Center; ⁵Northern California Institute for Research and Education, San Francisco, California; ⁶Keio University Department of Medicine, Tokyo; and ⁷Department of Anesthesiology, Tokyo Medical and Dental University, Tokyo, Japan

Submitted 10 July 2006 ; accepted in final form 9 March 2007

To study air space fluid clearance (AFC) under conditions that resemble the clinical setting of pulmonary edema in patients, we developed a new perfused human lung preparation. We measured AFC in 20 human lungs rejected for transplantation and determined the contribution of AFC to lung fluid balance. AFC was then compared with air space and perfusate levels of a biological marker of epithelial injury. The majority of human lungs rejected for transplant had intact basal (75%) and ₂-adrenergic agonist-stimulated (70%) AFC. For lungs with both basal and stimulated AFC, the basal AFC rate was 19 ± 10%/h, and the ₂-adrenergic-stimulated AFC rate was 43 ± 13%/h. Higher rates of AFC were associated with less lung weight gain (Pearson coefficient –0.90, P < 0.0001). Air space and perfusate levels of the type I pneumocyte marker receptor for advanced glycation end products (RAGE) were threefold and sixfold higher, respectively, in lungs without basal AFC compared with lungs with AFC (P < 0.05). These data show that preserved AFC is a critical determinant of favorable lung fluid balance in the perfused human lung, raising the possibility that ₂-agonist therapy to increase edema fluid clearance may be of value for patients with acute lung injury and pulmonary edema. Also, although additional studies are needed, a biological marker of alveolar epithelial injury may be useful clinically in predicting preserved AFC.

alveolar epithelial fluid transport; acute lung injury; acute respiratory distress syndrome; lung transplantation; biological markers; pulmonary edema; primary graft failure; air space fluid clearance

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