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American Journal of Respiratory Cell and Molecular Biology. Vol. 28, pp. 478-484, 2003
© 2003 American Thoracic Society
DOI: 10.1165/rcmb.2002-0024OC

Pulmonary Vascular Permeability and Ischemic Injury in Gelsolin-Deficient Mice

Patrice M. Becker, Armina A. Kazi, Raj Wadgaonkar, David B. Pearse, David Kwiatkowski and Joe G. N. Garcia

Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland; and Hematology Division, Brigham and Womens Hospital, Boston, Massachusetts

Address correspondence to: Patrice M. Becker, Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224. E-mail: pbecker1{at}jhmi.edu

Gelsolin is a potent actin filament regulatory protein that controls cytoskeletal assembly and disassembly. Because cellular gelsolin deficiency leads to pronounced actin stress fiber formation and defective chemotaxis, and similar cytoskeletal remodeling results in endothelial barrier dysfunction, we hypothesized that gelsolin deficient mice would exhibit increased vascular permeability. To test this hypothesis, we compared baseline lung lavage (BAL) protein concentration, wet/dry weight ratio, and osmotic reflection coefficient for albumin ({sigma}alb) in gelsolin-deficient (gsn-/-) and C57BL/6 (wild-type) mice. In addition, we assessed lung permeability in response to ischemia by evaluating BAL protein concentration after 4, 8, or 24 h of left pulmonary arterial (LPA) occlusion, and lung wet/dry weight ratio and histology after 24 h of LPA occlusion, in gsn-/- and wild-type animals, as compared with control and sham-operated mice. Baseline measurements revealed that BAL protein concentration was 18-fold higher in gsn-/- than in wild-type mice, whereas {sigma}alb averaged 0.62 + 0.15 in wild-type, as compared with 0.31 + 0.05 in gsn-/- animals, indicating that gelsolin deficiency caused increased pulmonary vascular permeability. Ischemia increased lung permeability (BAL protein and lung wet/dry weight) in both wild-type and gsn-/- mice. However, whereas the fold-increase in BAL protein concentration was less in gsn-/- mice (2- to 4-fold) as compared with wild-type (22- to 34-fold), the duration of ischemia-induced permeability changes was prolonged. Lung wet/dry weight and gross histology following ischemia were comparable in wild-type and gsn-/- animals. These data suggest that gelsolin significantly contributes to maintenance of vascular barrier function in the lung.

Abbreviations: baseline lung lavage, BAL • left pulmonary arterial, LPA • pulmonary artery, PA




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