Role of Rho-kinase in reexpansion pulmonary edema in rabbits.
Reexpansion of a collapsed lung increases the microvascular permeability and causes reexpansion pulmonary edema. Neutrophils and their products have been implicated in the development of this phenomenon. The small GTP-binding proteins Rho and its target Rho-kinase (ROCK) regulate endothelial permeability, although their roles in reexpansion pulmonary edema remain unclear. We studied the contribution of ROCK to pulmonary endothelial and epithelial permeability in a rabbit model of this disorder. Endothelial and epithelial permeability was assessed by measuring the tissue-to-plasma (T/P) and bronchoalveolar lavage (BAL) fluid-to-plasma (B/P) ratios with (125)I-labeled albumin. After intratracheal instillation of (125)I-albumin, epithelial permeability was also assessed from the plasma leak (PL) index, the ratio of (125)I-albumin in plasma/total amount of instilled (125)I-albumin. T/P, B/P, and PL index were significantly increased in the reexpanded lung. These increases were attenuated by pretreatment with Y-27632, a specific ROCK inhibitor. However, neutrophil influx, neutrophil elastase activity, and malondialdehyde concentrations in BAL fluid collected from the reexpanded lung were not changed by Y-27632. In endothelial monolayers, Y-27632 significantly attenuated the H(2)O(2)-induced increase in permeability and mitigated the morphological changes in the actin microfilament cytoskeleton of endothelial cells. These in vivo and in vitro observations suggest that the Rho/ROCK pathway contributes to the increase in alveolar barrier permeability associated with reexpansion pulmonary edema.
Sawafuji
Makoto
M
Dept. of Surgery, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. msawafuji@nifty.com
Ishizaka
Akitoshi
A
Kohno
Mitsutomo
M
Koh
Hidefumi
H
Tasaka
Sadatomo
S
Ishii
Yoshiki
Y
Kobayashi
Koichi
K
D008841:Actin Cytoskeleton / Q000378:metabolism; D000577:Amides / Q000008:administration & dosage; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002199:Capillary Permeability / Q000187:drug effects; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D047908:Intracellular Signaling Peptides and Proteins; D019272:Leukocyte Elastase / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011654:Pulmonary Edema / Q000201:enzymology* / Q000473:pathology; D011725:Pyridines / Q000008:administration & dosage; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases
D000577:Amides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; C108830:Y 27632; D008315:Malondialdehyde; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D019272:Leukocyte Elastase; D020741:rho GTP-Binding Proteins