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J Appl Physiol 89: 2241-2248, 2000;
8750-7587/00 $5.00
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Vol. 89, Issue 6, 2241-2248, December 2000

Inhibitors of myosin light chain kinase and phosphodiesterase reduce ventilator-induced lung injury

James C. Parker
(With the Technical Assistance of Sherri L. Martin)

Department of Physiology, University of South Alabama, Mobile, Alabama 36688

Alveolar overdistension due to high peak inflation pressures (PIP) is associated with an increased capillary filtration coefficient (Kfc). To determine which signal pathways contribute to this injury, we perfused isolated rat lungs with 5% bovine albumin in Krebs solution and measured Kfc after successive 30-min periods of ventilation with peak inflation pressures (PIP) of 7, 20, 30, and 35 cmH2O. In a high-PIP control group, Kfc increased significantly after ventilation with 30 and 35 cmH2O PIP, but significant increases were prevented by treatment with 100 µM trifluoperazine, an inhibitor of Ca2+/calmodulin, 500 nM ML-7, an inhibitor of myosin light chain kinase (MLCK), a combination of isoproterenol (20 µM) and rolipram (10 µM) to enhance intracellular cAMP levels, and a dose of KT-5720 (2 µM), which inhibits MLCK and protein kinase C. These studies suggest that the Ca2+/calmodulin-MLCK pathway augments capillary fluid leak after a modest high-PIP injury and that this is attenuated by kinase inhibition and increased intracellular cAMP.

pulmonary barotrauma; mechanical ventilation; capillary permeability; rolipram; isoproterenol; calmodulin


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