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

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