PHOSPHOTYROSINE PHOSPHATASE AND TYROSINE KINASE INHIBITION MODULATE AIRWAY PRESSURE-INDUCED LUNG INJURY

We determined whether drugs which modulate the state of protein tyrosi ne phosphorylation could alter the threshold for high airway pressure- induced microvascular injury in isolated perfused rat lungs. Lungs wer e ventilated for successive 30-min periods with peak inflation pressur es (PIP) of 7, 20, 30, and 35 cmH(2)O followed by measurement of the c apillary filtration coefficient (K-fc), a sensitive index of hydraulic conductance. In untreated control lungs, K-fc increased by 1.3- and 3 .3-fold relative to baseline (7 cmH(2)O PIP) after ventilation with 30 and 35 cmH(2)O PIP. However, in lungs treated with 100 mu M phenylars ine oxide (a phosphotyrosine phosphatase inhibitor), K-fc increased by 4.7- and 16.4-fold relative to baseline at these PIP values. In lungs treated with 50 mu M genistein (a tyrosine kinase inhibitor), K-fc in creased significantly only at 35 cmH(2)O PIP, and the three groups wer e significantly different from each other. Thus phosphotyrosine phosph atase inhibition increased the susceptibility of rat lungs to high-PIP injury, and tyrosine kinase inhibition attenuated the injury relative to the high-PIP control lungs.