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.