Phosphotyrosine phosphatase and tyrosine kinase inhibition modulate airway pressure-induced lung injury

We determinedwhether drugs which modulate the state of protein tyrosinephosphorylation could alter the threshold for high airwaypressure-induced microvascular injury in isolated perfused rat lungs.Lungs were ventilated for successive 30-min periods with peak inflationpressures (PIP) of 7, 20, 30, and 35 cmH₂O followed by measurement ofthe capillary filtration coefficient (K_fc), asensitive index of hydraulic conductance. In untreated control lungs,K_fc increased by1.3- and 3.3-fold relative to baseline (7 cmH₂O PIP) after ventilation with30 and 35 cmH₂O PIP. However, inlungs treated with 100 µM phenylarsine oxide (a phosphotyrosinephosphatase inhibitor),K_fc increased by4.7- and 16.4-fold relative to baseline at these PIP values. In lungs treated with 50 µM genistein (a tyrosine kinase inhibitor),K_fc increasedsignificantly only at 35 cmH₂OPIP, and the three groups were significantly different from each other.Thus phosphotyrosine phosphatase inhibition increased thesusceptibility of rat lungs to high-PIP injury, and tyrosine kinaseinhibition attenuated the injury relative to the high-PIP control lungs.