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

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Abstract
We determined whether drugs which modulate the state of protein tyrosine phosphorylation could alter the threshold for high airway pressure-induced microvascular injury in isolated perfused rat lungs. Lungs were ventilated for successive 30-min periods with peak inflation pressures (PIP) of 7, 20, 30, and 35 cmH2O followed by measurement of the capillary filtration coefficient ( Kfc), a sensitive index of hydraulic conductance. In untreated control lungs, Kfcincreased by 1.3- and 3.3-fold relative to baseline (7 cmH2O PIP) after ventilation with 30 and 35 cmH2O PIP. However, in lungs treated with 100 μM phenylarsine oxide (a phosphotyrosine phosphatase inhibitor), Kfcincreased by 4.7- and 16.4-fold relative to baseline at these PIP values. In lungs treated with 50 μM genistein (a tyrosine kinase inhibitor), Kfcincreased significantly only at 35 cmH2O PIP, and the three groups were significantly different from each other. Thus phosphotyrosine phosphatase 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.