Protamine-induced acute lung injury and the protective effect of agents that increase cAMP

Polycations, such as protamine sulfate and polylysine, have been implicated in acute lung injury. We studied the vascular effect of protamine sulfate and the protective effect of agents that increase cAMP in isolated rat lungs perfused with a cell- and plasma-free solution. Protamine sulfate (3 mg) markedly increased pulmonary artery pressure (PAP) from 15.6 +/- 0.5 to 30.8 +/- 1.2 mmHg (P < 0.01) and lung weight gain (LWG) by 7.8 +/- 1.5 g within 30 min (P < 0.001). The protective effects of pharmacological agents that increase intracellular cAMP were investigated. These agents included dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP, a cAMP analogue), aminophylline and pentoxifylline (both are phosphodiesterase inhibitors). Pretreatment with these agents 5 min before protamine administration largely attenuated the increases in PAP and LWG. Because DBcAMP, aminophylline and pentoxifylline all share the effects of increasing intracellular cAMP and were effective on the protamine-induced lung changes, the intracellular level of cAMP could be a major determinant of lung injury. Since there is no blood in the perfusate, the mechanism of cAMP on cellular components in the blood such as neutrophils, can be ruled out. The endothelial cells are likely to be the target cells because charge interaction is believed to occur on the endothelial surface. This result will be very important in the elucidation of the protective effect of cAMP in acute lung injury.