Phorbol myristate acetate produces injury to isolated rat lungs in the presence and absence of perfused neutrophils

Because lung injury induced by phorbol myristate acetate (PMA) has been reported by some to be mediated by blood neutrophils (PMN) and by others to occur independently of PMN, we examined the PMN dependency of PMA-induced injury in isolated, perfused lungs of rats. Depending on dose, PMA added to medium perfusing isolated rat lungs produced injury in the presence or in the absence of added PMN. When a high concentration of PMA (57 ng/ml) was added to medium devoid of added PMN, perfusion pressure and lung weight increased. Superoxide dismutase (500 U/ml) and catalase (400 U/ml) added to the medium prior to PMA had no effect on the increases in lung weight or perfusion pressure. When a concentration of PMA (21 ng/ml or less) that did not by itself cause lungs to accumulate fluid was added to perfusion medium containing PMN (1 X 10(8)), superoxide was produced, perfusion pressure increased, and lungs accumulated fluid. Addition of superoxide dismutase and catalase to this preparation prevented the increase in lung weight, but not the increase in perfusion pressure. We conclude that high concentrations of PMA produce lung injury which is independent of neutrophils and oxygen radicals and that lower concentrations produce injury which is neutrophil-dependent and mediated by oxygen radicals. These results may explain why PMA-induced lung injury has variously been reported to be PMN-dependent in some systems and PMN-independent in others.