Phorbol myristate acetate: in vivo effects upon neutrophils, platelets, and lung

Phorbol myristate acetate is a potent aggregator of platelets. It was found that it was similarly potent in aggregating neutrophils and in producing striking thrombocytopenia and neutropenia when infused intravenously into rabbits. Aggregation and cytopenia were further correlated in that both types of responses developed abruptly and persisted for more than 90 minutes. Animals infused with 40 microgram/kg of the phorbol ester exhibited moderately severe respiratory distress. Their respiratory rate doubled shortly after the infusion, and this tachypnea persisted for more than 2 hours. At necroscopic examination, the lungs of these rabbits contained two outstanding abnormalities: numerous foci of alveolar hemorrhage and extensive intravascular accumulations of platelets and neutrophils. Thus, these animals had evidence of increased permeability and potential occlusion of the pulmonary microvasculature. Increased permeability, occlusion of lung blood vessels, or the occurrence of both processes was further indicated in studies on animals pre-infused with the plasma protein marker 125I-albumin: animals infused with the phorbol ester had a significantly increased amount of this label in their lungs in spite of thorough postmortem perfusion of their pulmonary vasculature with saline and fixative. We conclude that phorbol myristate acetate has actions in vivo that resemble those of a variety of other platelet (eg, arachidonic acid) and neutrophil (eg, chemotactic factors) aggregating agents that cause cytopenia and lung dysfunction. However, compared with these other agents, the phorbol ester produces respiratory distress of intermediate severity and greater duration. The drug, therefore, induces a syndrome that more closely resembles that seen in a variety of clinical and experimental conditions that associate shocklike states with cytopenia and lung dysfunction. It may serve as a useful tool in the study of the pathophysiology of these states as well as in those produced by other aggregating agents.