title: Role of circulating granulocytes in sheep lung injury produced by phorbol myristate acetate.
abstract: Phorbol myristate acetate (PMA) and endotoxin cause pulmonary granulocyte sequestration and alteration in lung fluid and solute exchange in awake sheep that are felt to be analogous to the adult respiratory distress syndrome in humans. The basic hypothesis that PMA causes lung injury by activating circulating granulocytes has never been tested. The effects of infused PMA on lung mechanics and the cellular constituents of lung lymph have also not been reported. We therefore characterized the effects of intravenous PMA, 5 micrograms/kg, on lung mechanics, pulmonary hemodynamics, lung fluid and solute exchange, pulmonary gas exchange, blood and lymph leukocyte counts, and plasma and lymph cyclooxygenase products of arachidonate metabolism in 10 awake sheep with normal granulocyte counts and after granulocyte depletion with hydroxyurea. PMA significantly altered lung mechanics from base line in both nongranulocyte depleted and granulocyte-depleted sheep. Dynamic compliance decreased by over 50% and resistance to airflow across the lungs increased over threefold acutely following PMA infusion in both sets of experiments. Changes in lung mechanics, pulmonary hemodynamics, lung fluid and solute exchange, pulmonary gas exchange, and plasma and lymph arachidonate metabolites were not significantly affected by greater than 99% depletion of circulating granulocytes. We conclude that the lung injury caused by PMA in chronically instrumented awake sheep probably is not a result of activation of circulating granulocytes.
authors.forename: E L
authors.initials: EL
authors.lastname: Dyer
authors.forename: J R
authors.initials: JR
authors.lastname: Snapper
mesh_terms: D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D002302:Cardiac Output / Q000187:drug effects; D006098:Granulocytes / Q000187:drug effects* / Q000502:physiology; D007970:Leukopenia / Q000139:chemically induced; D008168:Lung / Q000187:drug effects* / Q000503:physiopathology; D055370:Lung Injury; D008196:Lymph / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D010101:Oxygen Consumption / Q000187:drug effects; D010704:Phorbols / Q000633:toxicity*; D011652:Pulmonary Circulation / Q000187:drug effects; D011654:Pulmonary Edema / Q000209:etiology; D012128:Respiratory Distress Syndrome / Q000209:etiology; D012756:Sheep; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D001095:Arachidonic Acids; D001798:Blood Proteins; D010704:Phorbols; D016718:Arachidonic Acid; D013755:Tetradecanoylphorbol Acetate