Neutrophil-derived Oxygen Metabolites Stimulate Thromboxane Release, Pulmonary Artery Pressure Increases, and Weight Gains in Isolated Perfused Rat Lungs1–4

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Abstract
Addition of normal human neutrophils and the neutrophil stimulant, phorbol myristate acetate (PMA), caused perfusate thromboxane (TXB2) elevations, pulmonary artery pressure (PAP) increases, and lung weight gains in isolated perfused rat lungs. Addition of PMA and neutrophils that do not generate O2 metabolites from a patient with chronic granulomatous disease (CGD) — or addition of PMA and normal neutrophils with the purported O2 metabolite scavenger, dimethylthiourea (DMTU) — also caused PAP increases but did not cause perfusate TXB2 elevations or lung weight gains in isolated lungs. In parallel, mixtures of normal neutrophils and PMA made hydrogen peroxide (H2O2) concentrations in vitro which exceeded concentrations found in mixtures containing PMA and CGD neutrophils or mixtures containing PMA, normal neutrophils, and DMTU. TXB2 levels were not detectable in mixtures containing normal neutrophils and PMA in vitro. Our results indicate that neutrophil-derived O2 metabolites contribute to perfusate TXB2 elevations and lung weight gains but not PAP increases in isolated perfused rat lungs.