Pentoxifylline reduces injury to isolated lungs perfused with human neutrophils

Neutrophils and neutrophil-derived oxidants have been implicated in the development of acute lung injury such as that seen in the adult respiratory distress syndrome (ARDS), in bronchopulmonary dysplasia (BPD), and in animal models of lung injury, including the isolated perfused lung. Both neutrophil-derived oxidant production and retention of neutrophils in the lung are required for injury in this model. Pentoxifylline can reduce lung injury from sepsis in the guinea pig and endotoxin-induced neutrophil sequestration and lung injury in the dog. It is also known to increase neutrophil deformability, which may affect retention in the pulmonary microvasculature. We evaluated neutrophil oxidant production, retention in isolated lungs, and neutrophil-mediated acute lung injury after phorbol myristate acetate (PMA) in the presence of pentoxifylline. Pentoxifylline (2 mM) significantly reduced superoxide anion and hydrogen peroxide production in vitro from PMA-stimulated neutrophils when pentoxifylline was directly added to the incubation mixtures, but not when neutrophils were preincubated with the agent. Pentoxifylline did not reduce retention of neutrophils in isolated lungs as determined by infusion of 111In-labeled neutrophils and gamma counting. Pentoxifylline prevented increases in total lung weight, lung-to-body-weight ratio, and perfusate thromboxane concentrations when it was present in perfusate buffer, whether or not neutrophils were preincubated in pentoxifylline prior to infusion into the lung. Pentoxifylline did not reduce injury to lungs perfused with glucose and glucose oxidase. We conclude that pentoxifylline reduces neutrophil oxidant production and neutrophil-dependent lung injury.