Pentoxifylline Decreases Endotoxin-induced Pulmonary Neutrophil Sequestration and Extravascular Protein Accumulation in the Dog

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Abstract
Since neutrophils may be important in endotoxin-induced acute lung injury, we sought to determine whether injury produced by endotoxin in vivo would be modified by pentoxifylline, which decreases neutrophil adherence and lessens neutrophil activation in vitro. Anesthetized dogs received 4 .mu.g/kg Salmonella enteritidis endotoxin intravenously after pretreatment with either saline or pentoxifylline 20 mg/kg intravenously administered followed by a continuous 0.1 mg/kg/min infusion. Two hours after endotoxin, pulmonary vascular permeability to protein was assessed as the lung extravascular accumulation of intravenously administered 113mIn-transferrin. Results expressed as the ratio of extra- to intravascular protein activities showed a clear increase over control values in dogs treated with endotoxin [0.064 .+-. 0.003 (mean .+-. SEM) and 0.31 .+-. 0.14 respectively, P < 0.05]. This increase with endotoxin was reversed by pentoxifylline to levels similar to control values (0.063 .+-. 0.044, P < 0.05). To determine whether pentoxifylline influenced neutrophil sequestration, thin sections of lung tissue were analyzed for neutrophil density using an intercept counting technique. Neutrophil density was doubled in dogs treated with endotoxin over that seen in controls (0.078 .+-. 0.008 versus 0.042 .+-. 0.006 neutrophils per alveolar septa, respectively, P < 0.05) and this increase was significantly reduced by pentoxifylline treatment (0.048 .+-. 0.009, p < 0.05). Endotoxin increased lung retention of radiolabeled neutrophils and this was also prevented by pretreatment of the neutrophils with pentoxifylline. In summary, pentoxifylline decreases neutrophil accumulation and prevents the increase in pulmonary vascular permeability to protein induced by endotoxin. These data support the premise that pentoxifylline is protective against endotoxin-induced lung injury in vivo.