Attenuation of Acute Lung Injury in Septic Guinea Pigs by Pentoxifylline

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Abstract
Pentoxifylline (PTXF), a drug demonstrated to improve intermittent claudication, is a methylxanthine that increases intracellular cyclic AMP (cAMP) and, unlike theopylline, has few side effects. Because increased cAMP levels have been associated with a decrease in lung injury, we examined the effects of PTXF on acute lung injury in a septic guinea pig model. Five groups of guinea pigs were studied over a period of 8 h. (Group I: saline control injected intravenously with 2 ml of saline; Group II: septic control injected intravenously with 2 .times. 109 Escherichia coli; Group III: E. coli septicemia plus PTXF bolus 20 mg/kg injected 5 min before E. coli injection; Group IV: E. colisepticemia plus PTXF continuous infusion, begun with bolus [20 mg/kg] followed by continuous infusion [20 mg/kg/h) started 60 min before injection of E. coli; Group V: PTXF continuous infusion [20 mg/kg/h] control). Arterial blood gases, arterial blood pressure, and blood WBC counts were monitored serially for 8 h. Lung water (wet-to-dry ratio), the concentration ratio of 125I-labeled albumin in bronchoalveolar lavage (BAL) fluid to that in plasma (albumin index; Al), total cell count in BAL fluid, thiobarbituric-acid-reactive material (TBARM), and the lysosomal enzyme beta-glucuronidase (beta-G) were examined. Lung tissue was studied histologically to assess neutrophil accumulation. Our results showed that E. coli septicemia caused significant peripheral neutropenia and histopathologic evidence of neutrophil alveolitis associated with an increased ratio of TBARM and beta-G in BAL fluid as compared with those in plasma (TBARM BAL ratio and beta-G BAL ratio). The wet-to-dry lung (W/D) ratio was increased in Group II (septic control) compared with that in Group I (control) (p < 0.01). The pulmonary edema in Group II was associated with a significantly increased Al (p < 0.01). There was no difference in the level of peripheral neutropenia between Group II and Groups III or IV. However, Group IV was different from Group II in that significantly fewer PMN were recovered by BAL (p < 0.01). Although the number of PMN per alveolus assessed by histopathologic examination was significantly higher in Groups III and IV than in Group I, the TBARM BAL ratio and beta-G BAL ratio in Group IV were similar to those in Group I. Group IV did not have an elevated W/D ratio, increased Al, or marked histopathologic changes. Therefore, this study demonstrated that continuous infusion of PTXF initiated before E. coli infection attenuated acute lung injury in septic guinea pigs, whereas a bolus injection of PTXF was only mildly protective.