Acute lung injury by endotoxin-induced mediators: prevention by HWA 138, a new xanthine derivative.

We attempted to mimic septic conditions in vitro by using a model of isolated perfused rabbit lung (IPRL) and evaluated the effects of endotoxin or endotoxin-induced mediators (or both) on it. Moreover, we determined the salutary effects of HWA 138, a new xanthine derivative, against endotoxin-related lung injury. To study this, heparinized human blood was centrifuged, following which the plasma complement was inactivated by heat treatment and the isolated and washed buffy coat cells were then added to it. This was followed by incubation of aliquot suspension with and without endotoxin (lipopolysaccharide [LPS], 100 ng/ml) at 37 degrees C for 2 hours. Plasma was then harvested and is referred to as sepsis-like plasma (SLP). Control plasma (CP) was not exposed to LPS. IPRLs were then perfused with SLP, CP, LPS itself, or both LPS and CP without additional white blood cells. Endotoxin itself did not induce any changes in the presence or in the absence of control plasma; however, sepsis-like plasma led to the development of lung edema, as evidenced by significantly elevated lung water and pulmonary artery pressure. Administration of HWA 138 before the addition of SLP prevented the SLP-induced lung injury. These results lead us to conclude that lung injury is caused by LPS-induced mediators rather than being directly caused by LPS. The results also suggest that HWA 138 may be a useful agent in the treatment of sepsis-induced pulmonary injury.