Role of poly-(ADP-ribose) synthetase in lipopolysaccharide-induced vascular failure and acute lung injury in pigs

Purpose:To assess the contribution of poly (adenosine 5'-diphosphate ribose ) synthetase (PARS) to the development of bacterial lipopolysaccharide (LPS )-induced acute lung injury and vascular failure in pigs. Materials and Methods: Four groups of anesthetized, paralyzed, and mechanic ally ventilated domestic white pigs. Group 1 served as control, whereas Esc herichia coil LPS (20 mu g/kg/h) was continuously infused in group 2, Group 3 received 20 mg/kg injection of 3-aminobenzamide (a selective inhibitor o f PARS activity) 15 minutes before LPS infusion. Only 8-aminobenzamide and not LPS was injected in group 4. All animals were examined for 180 minutes. Systemic and pulmonary hemodynamics and lung mechanics were measured durin g the experimental period. Lung wet/dry ratio, bronchoalveolar lavage (BAL) protein levels and cell counts and lung nitrotyrosine (footprint of peroxy nitrite) immunostaining were also measured in a few animals. Results: LPS infusion evoked a progressive decline in systemic arterial pre ssure, a small increase in cardiac output, and biphasic elevation of pulmon ary arterial pressure. Lung compliance declined progressively, whereas lung and total respiratory resistance rose significantly after LPS infusion. Pr ominent nitrotyrosine immunostaining was detected around small airways and pulmonary endothelium of LPS-infused animals. No significant changes in lun g wet/dry ratio and BAL protein levels and cell counts were produced by LPS infusion. Pretreatment with 1-aminobenzamide did not alter the systemic an d pulmonary hemodynamic responses to LPS infusion but eliminated the rise i n pulmonary and total respiratory resistance. Conclusions:We concluded that PARS activation plays an important role in th e changes of lung mechanics associated with LPS-induced acute lung injury b ut had no role in vascular failure. Copyright (C) 2000 by W.B. Saunders Com pany.