Time-dependent inhibition of immune complex-induced lung injury by catalase: Relationship to alterations in macrophage and neutrophil matrix metalloproteinase elaboration

Rats were subjected to acute lung injury by the intra-alveolar formation of IgG immune complexes of bovine serum albumin (BSA) and anti-BSA. In this m odel of injury, complement activation occurs and large numbers of neutrophi ls invade the interstitium and alveolar space. In the present study, animal s were treated with intratracheal catalase concomitantly with anti-BSA or a fter a lag period of 5-120 min. Catalase treatment at time-zero or at 5 min post injury failed to prevent lung injury as indicated by permeability cha nge, histological features, and neutrophil influx. However, treatment after a delay of 15-30 min (but not 120 min) afforded substantial protection. Co nsistent with past findings [9], lung injury was accompanied by an accumula tion of matrix metalloproteinase 9 (MMP-9) in bronchoalveolar lavage (BAL) fluid. There was a strong correlation between inhibition of injury and redu ction in MMP-9 levels. In vitro studies conducted in parallel revealed that unstimulated alveolar macrophages did not produce measurable MMP-9, while there was a large induction following exposure to the same immune complexes that initiated injury in vivo. MMP-2 was also slightly upregulated under t he same conditions. Concomitant treatment with catalase greatly inhibited M MP-9 production by macrophages in response to immune complexes, but this tr eatment had little effect on basal production of either MMP-9 or MMP-2 by m acrophage. The same concentration of catalase that suppressed MMP-9 elabora tion also inhibited the production of tumor necrosis factor cr. In contrast , when neutrophils were treated with catalase and then exposed to immune co mplexes, the antioxidant failed to prevent the release of either MMP-2 or M MP-9. Taken together, these findings demonstrate that antioxidant treatment interferes with elaboration of MMPs by alveolar macrophages. Protection ag ainst lung injury is correlated with reduction in MMP levels in the BAL flu id. (C) 2000 Elsevier Science Inc.