LUNG INJURY AND OXIDOREDUCTASES

Acute lung injury represents a wide spectrum of pathologic processes, the most severe end of the spectrum being the acute respiratory distre ss syndrome. Reactive oxygen intermediates have been implicated as imp ortant in the pathobiochemistry of acute lung injury. The endogenous s ources that contribute to the generation of reactive oxygen intermedia tes in acute lung injury are poorly defined but probably include the m olybdenum hydroxylases, NAD(P)H oxidoreductases, the mitochondrial ele ctron transport chain, and arachidonic acid-metabolizing enzymes. Our laboratory has focused, in particular, on the regulation of two of the se enzyme systems, xanthine oxidoreductase (XDH/XO) and NAD(P)H oxidas e. We observe that gene expression of XDH/XO is regulated in a cell-sp ecific manner and is markedly affected by inflammatory cytokines, ster oids, and physiologic events such as hypoxia. Posttranslational proces sing is also important in regulating XDH/XO activity. More recently, t he laboratory has characterized an NAD(P)H oxidase in vascular cells. The cytochrome components of the oxidase, gp91 and p22, appear similar to the components present in phagocytic cells that contribute to thei r respiratory burst. In human vascular endothelial and smooth muscle c ells, oncostatin M potently induces gp91 expression. We believe that r egulation of gp91 is a central controlling factor in expression of the vascular NAD(P)H oxidase, in summary, the studies support the concept that the oxidoreductases of vascular cells are expressed in a highly regulated and self-specific fashion.