Lung injury and oxidoreductases

Area of Science:

• Biochemistry
• Cell Biology
• Pathophysiology

Background:

• Acute lung injury, including acute respiratory distress syndrome, involves reactive oxygen intermediates.
• Endogenous sources of reactive oxygen intermediates in acute lung injury are not well-defined.
• Potential sources include molybdenum hydroxylases, NAD(P)H oxidoreductases, mitochondrial electron transport chain, and arachidonic acid-metabolizing enzymes.

Purpose of the Study:

• To investigate the regulation of xanthine oxidoreductase (XDH/XO) and NAD(P)H oxidase in the context of acute lung injury.
• To understand the cell-specific gene expression and posttranslational regulation of XDH/XO.
• To characterize the vascular NAD(P)H oxidase and identify key regulatory factors.

Main Methods:

• Studied gene expression of XDH/XO under various conditions (cytokines, steroids, hypoxia).
• Investigated posttranslational regulation of XDH/XO activity.
• Characterized NAD(P)H oxidase in vascular cells, focusing on cytochrome components gp91 and p22.
• Examined the effect of oncostatin M on gp91 expression in human vascular cells.

Main Results:

• XDH/XO gene expression is regulated in a cell-specific manner and influenced by inflammatory cytokines, steroids, and hypoxia.
• Posttranslational processing significantly impacts XDH/XO activity.
• A vascular NAD(P)H oxidase with gp91 and p22 components, similar to phagocytic cells, was identified.
• Oncostatin M potently induces gp91 expression in human vascular endothelial and smooth muscle cells.

Conclusions:

• The regulation of XDH/XO and vascular NAD(P)H oxidase is crucial in the pathobiology of acute lung injury.
• Regulation of gp91 expression is a central factor in controlling vascular NAD(P)H oxidase activity.
• Vascular cell oxidoreductases are expressed in a highly regulated and cell-specific manner.