02'" is formed in lungs and can be detected on the surface of pulmonary tissue and isolated PA under basal conditions. Pulmonary vascular tissue contains multiple oxidases whose expression and activity is highly regulated (Table 1). Pulmonary endothelial cells, PASMC, and macrophages generally have major 02" producing enzymes; vis-à-vis NAD(P)H oxidase, which contain cytochromes and subunits resembling the phagocytic cell NADPH oxidase system are present in the vascular tissue. For example, there is evidence for presence of p22phox, ç4Thox, p6Thm and homologues of the NOX-2 (gp9\phox subunit), currently termed NOX-1 andNOX-4 (10). In calfPASMC from small diameter PA, this enzyme is active under basal physiological conditions and there is evidence showing that it is activated under hypoxia (6, 33).
In contrast to the phagocytic oxidase, which uses NADPH for a co-factor, the PASMC generates significant levels of 02'" through the action of a microsomal-bound NADH oxidoreductase (22). Xanthine dehydrogenase, another NAD(P)H-dependent enzyme, is also present in the pulmonary endothelial cells, and is major source of02", during prolonged hypoxic conditions (6). Other proteins, like NO synthase (NOS), cytochrome P450, cyclooxygenase appear to be minor sources of 02'" under baseline physiological conditions. Previously discussed studies (2, 19, 29) suggest that the mitochondrial electron transport chain is an important Po2-regulated source of ROS in pulmonary tissue. Many receptor-linked regulatory mechanisms are capable of activating 02" production through the oxidases present in the vessel wall (See Table 1).
Table 1. The Sources of 02" in Pulmonary Artery and Their Stimulators
Sources of 0,'
NAD(P)H oxidasc-NOXl, N0X2, and N0X4
Vascular smooth muscle, fibroblasts
A-II, endothelium, TNF a, TxA2, Overexpression of NOX and p22f>ior APOj
Hy pox i a-reoxy genation AP02, apoptotic stimuli? Endothelial activation, Loss of L-arginine, Deficiency of t e trahy d rob i opterin Arachidonic acid release, Increase in peroxide tone Endothelial activation?
Xanthine oxidase Mitochondria Nitric oxide synthase
Endothelium All cell types Endothelium, Mitochondria,
Vascular smooth muscle Endothelium
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