Complex regulation of iNOS in lung.

Abstract

In a remarkably short period after the identification of nitric oxide (NO) as a novel signaling molecule in mammalian physiology, the critical role of L-arginine biosynthetic pathway in lung function became apparent (1). Numerous cell types within rodent and human lung (2) expressed one or more of the three known nitric oxide synthases (NOS) that catalyzed the five-electron oxidation of the N-terminal guanidino group of L-arginine to NO. The second of these oxidoreductases to be cloned (NOS2) is more commonly referred to as iNOS as a reflection of its unique features, including its ( 1 ) activation being independent of transient increases in intracellular calcium; and ( 2 ) inducibility at a transcriptional level in response to inflammatory or immunologic stimuli (3). The fundamental role of iNOS-derived NO in host defense contributed to the extraordinary large number of investigations into its regulation at transcriptional and post-transcriptional levels (4). Concurrent with these advances in iNOS regulation was an increasing awareness of the role of hypoxia in gene expression; and, thus, it is not surprising that these two areas of study have intersected. In this issue, Zulueta and colleagues (5) report that although hypoxia per se does not affect iNOS expression in cultured rat pulmonary microvascular endothelial cells, it does modulate IL-1 and TNFinduction of iNOS at pretranscriptional through post-transcriptional levels. The study underscores the complexity of iNOS regulation and provides important observations that can be used to assess cell-, stimulus-, and species-specific differences in such regulation.