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 TNF-␣ induction 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. iNOS in LungKobzik and coworkers (2) originally systematically localized iNOS in fixed tissue of rat and human lung. Immunoreactive iNOS was most apparent in rat alveolar macrophage after LPS and occasionally in human macrophage and endothelium in areas of chronic inflammation. Interestingly, both species showed immunoreactive iNOS in airway epithelium in normal tissue, suggesting the possibility of a constitutively active iNOS. Constitutively expressed iNOS in upper and lower airway epithelium was subsequently confirmed by Asano and coworkers (6) and Guo and colleagues (7). These latter investigators noted that this unusual expression was lost when human airway epithelium was cultured (8); and progress has been made in identifying a soluble, heat labile, acid insensitive autocrinederived mediator that accounts for such expression (9). The role of iNOS-derived NO and secondary reactive nitrogen intermediates in normal lung is unclear, but may be an important component of host defense (3), as well as a source of NO for S-nitrosylation of hemoglobin during its transpulmonary passage (10).The contribution of intrapulmonary iNOS-derived NO in experimental acute and chronic lung injury has been revealed by pharmacologic and genetic studies. Our laboratory has shown that exposure to mixtures of cytokines and endotoxin of cultured rat type II cells (11) and pulmonary artery (12) or intra-acinar (13) vascul...

Cytoskeletal Changes in Hypoxic Pulmonary Endothelial Cells Are Dependent on MAPK-activated Protein Kinase MK2

“…Work from our laboratory has demonstrated regulation of the constitutive as well as the inducible form of nitric-oxide synthase (eNOS and iNOS, respectively) in response to hypoxia (31,32). Hypoxia stabilizes iNOS mRNA expression induced by cytokine treatment (32), suggesting that hypoxia may alter the effects of inflammatory cytokines (33).…”

Nitric Oxide in Health and Disease of the Respiratory System

“…Of note, there is evidence for feedback inhibition of this NFB pathway by NO through two different S-nitrosylation pathways (280,324). An upstream site contains enhancer regions with binding sites for ␥-activated site (GAS) element and an IRF-1 specific response element (ISRE) that account for IFN-␥ induction (270,351). IFN-␥ is crucial for induction of iNOS expression in airway epithelial cells in vitro (155).…”

“…STAT is also able to activate another transcription factor, IRF-1. Both STAT-1 and IRF-1 interact with the response elements GAS and ISRE in the iNOS promoter regions (272,351).…”

Exhaled nitric oxide in neonates with or without hypoxemic respiratory failure

“…This pathophysiological mechanism may involve stimulation for NO production based on up-regulation of iNOS and/ or eNOS in the lungs. [11] Mechanical ventilation may also affect the NO output. Airway epithelium could produce more NO as a reaction to mechanical stretching and shear forces across the airways in the lung disease.…”