Nitric Oxide Synthase in Human and Rat Lung: Immunocytochemical and Histochemical Localization

Abstract

In this issue of TheJournal Clerch et al. (1) show that hyperoxia regulates lung manganese superoxide dismutase (MnSOD) through a nonreceptor-mediated pathway involving G proteins. These observations suggest a number of possibilities regarding the cell involved and signaling mechanism used. Regu lation of MnSOD expression is a critical element in the lung's response to multiple forms of oxidant stress. It is likely that the location of MnSOD in mitochondria imparts protection to electron transport chain components enabling maintenance of cell energy sources under conditions of metabolic stress. Exposure to hyperoxia leads to a specific upregulation ofMnSOD in the mitochondria of alveolar epithelial type II cells (2). Selective over-expression of MnSOD in the mitochondria oftype II cells protects mice against hyperoxic stress (3). Indeed, the enhanced whole lung expression of MnSOD identified by Clerch et al. (1) is likely to have occurred in type II cells. These cells have a number of specialized functions designed to protect the host against inflammatory stimuli, microbes, and pollutants. In particular, they express extracellular (EC)-SOD and produce the bioactive radicals superoxide (02-) and nitric oxide (NO) (4). Selected biological functions of these radicals may derive from their rapid interaction to form peroxynitrite (OONO-). Which species predominates at the cell surface will depend on the rates and sites ofproduction ofthe primary radicals and the local concentrations of antioxidant enzymes such as EC-SOD. In this context one wonders if EC-SOD is not also regulated in the model of Clerch et al. (1). Two important questions are raised by this study. First, what is the molecular mechanism by which small diffusible ligands are recognized (i.e., what is the molecular sensor)? Second , how are these redox signals transduced into changes in gene expression? It has become increasingly clear that redox-active species such as O2 and NO-play important servoregu-latory roles through activation of cytosolic enzymes and transcription factors. Signaling by these redox species may be initiated in or at the plasma membrane (1, 5). Indeed, NO and H202 have been shown to activate G proteins (6). A distinctive feature shared by redox-active biomolecules is that they exert biological activity by virtue of their chemical reactivity, as opposed to the traditional noncovalent interactions of ligands with receptors. Metal-or sulfur-containing proteins are molecular targets for these diffusible signals. Critical thiols on the G protein are, therefore, candidate regulatory sites. Such activation of G proteins by S-nitrosylation (7) would be consistent with reports that NO. opposes pertussis toxin-mediated ADP-ribosylation ofcysteinyl residues (6). Analogous covalent interactions of O2T with protein thiols should be entertained. Con-formational changes induced in the protein likely serve as a switching mechanism to transduce the chemical signal into a physiological response. It is possible that redox-active biomolecules (O2 and ...

Orally exhaled nitric oxide levels are related to the degree of blood eosinophilia in atopic children with mild-intermittent asthma

“…Consistent with the observation that corticosteroids inhibit the expression of inducible NOS (iNOS) in epithelial cells [14], it has been shown that inhaled steroids are effective not only in controlling airway inflammation, but also in lowering NO levels in exhaled air [13,19,20].…”

Cell-Specific Nitric Oxide Synthase-Isoenzyme Expression and Regulation in Response to Endotoxin in Intact Rat Lungs

“…Cellular expression of bNOS and eNOS in different cell types of normal lung tissue and pulmonary cell cultures has been reported earlier (Kobzik et al, 1993;Shaul et al, 1994;Sherman et al, 1999). Cellular expression of iNOS in the lung parenchyma has so far only been observed after experimental endotoxin stimulation or in sections from patients suffering from inflammatory lung disease (Kobzik et al, 1993;Robbins et al, 1994;Tracey et al, 1994). However, recently all three NOS isoforms were shown by immunohistochemistry to be expressed in the developing lung, and all were assumed to contribute to NO generation functioning in normal lung physiology (Sherman et al, 1999;Xue et al, 1996).…”

“…Three isoenzymes of NOS have been described Moncada and Higgs, 1993): the neuronal isoform bNOS (NOS-1) and an endothelial isoform eNOS (NOS-3) as constitutive isoenzymes, and a mitogeninducible isoform iNOS (NOS-2). Cellular expression of bNOS and eNOS in different cell types of normal lung tissue and pulmonary cell cultures has been reported earlier (Kobzik et al, 1993;Shaul et al, 1994;Sherman et al, 1999). Cellular expression of iNOS in the lung parenchyma has so far only been observed after experimental endotoxin stimulation or in sections from patients suffering from inflammatory lung disease (Kobzik et al, 1993;Robbins et al, 1994;Tracey et al, 1994).…”

The effects of nitric oxide on the immune response during giardiasis

“…13,22 The diverse actions of NO could be explained by its capacity to chemically attack several molecules containing metals. Moreover, soluble mediators of immune responses can differentially modulate the inducible isoform of NOS.…”