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The inflammatory milieu that characterizes allergic asthma and
other pathologies where inflammatory-immune processes are
activated encompasses elevated levels of reactive oxygen and
nitrogen species, which are believed to contribute to tissue injury and repair processes (1). Nitric oxide (NO) is an important
modulator of airway inflammatory responses, and increased
concentrations of expired NO have joined the presence of eosinophils as representing well-scored components of the human
asthmatic phenotype. Although the molecular pathways underlying this enhanced expired NO remain to be fully clarified
(2, 3), upregulation of the inducible NO synthase (NOS-2) is
thought to be an important factor in this response. Studies with
targeted deletion of NOS-2 have suggested that NOS-2-derived NO may contribute to the inflammatory response in asthmatic mice (4), and such proinflammatory properties are
thought to be related to oxidative metabolism of NO to more
reactive nitrogen intermediates that covalently modify various
biologic targets (5). Based on seminal work by Beckman and
colleagues (6), much attention has been given to peroxynitrite
(ONOO
), a product of the near-diffusion-limited reaction of
NO with superoxide anion (O2·), a major reactive product of
both phagocytic and nonphagocytic cells. Peroxynitrite is a
powerful oxidant/nitrosant and can react with tyrosine residues
to form the stable adduct nitrotyrosine. Indeed, increased concentrations of nitrotyrosine have been found in the airways of
asthmatics (7, 8), as in almost any other inflammatory-immune
process, and this is commonly interpreted as evidence for the
endogenous production of peroxynitrite in these disease states.
Over the last several years this paradigm has been challenged, as it has become clear that heme peroxidases, including those expressed by phagocytes, are equally capable of facilitating protein tyrosine nitration (9, 10). Because inflamed airways are typically endowed with multiple heme peroxidases (lactoperoxidase, myeloperoxidase, and eosinophil peroxidase) and increased concentrations of hydrogen peroxide (H2O2), which "activates" peroxidases, the involvement of these enzymes in the endogenous formation of nitrating oxidants can easily be rationalized. Indeed, the presence of halogenated tyrosine derivatives in the airways of asthmatic patients directly implicates the participation of peroxidase-dependent pathways in this disease (11).
In this issue of the Journal (pp. 1119-1126), Duguet and colleagues (12) have used the allergic ovalbumin-challenged mouse asthma model, superimposed on models of eosinophil peroxidase deficiency and targeted deletion of NOS-2, to disentangle the mechanisms of protein nitration in asthmatic airways. They demonstrate that "asthmatic" mice with NOS-2 deficiency display equivalent degrees of protein nitration compared with wild-type mice, whereas such nitration is nearly absent in mice deficient in eosinophil peroxidase. Thus, their results strongly support the concept that eosinophil peroxidase represents a major pathway for protein nitration in this model of allergic asthma, and furthermore illustrate that tyrosine nitration is not restricted by the absence of NOS-2 induction. Other NOS isozymes (or nonenzymatic pathways) may sustain respiratory tract concentrations of NO or its metabolite nitrite as substrates for H2O2-activated eosinophil peroxidase. Although Duguet and colleagues do not directly address the relevance of this peroxidase-mediated nitration mechanism to human asthma pathophysiology, they more convincingly implicate eosinophil peroxidase in nitration pathways previously proposed by MacPherson and coworkers (10). Additionally, the results presented by Duguet and colleagues illustrate that tyrosine nitration is another manifestation of peroxidase-mediated protein oxidation rather than simply a direct indicator of NO or oxidant overproduction.
In placing their results in perspective, several issues should be noted. First, in order to generate comparative degrees of allergic inflammation, Duget and colleagues had to deliver an overwhelming immunostimulus to NOS-2-deficient mice, further confirming a putative role for augmented NO in the initiation phases of allergic airway inflammation (4). Another issue needing further clarification concerns the fact that the neuronal isoform of NOS (NOS-1) contributes substantially to expired NO in mice (13), and it is NOS-1 that has been implicated in the pathophysiology of human asthma (14). Of note, eosinophils seem to cluster around airway nerves (15), which may play an important part in airway smooth muscle responsiveness and relaxation (1). Although it is not clearly established whether nitrotyrosine is simply a marker of reactive nitrogen species formation or a mediator of disease pathology (16), the findings of Duguet and colleagues pose the intriguing possibility that peroxidase-derived nitrating intermediates may selectively target nerves, thereby contributing to altered airway responsiveness.
Finally, although Duguet and colleagues provide compelling evidence implicating eosinophil peroxidase as a primary mediator of protein tyrosine nitration at allergic inflammatory foci, the comparison of multiple strains of mice makes their observations difficult to interpret and arrive at unequivocal conclusions. Indeed, the development of airway hyperresponsiveness, a hallmark of bronchial asthma, is mouse strain-dependent (17) and is modulated by a multiplicity of factors. The New Zealand White (NZW) mouse strain used by the investigators is naturally eosinophil peroxidase-deficient and was compared with the A/J and C57BL/6J mouse strains as "controls." Although it appears that the decrease of nitrotyrosine formation in NZW mice is caused by the absence of eosinophil peroxidase, other unknown differences in gene expression between the various mouse strains (e.g., differential expression of antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase) may have confounded this interpretation. The use of bona fide eosinophil peroxidase knockout mice produced by targeted deletion of the eosinophil peroxidase gene and comparison with mice of a genetically identical background will be instrumental in resolving the role of eosinophil peroxidase in protein nitration/halogenation and airway inflammatory injury (11). Indeed, it was recently demonstrated that targeted deletion of eosinophil peroxidase did not affect inflammation or pulmonary function in ovalbumin-challenged mice (18), despite lower levels of markers of eosinophil peroxidase catalyzed oxidation. A potential explanation for this result is the fact that this mouse model of allergic airway injury is associated with a relative lack of eosinophil degranulation and secretion of eosinophil peroxidase, common features of eosinophil activation in asthmatic humans (19). These issues further strengthen the need for developing improved animal models of human allergic airways diseases, as well as highly specific inhibitors of mammalian peroxidases, which could be useful as both alternative tools to elucidate their contribution to inflammatory processes and potentially as pharmacologic agents for modulating airway hyperresponsiveness and inflammatory injury.
In conclusion, the study by Duguet and colleagues (12) provides the most convincing evidence that mammalian peroxidases (specifically eosinophil peroxidase) play a major role in catalyzing tyrosine nitration during inflammation. However, it remains unresolved as to whether protein nitration per se (or other peroxidase-mediated oxidations) actively contribute to eosinophilic inflammation or the variable airway obstruction, hyperresponsiveness, and remodeling that characterize asthma (1). Because myeloperoxidase and eosinophil peroxidase deficiency (and polymorphisms) occur in the human population, epidemiologic studies may be helpful in providing clues as to the involvement of mammalian peroxidases in the pathologic outcome of asthma and other inflammatory diseases of the lung.
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