Reactive Nitrogen Species and Tyrosine Nitration in the Respiratory Tract: Epiphenomena or a Pathobiologic Mechanism of Disease?

Abstract

Since its discovery as a biologic messenger molecule just over a decade ago, nitric oxide (NO · ) has become well recognized for its participation in diverse biologic processes in nearly all aspects of life, including vasodilation, bronchodilation, neurotransmission, inhibition of phagocyte and platelet aggregation, and antimicrobial activity (1–3). Excessive production of NO · during inflammatory–immune processes of the respiratory tract is thought to provide a host defense mechanism, although this comes with a price, since high levels of NO · can also cause respiratory tract injury and thus contribute to the pathobiology of respiratory tract disease. These detrimental effects of NO · are generally assumed to be related to the formation of more reactive nitrogen intermediates via interactions of NO · with partially reduced oxygen species, a common hallmark of inflammatory processes. Conversely, NO · has in some cases been shown to also attenuate oxidant-induced lung injury, and NO · inhalation has been proposed as a therapeutic strategy in the management of pulmonary hypertension and in some forms of adult respiratory distress syndrome (ARDS). This dual property of NO · has been the subject of intense recent investigation, which has uncovered multifaceted biochemical pathways of NO · that are highly dependent on dose and on local redox status. NO · -derived reactive nitrogen intermediates can induce a number of covalent modifications in various biomolecules, such as nitrosoand nitroadducts, that result in functional and/or structural changes. One such modification yields 3-nitrotyrosine, and detection of this adduct in proteins is now commonly used as a diagnostic tool to identify involvement of NO · -derived oxidants in many disease states (4–6). Furthermore, a number of in vitro studies have established changes in enzyme activity upon nitration of critical tyrosine residues, which has raised suggestions that protein nitration in vivo may be causally linked to inflammation-related forms of lung injury. In this Pulmonary Perspective we will briefly summarize the involvement of NO · in the pathophysiology of inflammatory diseases of the respiratory tract, and will address characteristic diagnostic modifications in proteins or in other biomolecules, with special emphasis on 3-nitrotyrosine and related modifications in other aromatic substrates. We will examine the scope of bioreactive mechanisms known to contribute to aromatic nitration during inflammatory–immune processes, and will critically evaluate analytical procedures that have been developed and used to detect such modifications. We will also discuss the potential pathophysiologic consequences of tyrosine nitration and related modifications.