Reactive nitrogen species and tyrosine nitration in the respiratory tract: epiphenomena or a pathobiologic mechanism of disease?
Reactive nitrogen species and tyrosine nitration in the respiratory tract: epiphenomena or a pathobiologic mechanism of disease?
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呼吸道中的活性氮和酪氨酸硝化：副现象还是疾病的病理生物学机制？
DOI：
10.1164/ajrccm.160.1.9807044
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
Cross,CE
中科院分区：
文献类型：
--
作者：
vanderVliet,A;Eiserich,JP;Shigenaga,MK;Cross,CE
自十多年前作为生物信使分子被发现以来，一氧化氮（NO·）因其参与生命几乎所有方面的多种生物过程而得到广泛认可，包括血管舒张、支气管舒张、神经传递、抑制吞噬细胞和血小板聚集以及抗菌活性（1-3）。在呼吸道炎症免疫过程中过量产生NO·被认为提供了一种宿主防御机制，尽管这是有代价的，因为高水平的NO·也会导致呼吸道损伤，从而促进呼吸道疾病的病理生物学。通常认为，NO·的这些有害影响与通过NO·与部分还原的氧相互作用形成更多活性氮中间体有关，这是炎症过程的共同标志。相反，在某些情况下，NO·也被证明可以减轻氧化诱导的肺损伤，并且NO·吸入已被提出作为治疗肺动脉高压和某些形式的成人呼吸窘迫综合征（ARDS）的治疗策略。NO·的这种双重性质是最近研究的重点，揭示了NO·的多方面生化途径，这些途径高度依赖于剂量和局部氧化还原状态。NO·衍生的活性氮中间体可以诱导多种生物分子的共价修饰，如亚硝基和硝基加合物，从而导致功能和/或结构变化。一种这样的修饰产生3-硝基酪氨酸，检测蛋白质中的这种加合物现在通常用作诊断工具，以确定在许多疾病状态中NO·衍生氧化剂的参与（4-6）。此外，许多体外研究已经确定了关键酪氨酸残基硝化后酶活性的变化，这提出了体内蛋白质硝化可能与炎症相关的肺损伤形式有因果关系的建议。在这个肺部视角中，我们将简要总结NO·在呼吸道炎症性疾病的病理生理中的作用，并将讨论蛋白质或其他生物分子的特征性诊断修饰，特别强调3-硝基酪氨酸和其他芳香底物中的相关修饰。我们将研究已知的在炎症免疫过程中促进芳香硝化的生物反应机制的范围，并将批判性地评估已经开发和用于检测此类修饰的分析方法。我们还将讨论酪氨酸硝化和相关修饰的潜在病理生理后果。
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 nitroso-and nitro-adducts, 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.