Interactions between nitric oxide and hypoxia-inducible factor signaling pathways in inflammatory disease

Abstract

Induction and activation of nitric oxide (NO) synthases (NOS) and excessive production of NO are common features of almost all diseases associated with infection and acute or chronic inflammation, although the contribution of NO to the pathophysiology of these diseases is highly multifactorial and often still a matter of controversy. Because of its direct impact on tissue oxygenation and cellular oxygen (O 2 ) consumption and redistribution, the ability of NO to regulate various aspects of hypoxia-induced signaling has received widespread attention. Conditions of tissue hypoxia and the activation of hypoxia-inducible factors (HIF) have been implicated in hypoxia or in cancer biology, but are also being increasingly recognized as important features of acute and chronic inflammation. Thus, the activation of HIF transcription factors has been increasingly implicated in inflammatory diseases, and recent studies have indicated its critical importance in regulating phagocyte function, inflammatory mediator production, and regulation of epithelial integrity and repair processes. Finally, HIF also appears to contribute to important features of tissue fibrosis and epithelial-to-mesenchymal transition, processes that are associated with tissue remodeling in various non-malignant chronic inflammatory disorders. In this review, we briefly summarize the current state of knowledge with respect to the general mechanisms involved in HIF regulation and the impact of NO on HIF activation. Secondly, we will summarize the major recent findings demonstrating a role for HIF signaling in infection, inflammation, and tissue repair and remodeling, and will address the involvement of NO. The growing interest in hypoxia-induced signaling and its relation with NO biology is expected to lead to further insights into the complex roles of NO in acute or chronic inflammatory diseases and may point to the importance of HIF signaling as key feature of NO-mediated events during these disorders. Hypoxia, Oxygen Sensing and InflammationDramatic changes in metabolism including increased generation of reactive oxygen and nitrogen species (ROS/RNS), depletion of local nutrients, and an increased demand for oxygen (O 2 ) are characteristic features of the inflammatory response [1]. Increased metabolic activity in inflamed tissue results, in part, from the recruitment of myeloid cells, such as neutrophils and macrophages, to inflammatory lesions and their subsequent involvement in phagocytosis and inflammatory mediator release [2]. These processes, © 2010 Elsevier Inc. All rights reserved. 1 Corresponding author: Department of Pathology, D205 Given Building, 89 Beaumont Avenue, Burlington,.. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the...

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