Research Article: Hydrogen Peroxide in Inflammation: Messenger, Guide, and Assassin

Date Published: June 12, 2012

Publisher: Hindawi Publishing Corporation

Author(s): C. Wittmann, P. Chockley, S. K. Singh, L. Pase, G. J. Lieschke, C. Grabher.


Starting as a model for developmental genetics, embryology, and organogenesis, the zebrafish has become increasingly popular as a model organism for numerous areas of biology and biomedicine over the last decades. Within haematology, this includes studies on blood cell development and function and the intricate regulatory mechanisms within vertebrate immunity. Here, we review recent studies on the immediate mechanisms mounting an inflammatory response by in vivo analyses using the zebrafish. These recently revealed novel roles of the reactive oxygen species hydrogen peroxide that have changed our view on the initiation of a granulocytic inflammatory response.

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The innate immune system comprises the cells and mechanisms that defend the host from infection by other organisms or damage to tissue integrity, in a nonspecific manner. This means that the cells of the innate system recognise and respond to pathogens and trauma in a generic way, but unlike the adaptive immune system, it does not confer long-lasting or protective immunity to the host. The innate immune system provides an immediate defence. A typical vertebrate immune response depends on the orchestrated motility and activity of various haematopoietic compartments and their interactions that ultimately control the magnitude of the response [1–3]. Inflammation is one of the first responses of the immune system to infection or irritation. Stimulated by factors released from injured cells, it serves to establish a physical barrier against the spread of infection. This further promotes healing of any damaged tissue following the clearance of pathogens or cell debris. Molecules produced during inflammation sensitise pain receptors, cause localised vasodilatation of blood vessels, and attract phagocytes, especially neutrophils and macrophages, which then trigger other parts of the immune system.

Hydrogen peroxide belongs to a group of chemically reactive molecules known as reactive oxygen species (ROS) that arise through oxidative metabolism. ROS comprise oxygen derived small molecules such as the oxygen radicals: superoxide, hydroxyl, peroxyl, and alkoxyl; or the nonradicals: hypochlorous acid, ozone, singlet oxygen, and the current topic in focus, hydrogen peroxide [7]. ROS generation can either occur as a by-product of cellular metabolism (e.g., in mitochondria through autoxidation of respiratory chain components) or it can be created by enzymes with the primary function of ROS generation [8]. Enzymes capable of rapidly increasing local H2O2 levels include the family of NADPH oxidases [7] and other oxidases such as xanthine oxidase [9] and 5-lipoxygenase [10]. The mammalian NADPH oxidase family encompasses 7 members, which are NOX1-5 and DUOX1-2. To date, a single isoform of duox and four nox genes (nox1, 2, 4, 5) have been identified in the zebrafish genome [11]. Each member is capable of converting NADPH to NADP+ and then transporting the freed electrons across membranes. DUOX enzymes are capable of direct hydrogen peroxide production, while NOXes1-5 produce superoxide, which is rapidly converted to H2O2 by a separate superoxide dismutase or occurs spontaneously [12]. H2O2 may subsequently be utilised by peroxidase, such as thyroperoxidase, to produce thyroid hormones or myeloperoxidase and lactoperoxidase to generate more potent ROS. However, if not consumed, high concentrations of H2O2 may result in DNA damage and modifications of proteins, lipids and other molecules [13]. Thus, to avoid H2O2-mediated deleterious effects, excess H2O2 is usually rapidly catalysed or reduced by various antioxidant enzymes: such as glutathione peroxidase and catalase [14].

H2O2 is also involved in many regulatory cellular events including the activation of transcription factors, cell proliferation, and apoptosis [8]. H2O2 produced from the mitochondrial electron transport chain has been shown to play a role in haematopoietic cell differentiation and cell division in flies [15, 16]. NADPH oxidase generated H2O2 can affect cardiac differentiation [17], vascularisation [18], and angiogenesis [19]. In targeting cysteine and methionine residues of protein kinases and phosphatases, H2O2 is capable of modulating a number of principal signalling cascades including ERK, JNK, p38, MAPK, and PI3K/Akt [20, 21].

The discovery of a new biological mechanism opens up a new line of research and poses numerous new questions to address. The most obvious being: How is Duox activated in epithelial cells upon wounding and how is the H2O2 gradient resolved? One hypothesis would place calcium as the immediate injury signal to the wounded cell in order to produce hydrogen peroxide through Duox. Physical disruption of plasma membranes results in an uncontrolled influx of calcium [41]. Giving credence to this hypothesis, evidence exists showing that DUOX activation by calcium regulates H2O2 generation [42].




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