The role of hydrogen peroxide during the inflammatory response. (a) Upon tissue injury/trauma, epithelial cells adjacent to damaged cells activate the NADPH oxidase, Duox. Duox generates and establishes a localised tissue scale gradient of hydrogen peroxide, (b) Potential cellular events that result in Duox activation in epithelial cells. Disruption of epithelial cell membranes by mechanical trauma could lead to an increased influx of calcium in adjacent cells. Calcium binding to the EF-hand domain of Duox (residing in plasma membranes of epithelial cells), may initiate generation of hydrogen peroxide. (c) A tissue scale gradient of hydrogen peroxide acts as the first attraction signal for leukocytes. (d) Neutrophils sense hydrogen peroxide emanating from the wound partly through Lyn, a Src family kinase. Oxidation of Cys466 activates Lyn, resulting in autophosphorylation (pLyn) and punctate appearance of pLyn at the neutrophil leading edge is observed. (e) At the site of injury, neutrophils may alter hydrogen peroxide levels, both by consuming epithelial-derived hydrogen peroxide (A) or by local production of hydrogen peroxide through oxidative bursts (B). (f) Antioxidants, such as glutathione peroxidase and catalase could catalyse the decomposition of hydrogen peroxide into oxygen and water, while myeloperoxidase (Mpo) may consume hydrogen peroxide to produce hypochlorous acid (A). Neutrophils are equipped with multiple mechanisms to kill foreign organisms, one of them being the generation of ROS. Upon activation, phagosomal Nox2 generates superoxide, which is further converted into hydrogen peroxide by superoxide dismutase (SOD). Hydrogen peroxide alone and in conjunction with hypochlorous acid, generated by myeloperoxidase and other ROS exert bactericidal functions (B).