Oxidant Release from Pulmonary Phagocytes

"One of the proposed mechanisms involved in the pathogenesis of silicosis is that inhaled silica dust activates a ""respiratory burst"" in pulmonary phagocytes, such as macrophages and neutrophils. This increase in oxidative metabolism results in enhanced generation of reactive oxygen species which if produced in excess, would overwhelm natural defense mechanisms and cause damage to the lung parenchyma. This damage would then result in scarring, fibrosis, and decreased gas exchange.Weiss and LoBuglio' have listed several oxygen species produced by phagocytes which may be involved in cellular injury. These oxidants include superoxide anion, hydrogen, peroxide, hydroxyl radical, and hypochlorous acid. Superoxide anion (0;) is generated from molecular oxygen by the plasma membrane bound enzyme NADPH oxidase according to the following reaction:Once generated, superoxide anion can form hydrogen peroxide:In the presence of myeloperoxidase and halide, hydrogen peroxide can form hypochlorous acid:Superoxide and hydrogen peroxide can also form highly reactive hydroxyl radicals. Hydroxyl radicals can be generated slowly by the Haber-Weiss reaction:In addition. hydroxyl radical production can be catalyzed via the Fenton reaction:Hydroxyl radicals can also be generated from the reaction of superoxide and hypochlorous acid as follows:Recent investigations suggest that, in addition to the reactive oxygen species discussed above, nitric oxide may be a potential mediator of silica-induced toxicity.2-4 Nitric oxide (NO') can be generated by the cytosolic enzyme nitric oxide synthase according to the following reaction:NO synthase exists in two forms. i.e.. a constitutive. Ca2+-calmodulin-dependent form and an inducible. Ca2+-calmodulin-independent form. In pulmonary phagocytes. the activity of the constitutive form of NO synthase is low. However. NO synthase can be induced in macrophages and neutrophils by a variety of stimulants such as lipopolysaccharide. interferon y. chemotactic peptide, platelet activating factor, or leukotriene B4.3.5Once generated. nitric oxide can combine with superoxide anion to form peroxynitrite as follows:Peroxynitrite is a potent oxidizing agent. In addition, peroxynitrite can form peroxynitrous acid. which in turn can produce hydroxyl radical and nitrogen dioxide (all of which exhibit strong oxidizing potential) by the following reactions:Oxygen metabolites have been shown to cause lung damage in vivo.6 Such damage includes edema. leakiness of the alveolar endothelial/epithelial barriers, and airway constriction.7 Superoxide and hydrogen peroxide have been associated with membrane damage and cell lysis.8 These oxidants have also been associated with alteration of cytoskeletal structures at cell-cell junctions and elevation of transepithelial conductance in cultured monolayers.9 Macrophages or neutrophils can be stimulated by bacteria or phorbol myristate acetate to produce sufficient oxidant levels to lyse lymphoma cells.10 This cell killing is inhibited by catalase but is unaffected by superoxide dismutase. hydroxyl radical scavengers. or azide. i.e., an inhibitor of peroxidase. This implicates hydrogen peroxide as the active oxidant. Similarly. Weiss et al.11 have reported that hydrogen peroxide is critical in the death of cultured endothelial cells due to neutrophil activation. In addition. hydroxyl radicals generated by monocytes have been associated with cell injury.12 Lastly. peroxynitrite has been shown to oxidize sulfhydryl groups and to inactivate proteinase inhibitor making the lung more susceptible to damage caused by phagocytotic enzymes.' Therefore. a strong case can be made that activated pulmonary macrophages and neutrophils are capable of causing oxidant injury. This chapter presents in vitro and in vivo data indicating that silica is associated with the production of reactive oxygen species from these pulmonary phagocytes."