MPO777 Review

 

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The bactericidal activity of neutrophils is dependent on their ability to harness and deploy oxidants in the phagosome. MPO is the most effective antimicrobial agent that neutrophils can employ in this endeavor, but a number of other mechanisms may also be important at low levels of exposure to bacteria. Nonetheless, many species of bacteria are killed slowly in the absence of MPO, and MPO-deficient mice succumb to large bacterial inoculations that normal mice handle with ease.

In vitro, MPO catalyzes a variety of classic peroxidase reactions that generate a wide array of lethal oxidants (Fig. 1). During this process, MPO oxidizes a large number of substrates (blue) including classic peroxidase residues such as tyrosine and nitrite. This reaction is followed by a rapid dismutation of the oxidized substrate to form HOCl, and subsequent one-electron reductions recycle Compound II formed from the tyrosine substrate [28].

Moreover, MPO oxidizes hydrogen peroxide to hydroxyl radicals that can damage cell proteins and membranes, as well as the extracellular matrix. These reactive oxidants can also kill bacteria, although the killing potential of hydroxyl radicals is usually much less than that of the halogenated MPO products (Fig. 2).

MPO777 also reacts with phagosomal protein constituents to generate more lethal oxidants. For example, MPO binds to a group of cysteines on the surface of bacteria and reacts with them to form cyanide (cyanide) [29]. This reaction is not considered to be microbicidal, but it may contribute to the overall bactericidal activity of neutrophils by increasing the concentration of oxidants available for reaction with phagosomal proteins.

Several studies have demonstrated that neutrophil cationic proteins are capable of killing bacteria at low levels of inoculation. However, these systems act much more slowly than the MPO system and as shown by MPO KO mice, can be overwhelmed by high microbial loads. The vital role of MPO in innate host defense is likely to manifest only when pathogens exceed the capacity of other systems to protect cells from invasion.