# MYELOPEROXIDASE AND LEUKOCYTE GRANULE COMPONENTS

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 1988 · $178,055

## Abstract

Stimulation of neutrophilic leukocytes results in secretion of toxic
proteins and the enzyme myeloperoxidase (MPO) from
cytoplasmic granules and activates neutrophil oxygen (O2)
metabolism, which produces toxic oxidants.  Neutrophil toxins
combat infection by killing invading microorganisms but also
contribute to inflammatory tissue destruction.  Long-range goals
are to characterize the oxidants, determine their role in
antimicrobial activity and damage to host cells, and elucidate
mechanisms that regulate their potency and selectivity.  The
working hypothesis is that hydrogen peroxide (H202) and products
of the MPO/H202/chloride (C1-) system are the major oxidative
toxins.  Superoxide (02-) is the first product of leukocyte 02
metabolism, but the principal role of 02- is not as a toxin.
Instead, 02- is an intermediate in H202 production and an oxidant
for extracellular reductants such as ascorbate (vitamin C) and
sulfhydryl compounds.  Oxidation of these reductants by 02-
increases H202 production and consumes the reductants so that
they can't detoxify H202 and products of the MPO system.
Toxicity of the MPO system is also regulated by ammonia (NH4+),
and lysine-rich peptides from the cytoplasmic granules.  MPO
catalyzed the oxidation of C1- by H202 to yield hypochlorous acid
(HOC1), which reacts with NH4+ to yield the bactericidal agent
monochloramine (NH2C1).  However, NH2C1 can also suppress
toxicity by inhibiting neutrophil 02 metabolism, and NH4+ or
NH2C1 may inhibit MPO secretion.  The reaction of HOC1 with
the lysine-peptides yields relatively non-toxic though long-lived
peptide-chloramines.  The proposed studies will characterize the
interaction of 02-, H202, and products of the MPO system with
ascorbate and other extracellular reductants, and examine effects
of the reductants on antibacterial and cytotoxic activities of
isolated neutrophils.  The ability of manganese (Mn2+) to promote
oxidation of reductants by MPO will be studied, to determine
whether MPO could act as an oxidase and produce toxic oxidants
in neutrophils with defective 02 metabolism.  The effect of NH4+
on neutrophil 02 metabolism, MPO secretion, and antibacterial
activity will be measured, and the interaction of lysine-peptides
with the MPO system will be studied using purified peptides and
MPO.  These studies will provide new insights into the role of
oxidants and reductants in neutrophil function and may lead to
improved methods for combating infection while suppressing
damage to host tissues.

## Key facts

- **NIH application ID:** 3126833
- **Project number:** 2R01AI016795-07
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **SAM.gov UEI:** JL4JHE9SDRR3
- **Principal Investigator:** EDWIN L THOMAS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1988
- **Award amount:** $178,055
- **Award type:** 2
- **Project period:** 1981-04-01 → 1993-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3126833

## Citation

> US National Institutes of Health, RePORTER application 3126833, MYELOPEROXIDASE AND LEUKOCYTE GRANULE COMPONENTS (2R01AI016795-07). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3126833. Licensed CC0.

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