# INTERACTIONS OF ENDOTOXIN WITH HUMAN PLASMA & CELLS

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 1987 · $231,842

## Abstract

Endotoxins (lipopolysaccharides) are thought to play a major role
in the pathogenesis of invasive gram-negative bacterial diseases;
the infected host's inflammatory reaction to these molecules may
produce considerable morbidity and even death.  Little is known
about host mechanisms for detoxifying lipopolysaccharides (LPS).
During the past four years we identified a novel human enzyme
that cleaves certain fatty acids from LPS and showed that this
enzymatic deacylation greatly modifies the bioactivities of LPS.
We now propose to evaluate the biological significance of this
enzyme in man.

Lipid A, the bioactive moiety of LPS, is a glucosamine
disaccharide that has covalently linked fatty acids, phosphates,
and a polysaccharide chain.  Hydroxylated fatty acids (e.g., 3-
hydroxymyristate) are linked directly to glucosamine, whereas
normal fatty acyl chains (myristoyl and lauroyl) are substituted to
the hydroxyl groups of some of the 3-hydroxymyristoyl residues to
form acyloxyacyl linkages.  We found an enzymatic activity in
human neutrophils that removes (only) the normal fatty acids
from LPS--breaking the acyloxyacyl linkages.  This acyloxyacyl
hydrolysis was then shown to reduce the bioactive potency of LPS.
Interestingly, the impact of enzymatic deacylation was greater on
the tissue toxicity of LPS than on the immunostimulatory
activity, suggesting that the enzyme may act in vivo to reduce
LPS toxicity while retaining potentially beneficial stimuli to the
immune system.

The proposed research will (1) complete the purification and
characterization of human neutrophil acyloxyacyl hydrolase
(AOAH), (2) clone the gene for AOAH, (3) determine the cellular
location(s) of AOAH and evaluate its regulation in cultured cells
and in vivo, and (4) use deacylated LPS (which inhibit the ability
of LPS to stimulate human endothelial cells) to study the
stimualtion of cells by LPS.

Acyloxyacyl hydrolase is the only enzyme that is known to
interact with LPS in animal cells.  We hope that understanding its
biological role(s) will suggest new strategies for controlling
inflammatory responses to LPS and consequently improve the
outcome of gram-negative bacterial diseases in man.

## Key facts

- **NIH application ID:** 3127740
- **Project number:** 2R01AI018188-07
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **SAM.gov UEI:** YZJ6DKPM4W63
- **Principal Investigator:** ROBERT S MUNFORD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1987
- **Award amount:** $231,842
- **Award type:** 2
- **Project period:** 1981-08-01 → 1992-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3127740

## Citation

> US National Institutes of Health, RePORTER application 3127740, INTERACTIONS OF ENDOTOXIN WITH HUMAN PLASMA & CELLS (2R01AI018188-07). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3127740. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*