# Mechanisms of Inflammation in Sickle Cell Disease

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2022 · $550,435

## Abstract

Project Summary/Abstract
Numerous studies show the mechanisms by which sickle cell disease (SCD) induces vasculopathy and
increases vasocongestion are complex and multifactorial. In this revised, renewal application, we hypothesize
that SCD induces vasculopathy as one of the first steps in the mechanism by which SCD increases vaso-
occlusion. Our studies show that SCD induces a destructive cycle that is initiated by MPO and propagated by
high mobility group box-1 (HMGB1), and one other inflammatory component that alters pulmonary physiology,
impairs vascular function, and increases vasocongestion.
Previously, we reported L-acetyl-lysyltyrosylcysteine amide (KYC) inhibits MPO, improves vascular function and
reduces liver injury induced by excessive vasocongestion in SCD mice. New studies suggest that KYC not only
reduces sickle RBC (sRBC) congestion but also increases the number of round sRBC in the lungs of SCD mice.
Mechanistic studies reveal that KYC isn't just an inhibitor of MPO toxic oxidant production, but rather, is a unique
tripeptide substrate that exploits MPO peroxidase activity to be converted into a novel anti-inflammatory agent
that inactivates HMGB1 and activates the cellular pathways that are responsible for antioxidant defense enzyme
expression in the lung. As KYC inhibits multiple inflammatory components in our hypothesized destructive cycle,
and even activates a component that mediates antioxidant gene expression, new studies using mechanistic
inhibitors are required for determine which components increase vasculopathy and vasocongestion in SCD.
While a systems pharmaceutical agent may be useful for treating multifactorial diseases, they cannot be used to
identify causal mechanisms directly. In this revised application, we hypothesize that SCD induces a destructive
cycle, mediated by at least three major components. Our working hypothesis is SCD induces a destructive cycle
that is composed of MPO, HMGB1 and a novel, dysregulate gene and together induce vasculopathy and
increase vasocongestion. By treating sickle mice, sickle MPO knockout (ko) mice, chimeric sickle Tamoxifen-
inducible HMGB1 ko mice and another chimeric sickle ko mice with highly selective mechanistic inhibitors we
will be able to determine if and the extent to which MPO, HMGB1 and the third gene product, alone and/or in
combination induces vasculopathy and increases vasocongestion. To assess vasculopathy, we will quantify
differences in pulmonary artery relaxation, pulmonary permeability, sRBC vasocongestion, and susceptibility of
each mouse strain to sRBC vasocongestion induced by hypoxia-reoxygenation injury (HRI) in Townes
homozygote sickle Hb (SS) wt SS Mpo ko mice, and chimeric SS novel gene ko mice. Our long-term goals are
to confirm the identities of each component and develop novel therapies aimed at improving vascular function
and reducing sRBC vasocongestion.

## Key facts

- **NIH application ID:** 10380784
- **Project number:** 5R01HL128371-06
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Kirkwood Arthur Pritchard
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $550,435
- **Award type:** 5
- **Project period:** 2016-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10380784

## Citation

> US National Institutes of Health, RePORTER application 10380784, Mechanisms of Inflammation in Sickle Cell Disease (5R01HL128371-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10380784. Licensed CC0.

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