# Therapeutic Use of High Molecular Weight Hyaluronic Acid in Acute Lung Injury Following Severe Bacterial Pneumonia or Sepsis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $794,956

## Abstract

ABSTRACT
Bacterial pneumonia with or without sepsis is among the most common cause of acute respiratory failure in
critically ill patients leading to acute respiratory distress syndrome (ARDS). Despite improvements in
supportive care and appropriate antibiotic use, mortality from ARDS remains as high as 40%. Therefore, new
innovative therapies are needed. Hyaluronan or hyaluronic acid (HA) is normally synthesized as a high
molecular weight (HMW) nonsulfated glycosaminoglycan and is a chief component of the extracellular matrix
and critical for maintaining the normal structure of alveolar air-blood barrier. In multiple pulmonary disorders
including acute lung injury (ALI), asthma, COPD or pulmonary hypertension, HA undergoes degradation by
hyaluronidases, reactive oxygen and nitrogen species and inflammatory mediators. The degradation products,
low molecular weight (LMW) HA, has inflammatory properties and can decrease endothelial cell barrier
function and induce expression of inflammatory mediators. In patients with ARDS, elevated levels of alveolar
LMW HA have been associated with increased Lung Injury Score. Surprisingly, HMW HA has biologic
properties opposite of LMW HA based primarily due to its molecular size. Therefore, investigators have
previously studied the therapeutic use of exogenous administration of HMW HA in lung disorders. Despite
promising pre-clinical data, a major limitation for the use of HMW HA for ARDS has remained the concern of
giving an immunosuppressive therapy in patients with severe infection. In the current proposal, we hypothesize
that administration of HMW HA will further restore major indices of ALI from severe bacterial pneumonia and/or
sepsis in part through increased (1) antimicrobial activity and (2) through neutralization of inflammatory
extracellular vesicles (EV) released during the exudative phase of ALI. In Aim 1, we will determine the
therapeutic effects of HMW HA administration in established mouse models of severe bacterial pneumonia.
We hypothesize that the mechanisms underlying the therapeutic effects of HMW HA will be due to increased
antimicrobial activity of innate immune cells, binding of inflammatory EVs released early in the exudative phase
of ALI, and through the restoration of the endothelial glycocalyx layer. To make the small pre-clinical animal
studies more clinically relevant, in Aim 2, we will determine the therapeutic effects of HMW HA administration
in an ex vivo perfused human lung injured with severe E.coli or Pseudomonas aeruginosa bacterial
pneumonia. And to overcome some of the limitations of the perfused human lung such as a lack of the liver
and spleen which are the major sites of HA degradation, in Aim 3, we will determine the therapeutic effects of
HMW HA administration in a well-established ovine model of septic shock induced by smoke inhalation and
Pseudomonas aeruginosa pneumonia. If successful, HMW HA, an inexpensive, non-immunogenic biologic
already in use in clinical tria...

## Key facts

- **NIH application ID:** 10148808
- **Project number:** 5R01HL148781-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Perenlei Enkhbaatar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $794,956
- **Award type:** 5
- **Project period:** 2020-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10148808

## Citation

> US National Institutes of Health, RePORTER application 10148808, Therapeutic Use of High Molecular Weight Hyaluronic Acid in Acute Lung Injury Following Severe Bacterial Pneumonia or Sepsis (5R01HL148781-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10148808. Licensed CC0.

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