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

Award Number: R01HL148781
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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 trials for other sterile inflammatory pulmonary disorders such as COPD, may prove to be a viable therapy for ARDS and/or sepsis.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Lung Diseases Research	002	5	10/15/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$294,494
2025	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	001	4	10/15/2024	NON-COMPETING CONTINUATION	-$153,425
2025	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	000	3	10/15/2024	NON-COMPETING CONTINUATION	-$141,069
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Lung Diseases Research	001	5	3/21/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$629,119
2024	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	000	4	3/18/2024	NON-COMPETING CONTINUATION	-$629,119
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $782,544 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	4	4/29/2023	NON-COMPETING CONTINUATION	$782,544
														Subtotal = $782,544

Issue Date FY: 2022 ( Subtotal = $788,880 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	3	4/27/2022	NON-COMPETING CONTINUATION	$788,880
														Subtotal = $788,880

Issue Date FY: 2021 ( Subtotal = $794,956 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	2	4/28/2021	NON-COMPETING CONTINUATION	$794,956
														Subtotal = $794,956

Issue Date FY: 2020 ( Subtotal = $815,317 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	1	4/22/2020	NEW	$815,317
														Subtotal = $815,317

Grand Total All Awards = $3,181,697

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

Award Number: R01HL148781

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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