# Novel Mechanisms of Hepatopulmonary Syndrome

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $769,513

## Abstract

Cirrhosis afflicts nearly 3 million people in the US, and complications from resultant portal hypertension are
the fourth leading cause of death in individuals age 45-65 years. One common complication is the
hepatopulmonary syndrome (HPS) which results when lung microvascular dilations cause intrapulmonary
shunting and impair arterial oxygenation. HPS occurs in 20% of patients evaluated for liver transplantation
(LT), regardless of the severity of liver disease, and significantly increases mortality and worsens quality of life.
Affecting approximately 900,000 Americans, HPS rivals other well-established sequelae of portal hypertension
in terms of incidence and clinical impact. Although LT can resolve HPS, costs are high and mortality is
increased post-transplantation in HPS. Unfortunately, there are no large human studies of HPS.
 To address this need, the investigators have spearheaded the study of HPS with an experimental animal
model and through patient-oriented research. We have found abnormal sphingolipid signaling in both patients
with HPS and the experimental animal model which may be linked to the angiogenesis seen in the lungs. We
have also generated preliminary data suggesting that higher levels of bile acids are associated both with
alveolar Type II cell apoptosis, increased circulating surfactant protein D levels, and HPS.
 The overall objective of this application is to examine whether increased sphingosine 1 phosphate :
ceramide ratio and circulating bile acids are associated with HPS in patients with advanced liver disease. We
will also determine if liver transplant reduces SPD levels in proportion to changes in gas exchange and
resolution of HPS. Finally, we will study these novel mechanisms in the animal model of HPS by administering
bile acids and sphingosine kinase inhibition. The major impact of this first large multicenter study in HPS will be
to identify mechanisms and therapeutic targets of this poorly understood pulmonary vascular disease.

## Key facts

- **NIH application ID:** 10166906
- **Project number:** 5R01HL142269-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Steven M Kawut
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $769,513
- **Award type:** 5
- **Project period:** 2018-06-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10166906

## Citation

> US National Institutes of Health, RePORTER application 10166906, Novel Mechanisms of Hepatopulmonary Syndrome (5R01HL142269-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10166906. Licensed CC0.

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