# Role of intestinal inflammation in oxidized lipid induced pulmonary hypertension

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $598,902

## Abstract

SUMMARY
Pulmonary arterial hypertension (PAH) is a chronic lung disease characterized by a progressive increase in
pulmonary arterial pressure leading to right ventricular (RV) heart failure and death. Over the last five years, our
group and others have demonstrated the critical role of oxidized fatty acids in the pathogenesis of PAH. Levels
of oxidized fatty acids of the lipoxygenase (LOX) pathway; hydroxyeicosatetraenoic acids (HETEs) are
upregulated in the lungs of patients with PAH as well as in rats with pulmonary hypertension (PH). We were the
first to establish that dietary supplementation of a single oxidized fatty acid (15HETE) of the LOX pathway is
sufficient to cause PH in wild type mice in the absence of any other PH stimulus. In our very recent publication
in Hypertension, we reported T cell-dependent endothelial cell apoptosis as one of the mechanisms underlying
15HETE induced PH. However, the exact molecular mechanisms leading to PAEC apoptosis and onset of PH
are not known. To unravel the molecular mechanisms, we performed RNA-Seq on the lungs and intestine of
mice on 15HETE diet and integrated our RNA-Seq data with online microarrays of human PAH lungs and
identified IFI44 (IFN inducible protein 44) as the only novel common gene that was significantly upregulated.
IFI44 is an interferon inducible protein and our preliminary data shows that IFNα4 is specifically increased in the
small intestine of mice on 15HETE diet. Our preliminary time course experiments revealed increased expression
of IFI44 in the small intestine, which precedes its upregulation in the lung, suggesting that 15HETE may act on
the small intestine initially. In addition, our pilot data shows that IFI44 is expressed in the immune cells in the
lungs of human PAH patients and in T cells in mouse lungs on 15HETE diet. Our bioinformatic analysis also
revealed that expression of IFI44 in immune cells in the lungs correlates with CXCL10 (a proinflammatory
cytokine) and TRAIL (Tumor Necrosis Factor Related Apoptosis Inducing Ligand). TRAIL and CXCL10 are both
known to induce endothelial cell apoptosis. Our preliminary data also shows i) Knockdown of IFI44 in the lungs
of mice on 15HETE diet prevented development of PH, and ii) blocking the pathologic action of Cxcl10 rescues
PH development. Taken together, our overall hypotheses are i) dietary 15HETE acts on intestinal epithelial cells
to produce IFN4, which induces IFI44 in specific immune cells of the Lamina Propria. IFI44 positive immune
cells migrate to the lungs and in coordination with CXCL10/TRAIL trigger PAEC death, causing PH; and ii) IFI44
and CXCL10 can serve as novel therapeutic targets in the lungs to prevent or even rescue development of PH
in mice on 15HETE diet. Aim 1 will determine the mechanisms by which 15HETE activates the intestinal
epithelium resulting in the development of PH; Aim 2 will examine how activation of IFI44 in immune cells in the
small intestine induces endothelial cell apoptosis in t...

## Key facts

- **NIH application ID:** 10772032
- **Project number:** 5R01HL162124-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Mansoureh Eghbali
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $598,902
- **Award type:** 5
- **Project period:** 2022-02-10 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10772032

## Citation

> US National Institutes of Health, RePORTER application 10772032, Role of intestinal inflammation in oxidized lipid induced pulmonary hypertension (5R01HL162124-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10772032. Licensed CC0.

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