# Hypoxia inducible factors in pulmonary endothelial cells regulate allergic inflammatory airways disease

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2023 · —

## Abstract

Asthma affects 1 in 12 Americans. More than 50% of asthmatics (12 million) have asthma attacks each
year. Asthma is a chronic inflammatory disease which has great impact on quality of life. Uncontrolled and
untreated asthma leads to missed work and school, as well as high healthcare costs. There are many different
types of asthma, some of which are well targeted by current therapeutics leading to disease control. However,
there are some endotypes of asthma, such as TH2-low neutrophilic asthma, that do not have targeted therapies
available. These endotypes are driven by inflammatory pathways that do not respond to steroids, and thus they
are commonly found in steroid-resistant asthma. The premise of our proposed work is that there are additional
cell types and pathways that can be identified and targeted in asthma.
 Hypoxia inducible factors (HIF) have been found to be master regulators of inflammation when expressed
in immune cells. HIF-1α is constitutively expressed in all cells, and is important in the regulation of metabolism,
cell proliferation and cell migration, in addition to regulating inflammatory pathways. HIF-2α has more limited
expression, but like HIF-1α it is expressed in pulmonary endothelial cells and regulates both metabolism and
inflammation. We have studied both HIF-α subunits in the setting of asthma, and have found that each regulates
inflammation through myeloid cells in a pro-inflammatory manner. When either was suppressed through systemic
administration of small molecule inhibitors, a more profound effect on allergic inflammation was seen, which
suggests that non-myeloid cells also promote inflammation via HIF-α subunits.
 Pulmonary endothelial cells are the gateway to the lungs from the circulation. We hypothesize that HIF-
1α and HIF-2α play a role in activation of pulmonary endothelial cells during pulmonary inflammation, leading to
expression of adhesion molecules on the vascular surface and transmigration of circulating inflammatory cells
into the lungs. We propose to use pulmonary endothelial cell specific HIF-1α and HIF-2α knock-out mice to
evaluate the role of HIFs in the recruitment of inflammatory cells such as eosinophils during asthma-like
inflammation. Because of the heterogeneity of asthma, and the lack of therapeutic options for non-TH2 non-
allergic phenotypes of asthma, we will use three immunologically disparate mouse models of asthma to evaluate
the role of these HIF molecules in asthma pathogenesis.
 Mouse models are powerful in that they can assess for physiologic changes, and organ and system-level
effects. In addition, gene knockouts in mice are a powerful tool for understanding the roles of individual proteins
on disease induction and progression. However, there are differences in immune function and inflammatory
responses between murine and human cells, such that murine data does not always reflect human responses.
Thus, we will use human endothelial cells and human immune cells ex vivo to study th...

## Key facts

- **NIH application ID:** 10515302
- **Project number:** 5I01BX004767-04
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** Laura Elise Crotty Alexander
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-10-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10515302

## Citation

> US National Institutes of Health, RePORTER application 10515302, Hypoxia inducible factors in pulmonary endothelial cells regulate allergic inflammatory airways disease (5I01BX004767-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10515302. Licensed CC0.

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