# Interplay between Heme Oxygenase-1 and Chitinase 3-like-1 in Protection against Neonatal Hyperoxic Lung Injury

> **NIH NIH F31** · BROWN UNIVERSITY · 2020 · $28,857

## Abstract

SUMMARY
Due to advances in neonatal and perinatal care, premature infants can survive at extremes of gestation (> 22
weeks). In order to sustain life following extreme prematurity, mechanical ventilation and supplemental oxygen
are employed, which can disrupt normal lung development and blunt the growth of distal airspaces. This
results in continued dependency on supplemental oxygen beyond 36 weeks corrected gestation, referred to as
bronchopulmonary dysplasia (BPD). Chitinase 3-like-1 (Chi3l1) is a member of the evolutionary conserved 18
glycosyl hydrolase family, which is downregulated in adult mouse lungs and human bronchial epithelial cells
exposed to hyperoxia, as well as in tracheal aspirates from premature infants that developed BPD. Although
Sp1 transcription factor has been characterized as a strong activator of the Chi3l1 gene promoter, the
mechanisms underlying the reduction of Chi3l1 by hyperoxia are not understood. Another protein whose levels
are altered in hyperoxia is heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation. HO-1 has
been shown to localize to the nucleus in neonatal mouse lungs, which can downregulate the activity of Sp1
transcription factor. Our preliminary data show that HO-1 knockout mouse embryonic fibroblasts have higher
levels of Chi3l1 than wild type cells. Hence, we speculate that nuclear HO-1 could regulate Chi3l1 gene
expression through modulation of Sp1. Chi3l1 has been shown to attenuate hyperoxia-induced lung apoptosis
and acute lung injury in adult mice. Given lung injury responses to hyperoxic exposure differ between neonatal
and adult mice, it is not known whether Chi3l1 protects against hyperoxia-induced arrest of alveolarization in
neonatal mice. Autophagy has been shown to act as a protective response to reduce stress-induced apoptosis.
We have preliminary data showing that mice overexpressing Chi3l1 have increased levels of autophagy
marker, LC3-II in the lungs. Currently, there is no evidence indicating that Chi3l1 utilizes autophagy to mediate
its protective responses to hyperoxic exposure. We hypothesize that Chi3l1 is regulated by HO-1 in basal
conditions and that Chi3l1 mediates its protective response against hyperoxic lung injury through the induction
of autophagy in neonatal mice. Therefore, we propose to: 1) determine the mechanisms by which HO-1
regulates the expression of Chi3l1; 2) determine how Chi31 induces autophagy during hyperoxia-induced
apoptosis. This proposal will not only evaluate how Chi3l1 is transcriptionally regulated by HO-1, but also
unravel novel molecular mechanisms underlying apoptotic cell death and lung injury induced by hyperoxia.

## Key facts

- **NIH application ID:** 9859445
- **Project number:** 5F31HL139080-03
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** David Garcia
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $28,857
- **Award type:** 5
- **Project period:** 2018-01-01 → 2020-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859445

## Citation

> US National Institutes of Health, RePORTER application 9859445, Interplay between Heme Oxygenase-1 and Chitinase 3-like-1 in Protection against Neonatal Hyperoxic Lung Injury (5F31HL139080-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9859445. Licensed CC0.

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