# Ceramide-Induced Destruction In Emphysema

> **NIH NIH R01** · NATIONAL JEWISH HEALTH · 2020 · $439,050

## Abstract

Abstract
 This application will test the hypothesis that inhibition of sphingosine-1 phosphate (S1P) production and
signaling in lung endothelial cells by chronic cigarette smoke (CS) exposure is a critical event in emphysema
pathogenesis. We propose that inhibition of sphingolipid metabolism upstream of S1P production will have a
dual effect: loss of protective, pro-survival S1P production and signaling, coupled with accumulation of
cytotoxic sphingolipid metabolites such as ceramide that cause cell death. We will test this paradigm primarily
in lung endothelial cells, since their loss is known to be a key element of emphysema pathogenesis. Despite an
abundance of data highlighting the beneficial effects of S1P on the vasculature, little is known about its
regulation and importance in CS-induced lung injury and emphysema and the mechanisms by which S1P
prevents or disengages various types of cell injury triggered by upstream sphingolipid metabolites. These
newly uncovered cell stress responses, injury, and death are present in emphysema lungs and include
mitochondria damage, inappropriate clearance by mitophagy, and a new form of cell death, necroptosis. We
hypothesize that CS decreases S1P production and its S1P receptor 1-dependent signaling, leading to
accumulation of necroptosis-inducing palmitoyl-ceramide and to decreased pro-survival signaling in lung
endothelial cells, culminating in emphysema. We will test this hypothesis using a translational approach of CS
exposure in mice coupled with primary human lung cells. Our work will provide a mechanistic link between CS,
the steady and conditional state levels of S1P and cellular injury and will reveal novel therapeutic targets to
limit lung destruction in this common disease.

## Key facts

- **NIH application ID:** 9883024
- **Project number:** 5R01HL077328-15
- **Recipient organization:** NATIONAL JEWISH HEALTH
- **Principal Investigator:** Irina Petrache
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $439,050
- **Award type:** 5
- **Project period:** 2006-07-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9883024

## Citation

> US National Institutes of Health, RePORTER application 9883024, Ceramide-Induced Destruction In Emphysema (5R01HL077328-15). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9883024. Licensed CC0.

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