# Alveolar epithelial carbohydrate metabolism in acute lung injury

> **NIH NIH K08** · UNIVERSITY OF COLORADO DENVER · 2020 · $165,240

## Abstract

Acute lung injury (ALI) is an inflammatory lung disease characterized by its acute onset, severe hypoxia and
pulmonary edema; which manifests itself in patients as acute respiratory distress syndrome (ARDS). At
present, specific therapeutic approaches for ARDS are essentially unknown. Alveolar epithelial cells line the
alveolar surface and type II alveolar epithelial cells (AT II) are known for their susceptibility to injurious insults
that can lead to ALI. Inflammatory and immune responses in ALI are associated with dramatic shifts in tissue
metabolism, which can either injurious or protective. A key protective mechanism involves enhanced
pulmonary glycolysis, mediated through stabilization of the transcription factor hypoxia-inducible factor (HIF);
however, how specific metabolic processes, notably those involving specific enzymatic glycolytic steps (and
increase or decreases in intermediate substrates) affect the response of AT II cells during injury onset are
largely unknown. We have developed a novel concept that in response to acute lung injury
phosphofructokinase-2/fructose-2,6-bisphosphatase (PFKFB3 ) and its transcriptional regulator HIF1A are
mediating anti-inflammatory activities of AT II cells. We hypothesize that excessive inflammation and cell injury
in ALI are dampened by increases in intracellular lactate and pyruvate, which are induced by HIF1A-driven
glycolysis and activation of PFKFB3 in alveolar type II cells. Harnessing those innate protective pathways
could provide the base for novel therapeutic targets for ALI. In this resubmission we will: 1. Determine whether
HIF1A is required for PFKFB3 activation in AT II cells (Specific Aim 1); 2. Determine whether the activation of
PFKFB3 in AT II cells dampens inflammation due to ALI. We will uncover downstream effects of PFKFB3
activation, specifically the augmentation of glycolytic flux, and whether the glycolytic end products
lactate/pyruvate quench excessive inflammation in AT II cells (Specific Aims 2a); 3. We will target alveolar-
epithelial PFKFB3 therapeutically during ALI as we hypothesize, that activation of PFKFB3 will enhance the
glycolytic flux and attenuate inflammation due to a dominant anti-inflammatory effect in AT II cells (Specific Aim
2b). To discern the role of the alveolar epithelium we utilize primary alveolar type II cells and tissue specific
know out animals. Ventilator induced lung injury and acid aspiration will be used as murine models of ALI. To
model lung injury ex vivo we will utilize an in vitro cyclic stretch system. Pharmacologic and genetic
approaches will be utilized to study the functional role of HIF1A and PFKFB3 in vitro or ALI in vivo. We will
target the AT II cells ex vivo and provide mechanistic data based on enhanced delivery of the glycolysis
activator 2-6 fructose bisphosphate encapsulated by nanoparticles. We will characterize the epithelial glycolytic
flux (metabolites, PFKFB3 and LDH activity, NADH/NAD measurement) and inflammatory resp...

## Key facts

- **NIH application ID:** 9852341
- **Project number:** 5K08HL130586-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Christine U Vohwinkel
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $165,240
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-03-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852341

## Citation

> US National Institutes of Health, RePORTER application 9852341, Alveolar epithelial carbohydrate metabolism in acute lung injury (5K08HL130586-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9852341. Licensed CC0.

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