# Mechanistically Disentangling the Infected, Inflamed Lung

> **NIH NIH K08** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $173,879

## Abstract

PROJECT SUMMARY
Pneumonia is a leading cause of pediatric death world-wide. This mortality is not solely related to infection;
unmitigated neutrophilic inflammatory responses destroy pulmonary parenchyma and contribute to respiratory
decline. Neutrophilic destruction can occur quickly, as seen in acute respiratory distress syndrome (ARDS), or
progressively, as seen in cystic fibrosis (CF). In ARDS, neutrophils flood the lung and drive subsequent edema
and injury. In CF, thick, purulent airway secretions filled with neutrophils and bacteria, most commonly
Pseudomonas aeruginosa, lead to progressive bronchiectasis. It has been shown that pathogen engagement
with airway epithelium results in release of the arachidonic acid metabolite, hepoxilin A3, a neutrophil-specific
chemoattractant, driving neutrophils to breach the airway mucosa. Migrated neutrophils then release LTB4, a
second arachidonic acid metabolite and neutrophil chemoattractant, greatly augmenting neutrophil airway
breach. Further elucidation of the mechanisms driving this process warrant exploration. I plan to specifically
focus on the role of LTA4 hydrolase in bacterial-induced neutrophil transepithelial migration. Additionally, I have
identified Pseudomonas genes that appear to play a role in neutrophil transepithelial migration. In this grant
proposal, I will further define the role of bacterial factors in this inflammatory process, which may shed light on
novel bacterial targets to promote tolerance of bacteria within the airway and minimize the excessive, destructive
inflammatory process. Together, the aims outlined in this grant proposal will focus on unique aspects of airway
inflammation, with the goal of identifying novel therapeutic targets, ultimately reducing the morbidity and mortality
associated with pediatric pneumonia.

## Key facts

- **NIH application ID:** 9985218
- **Project number:** 5K08HL143183-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Lael Yonker
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $173,879
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985218

## Citation

> US National Institutes of Health, RePORTER application 9985218, Mechanistically Disentangling the Infected, Inflamed Lung (5K08HL143183-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9985218. Licensed CC0.

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