# Fine-tuning the Neutrophilic Response to Pneumonia

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $436,335

## Abstract

Project Summary/Abstract
The lung is a portal of entry for a variety of pathogenic organisms that may cause pneumonia or even the acute
respiratory distress syndrome (ARDS), which is a life-threatening syndrome that has no specific treatments
except for the provision of gentle mechanical ventilation and supportive care. The neutrophil is a critical
cellular mediator of the early immune response to pathogenic lung infections, but an overly exuberant
neutrophil response may cause collateral damage to the lung and lead to acute lung injury. In this application,
a new function of neutrophils, the release of neutrophil extracellular traps (NETs), will be investigated in mouse
models of acute lung infection. NETs are composed of extracellular chromatin decorated with neutrophil
granular proteins and have been proposed to serve an important role in the trapping and killing of bacteria and
other pathogens. However, we propose that NETs are toxic to adjacent cells and are on balance a
maladaptive and dispensible host response in pneumonia and acute lung injury. Aim 1 of this application will
investigate the role of NETs in mouse models of bacterial and viral pneumonia using novel techniques to
visualize and quantify NETs. We will also test the role of lipoxin mediators signaling through Fpr2 on
neutrophils in regulating NET production and the progression to acute lung injury. Aim 2 will test the role of
DNase1 in regulating the degradation of NETs in the lung and the important effects of DNase1 treatment on
the containment of infection and preservation of the lung barrier. In translational studies, Aim 2 will also use
biological samples from critically ill patients with severe infections to test if NETs and DNase1 bioactivity (a)
predict the progression to ARDS or (b) are associated with poor clinical outcomes in ARDS. The factors that
determine whether a localized lung infection progresses to acute lung injury are not known, but this application
proposes that NETs are critical mediators in this process and targetable. Our studies using live bacterial and
viral infections, novel approaches to visualize acute lung inflammation and injury, and NETs, pharmacologic
and genetic approaches to neutralize NETs, and translational studies to complement our mouse models, are
well-positioned to provide definitive evidence on the in vivo significance of NETs, and to position NETs as a
novel target for the treatment of pathogen-induced lung injury.

## Key facts

- **NIH application ID:** 9934984
- **Project number:** 5R01AI125445-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** MARK ROBERTS LOONEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $436,335
- **Award type:** 5
- **Project period:** 2016-06-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934984

## Citation

> US National Institutes of Health, RePORTER application 9934984, Fine-tuning the Neutrophilic Response to Pneumonia (5R01AI125445-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9934984. Licensed CC0.

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