# Nanoparticle Targeting of Neutrophil Subpopulations in Inflammatory Lung Injury

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2021 · $599,217

## Abstract

PROJECT SUMMARY / ABSTRACT
ARDS results from a severely dysregulated immune response that leads to lung vascular injury and protein-rich
edema. Excessive activation of neutrophils (PMNs) is a primary cause of the lung damage. In experimental
sepsis and septic patients, some PMNs are intensely activated and sequestered in lungs while others pass
through the lung microvasculature unimpeded and function as essential host-defense cells. Previous findings
suggest that PMNs might exist as various subsets and in different stages of activation. The concept of
heterogeneity of PMNs raises the possibility that a subset of activated PMNs may contribute to a maladaptive
inflammatory response and be responsible for lung injury. We found that a subset of PMNs specifically
internalized 100 nm albumin nanoparticles (ANPs). As our Supporting Data show this population of PMNs
increased significantly in experimental sepsis in mice and they were shown to be essential for the development
of inflammatory lung injury. We also conjugated drugs to ANP for their precise delivery into these PMNs. These
results raise several fundamental questions: What is the nature of this PMN population? Is there a related
population in humans? What is their function and what is their origin? What is the mechanism of ANP
internalization? Do these cells mediate lung injury and can ANP deliver drugs into this PMN population to reverse
the course of the disease? We will address these PMNs by characterizing the function of
CD11bhighCD16+CD45highANPhigh PMN subset as opposed to control CD11bhighCD16+CD45highANPlow PMNs
in mediating inflammatory lung injury (Aim 1). Here we will test the hypothesis that ANPhigh PMNs are
functionally distinct from ANPlow PMNs and that the former are crucial in mediating lung injury. Next, we will
determine differential β2 integrin signaling in the distinct PMN sub-populations and their role in
mediating lung injury (Aim 2). Here we will test the hypothesis that β2 integrins and downstream signaling
pathway are hyper-activated in ANPhigh PMNs compared to ANPlow PMNs and differential PMN signaling is
required inflammatory lung injury. Finally, we will define the origin, fate, and phenotypic heterogeneity of
PMNs mediating lung injury (Aim 3). Here, RNA-Seq profiling has thus far revealed distinct chemokine
receptors as markers of ANPhigh PMNs in lungs, and we will use this information to isolate this subset to further
characterize them and assess their functional role in mediating lung injury. We will also define the time-
dependent transcriptomic profiles and networks of ANPhigh vs. ANPlow PMNs during inflammatory activation to
assess their differential properties. Thus, together studies will not only define a population toxic injury-promoting
population of PMN but also hopefully identify new therapeutic targets to reverse the course of inflammatory lung
injury.

## Key facts

- **NIH application ID:** 10186803
- **Project number:** 5R01HL149300-03
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Asrar B. Malik
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $599,217
- **Award type:** 5
- **Project period:** 2019-08-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10186803

## Citation

> US National Institutes of Health, RePORTER application 10186803, Nanoparticle Targeting of Neutrophil Subpopulations in Inflammatory Lung Injury (5R01HL149300-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10186803. Licensed CC0.

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