# Immune mechanisms of acute respiratory distress syndrome

> **NIH NIH F32** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $69,306

## Abstract

PROJECT SUMMARY/ABSTRACT
The acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in the intensive care
unit due to overwhelming inflammation in the lung without effective disease modifying treatments. Two sub-
phenotypes of ARDS have been identified based on clinical parameters and biomarkers. Compared to hypo-
inflammatory ARDS, hyper-inflammatory ARDS is characterized by shock, acidosis, and elevated inflammatory
biomarkers. Patients with hyper-inflammatory ARDS have a higher mortality and may respond differentially to
treatment. The overarching goal of this training grant proposal is to utilize cutting edge immunology techniques
to dissect the immune mechanisms underlying ARDS development and the differentiation between the two
sub-phenotypes. In our preliminary data, we identified reduced expression of tristetraprolin (TTP), a negative
regulator of cytokine production, in natural killer (NK) cells of patients with ARDS. In Aim 1, we will investigate
the mechanisms by which TTP regulates NK cell activation. Additionally, we will use PrimeFlow, a novel flow
cytometry-based mRNA quantification technique, to determine if NK cells from patients with ARDS are
refractory to negative feedback by inflammatory cytokines due to reduced TTP expression. In Aim 2, we will
focus on discovery of immune mechanisms that differentiate hyper- and hypo-inflammatory ARDS. We have
found increased frequency of circulating inflammatory non-classical CD14-CD16+ monocytes in hyper-
inflammatory ARDS when compared to hypo-inflammatory ARDS patients. We propose using cellular indexing
of transcriptomes and epitopes with sequencing (CITE-seq) to investigate signaling pathways at the single cell
level in monocytes that differentiate hyper- and hypo-inflammatory ARDS. CITE-seq references single cell
RNA sequencing transcriptomic data to surface expression of proteins thereby correlating the transcriptome
with flow cytometric surface phenotypes. Together, aims 1 and 2 will test our overall hypotheses that NK
cells in ARDS patients are resistant to negative feedback due to reduced TTP expression, and
persistent activation of CD16+ non-classical monocytes determines the hyper-inflammatory phenotype
of ARDS. Further delineation of immune mechanisms in the development and maintenance of ARDS will
advance our understanding of its pathogenesis and identify potential therapeutic targets to modify the disease
course of ARDS. The research proposed within this training fellowship will be undertaken at the University of
Pittsburgh through a collaborative training environment between the Division of Pulmonary, Allergy and Critical
Care Medicine and Department of Immunology to develop research skills in translational human and
computational systems immunology. Formal training in the responsible conduct of research and scientific rigor
are included in this training proposal, and career development through presentation of research, publication
and a multi-di...

## Key facts

- **NIH application ID:** 9990101
- **Project number:** 1F32HL152497-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Brian Robert Rosborough
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $69,306
- **Award type:** 1
- **Project period:** 2020-05-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990101

## Citation

> US National Institutes of Health, RePORTER application 9990101, Immune mechanisms of acute respiratory distress syndrome (1F32HL152497-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9990101. Licensed CC0.

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