# Mechanisms of host protection against pathogen-secreted proteases in acute lung injury

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $432,536

## Abstract

Project Summary/Abstract:
Acute lung injury, or acute respiratory distress syndrome (ARDS) is characterized by persistent neutrophilic
inflammation and is the final common pathway of a variety of direct and indirect insults to the lungs. A critical
gap in knowledge exists in why some individuals exhibit persistent respiratory failure. One of the most common
risk factors for ARDS development is bacterial pneumonia, but bacterial pneumonia is also a common
complication of ARDS and either of these scenarios can present itself clinically as failure to resolve. Thus, we
propose to study distinct host-pathogen interactions as the framework for understanding complication and
persistence of ARDS. Although proteases secreted by the extracellular gram-negative bacteria Pseudomonas
aeruginosa (PA) subvert host immunity and trigger aberrant neutrophil activation during acute PA intra-
pulmonary infection, mechanisms of host protection are less known. The broad, long term objective is to
identify host-protective mechanisms that counter pathogen-initiated lung inflammation and injury. We have
previously shown that thrombospondin-1, a matricellular protein released by a variety of cells during
inflammation, is a host-protective molecule during sterile lung injury. Our main hypothesis is that
thrombospondin-1 disarms pathogen-secreted proteases and limits both pathogen-initiated tissue damage and
secondary host-sustained proteolysis. We developed an in vitro protease screening assay and in vivo screen
using an acute lung infection injury model to identify TSP1 as a potent inhibitor of a PA secreted virulence
factor, and neutrophil granule proteases. Based upon these findings, we propose the following aims utilizing
genetically deficient mice, tissue-specific conditional knockout models and PA clinical respiratory isolates
obtained from the ICU to (1) identify the mechanism by which TSP-1 provides host defense against proteolytic
injury during acute intra-pulmonary infection with PA; (2) elucidate the role of platelets in promoting alveolar
barrier repair and protection by platelet TSP-1 against pathogen-triggered lung injury; and, (3) evaluate PA
elastase activity from ICU respiratory isolates and determine their propensity toward disabling host resilience
mechanisms in the lungs. Findings from this study is highly significant as it will lead to the identification of key
mechanisms that promote host protection against aggressive lung injury triggered by infection and may lead to
potential targets to combat ARDS and overwhelming sepsis in the future.

## Key facts

- **NIH application ID:** 9972955
- **Project number:** 5R01HL136143-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Janet Sojung Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $432,536
- **Award type:** 5
- **Project period:** 2017-08-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972955

## Citation

> US National Institutes of Health, RePORTER application 9972955, Mechanisms of host protection against pathogen-secreted proteases in acute lung injury (5R01HL136143-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9972955. Licensed CC0.

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