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

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $568,095

## Abstract

Project Summary/Abstract: The broad, long term objective is to identify host-protective mechanisms that
counter pathogen-initiated lung inflammation and injury. Many pathogens secrete proteases to cause direct
damage to the lung, but bacteria, fungi and viruses can also co-opt host proteases to increase pathogenicity
and promote lung injury. We have studied Pseudomonas aeruginosa (PA) as a model of infection-induced
injury to probe how a pathogen-encoded protease called Pseudomonas elastase LasB, a metalloprotease
released into the extracellular milieu by the PA type II secretion system, induces lung tissue damage and
secondary trigger of host-derived serine proteases such as neutrophil elastase (NE). We previously identified
thrombospondin-1 (TSP-1), a matricellular protein secreted by a variety of cells following injury that disarms
both pathogen-encoded LasB and host protease NE, to limit lung injury and inflammation. Key questions that
have arisen from this work is how an unregulated proteolytic environment drives excessive inflammatory
response and dysregulated repair following injury, and what are the host factors that calibrate this response in
the lung. Our preliminary findings suggest that a feed-forward neutrophilic inflammatory response occurs in the
proteolytic environment of PA infection through N-terminal processing of IL-36γ that is exaggerated in the
absence of TSP-1. Moreover, platelet TSP-1 appears protective against PA-induced lung injury, but the precise
mechanism related to TSP-1's role at the alveolar-capillary interface remains unknown. Furthermore, we show
that PA elastase activity in clinical strains confer excessive inflammation and injury in mice and is associated
with worse clinical outcomes when compared with non-elastase producers. Based upon these findings, we
propose the following aims utilizing genetically deficient mice, cell-specific conditional knockout systems, and
PA clinical respiratory isolates obtained from the ICU to (1) elucidate the mechanisms by which TSP-1
counters the hyperinflammatory response mediated by proteolytic processing of the pro-inflammatory cytokine
IL-36γ; (2) examine the contribution of TSP-1 and platelet TSP-1 in protection against alveolar barrier
disruption and stabilization of the early provisional matrix following lung injury; (3) determine whether PA ICU
respiratory isolates with elastolytic properties drive unwarranted inflammation and persistent tissue injury in the
susceptible host. A better understanding of host biology during severe respiratory infection could prove useful
in the rational design of targeted therapeutics against pathogen-derived proteases and deregulated host
inflammation as adjuncts to current antimicrobial agents and supportive pulmonary and critical care
management.

## Key facts

- **NIH application ID:** 10478014
- **Project number:** 5R01HL136143-06
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Janet Sojung Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $568,095
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10478014

## Citation

> US National Institutes of Health, RePORTER application 10478014, Mechanisms of host protection against pathogen-associated proteases in acute lung injury (5R01HL136143-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10478014. Licensed CC0.

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