# Endothelial thrombospondin-1 in matrix proteolysis during Pseudomonal lung injury

> **NIH NIH F32** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $16,323

## Abstract

Project Summary/Abstract:
Acute Respiratory Distress Syndrome (ARDS) is a syndrome characterized by rapidly progressive respiratory
failure and refractory hypoxemia and is a major cause of morbidity and mortality in critically ill patients worldwide.
The most common risk factor for ARDS is severe bacterial pneumonia and patients with ARDS are also
frequently plagued by nosocomial infections including lower respiratory tract infections (LRTIs). Pseudomonas
aeruginosa (PA) is a common ICU pathogen and PA pneumonia is associated with increased mortality in
ventilator associated pneumonia compared to other gram-negative pathogens. PA has been shown to cause
extensive proteolytic injury leading to tissue damage and degradation of the alveolar-capillary barrier in animal
models, in part through secreted exoproteases such as LasB. The metalloprotease LasB has also been shown
to degrade junctional proteins important in barrier integrity. While pathogen derived virulence factors have been
extensively characterized, there is limited knowledge regarding the host mechanisms that protect against
proteolytic injury and vascular permeability in the lungs. Thrombospondin-1 (TSP-1) is a matrix glycoprotein with
a variety of functions including regulation of inflammation. TSP-1 has been previously shown to inhibit host-
derived serine proteases and the pathogen-derived exoprotease, LasB. TSP-1 is expressed by lung endothelial
cells but its role in pathogen-induced injury is unknown. The main objective of this proposal is to determine the
role of endothelial TSP-1 in protection against matrix proteolysis and barrier dysfunction following PA induced
lung injury. Aim 1 will determine if TSP-1 is protective against the disruption of intercellular junctional complexes
and barrier function in vitro. Aim 2 will determine if endothelial TSP-1 promotes vascular integrity in vivo. By
improving our understanding of host protective mechanisms during pathogen triggered lung injury, this project
may provide rationale for potential therapeutic targets in patients with ARDS. The proposed training plan will
promote development of advanced laboratory skills including cell and tissue imaging, mouse genetics and in vivo
models of infection-induced lung injury. Moreover, this project with provide the applicant with the opportunity to
develop expertise as a physician-scientist under the close mentoring and involvement of dedicated sponsors in
a robust research environment at the University of Pittsburgh.

## Key facts

- **NIH application ID:** 10461702
- **Project number:** 5F32HL152504-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Jill Ann Zupetic
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $16,323
- **Award type:** 5
- **Project period:** 2020-07-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10461702

## Citation

> US National Institutes of Health, RePORTER application 10461702, Endothelial thrombospondin-1 in matrix proteolysis during Pseudomonal lung injury (5F32HL152504-02). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10461702. Licensed CC0.

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