# Platelet factors attenuate alveolar injury during severe pneumonia

> **NIH VA IK2** · VETERANS HEALTH ADMINISTRATION · 2021 · —

## Abstract

Lower respiratory tract infections are a leading cause of death worldwide and can be complicated by the acute
respiratory distress syndrome (ARDS), which is a major cause of morbidity and mortality in critically ill patients.
Veterans are at increased risk of mortality from pneumonia so identifying novel mechanisms of protection may
help improve veteran outcomes. Platelet deficiency, or thrombocytopenia, has consistently been associated with
increased mortality in patients with severe pneumonia and ARDS. However, the mechanisms by which platelets
may protect the host are poorly understood. We have recently shown a role for platelets in limiting alveolar-
capillary barrier disruption and lung injury during acute Pseudomonas aeruginosa (PA) pneumonia in mice. We
further showed that PA cell-free supernatant was sufficient to induce lung epithelial cell death with features of
apoptosis as well as severe lung injury. Finally, we showed that released platelet factors can limit apoptotic cell
death in lung epithelial cells in vitro as well as limit cell death and lung injury during acute PA infection in
thrombocytopenic mice. However, it remains unclear the mechanisms by which platelet factors contribute to lung
epithelial cyto-protection during PA infection. The main objective of this proposal is to investigate the
mechanisms and implications of infection-triggered lung epithelial cell death as well as the mechanisms by which
platelets and their factors provide lung epithelial cyto-protection during PA pneumonia and lung injury. Three
aims will be studied. Aim 1 will investigate whether PA supernatant induces lung epithelial mitochondrial damage
that leads to initiation of cell death pathways, whether the intrinsic pathway of apoptosis that classically follows
mitochondrial damage contributes to PA-triggered lung epithelial cell death in vivo, and whether inhibition of lung
cell death limits disruption of the alveolar-capillary barrier during PA infection in both wildtype and platelet
deficient mice. Aim 2 will investigate whether platelet factors modulate post-translational anti-apoptotic
pathways, examine the transcriptional profile of lung epithelial cells after PA-mediated injury in the presence or
absence of platelet releasate, and survey the role of candidate platelet proteins in providing lung epithelial cyto-
protection. Aim 3 will utilize development of a novel thrombocytopenic type 2 lung epithelial reporter mouse to
quantify the survival and proliferation of alveolar epithelial cells to determine whether platelets are required for
optimal lung epithelial repair after injury. We will also expand the generalizability of our findings by investigating
the role of platelets in protecting the lung during Staphylococcus aureus pneumonia, which is similar to PA in its
ability to mediate lung epithelial damage with secreted toxins. By improving understanding of the mechanisms
by which platelets may provide protection during severe pneumonia, this pro...

## Key facts

- **NIH application ID:** 10124988
- **Project number:** 5IK2BX004886-02
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** William G Bain
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10124988

## Citation

> US National Institutes of Health, RePORTER application 10124988, Platelet factors attenuate alveolar injury during severe pneumonia (5IK2BX004886-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10124988. Licensed CC0.

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