# Liver-derived protection during pneumonia and sepsis

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $317,625

## Abstract

Abstract
Pneumonia and sepsis are integrally linked, each representing a major public health concern, and each
significantly increasing the likelihood that the other will occur. However, the host mechanisms guiding this
dangerous interaction remain speculative. The acute phase response is a common feature of both pneumonia
and sepsis, involving robust remodeling of the hepatic transcriptome followed by mobilization of numerous
liver-derived acute phase proteins, several of which are known clinical biomarkers of disease severity. The net
physiological significance of these integrated acute phase changes is only beginning to be understood. We
recently showed that pneumonia elicits a robust acute phase response that is functionally relevant and highly
dependent on hepatocyte expression of the transcription factors NF-κB RelA and STAT3. Using hepatocyte-
targeted mouse models, our preliminary studies implicate the liver as a gatekeeper that compartmentalizes
infection during sepsis or pneumonia, reducing the likelihood that one will promote the other. Specifically, we
now have evidence that: 1) STAT3-dependent liver responses to endotoxemia protect against pneumonia
susceptibility, associated with expression of iron-regulating acute phase proteins; and 2) RelA-dependent liver
responses during pneumonia protect against sepsis outcomes, including liver failure and bacteremia. Here we
propose the central hypothesis that hepatocyte transcriptional responses are critical for limiting the deleterious
interactions between pneumonia and sepsis. This hypothesis will be tested by pursuing the following three
aims: Aim 1) Test the hypothesis that hepatocyte STAT3 activation counters sepsis-induced pneumonia
susceptibility by promoting iron withdrawal and lung mucosal defense; Aim 2) Test the hypothesis that
hepatocyte RelA activation counters pneumonia-induced sepsis by preventing programmed cell death, organ
failure, and bacteremia; and Aim 3) Test the hypothesis that STAT3 and RelA are each essential for human
hepatocytes to elicit acute phase gene programs that direct alveolar macrophage responses. Studies designed
to address these aims will use a multidisciplinary approach to comprehensively determine the mechanistic
basis of liver-derived protection at the interface of pneumonia and sepsis. These investigations will be the first
to directly interrogate liver function in this capacity, possibly revealing important determinants of clinical
outcome in patients with pneumonia or sepsis.

## Key facts

- **NIH application ID:** 9851910
- **Project number:** 5R01GM120060-04
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Lee Quinton
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $317,625
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851910

## Citation

> US National Institutes of Health, RePORTER application 9851910, Liver-derived protection during pneumonia and sepsis (5R01GM120060-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9851910. Licensed CC0.

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