# The Role of Sex Dimorphism in Post-TBI Bacterial Pneumonia

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2022 · $334,125

## Abstract

Project Summary/Abstract
Traumatic brain injury (TBI) is the leading cause of injury-related death in patients under the age of 46 years.
Survivors of the initial brain injury face numerous extracranial complications that are a major determinant of
long-term outcome and impede their most productive years of life. Post-TBI pulmonary infection rate is as high
as 50-60% and results in an infection-related mortality rate of ~30%. Additionally, after severe TBI, the
parasympathetic nervous system is activated to attenuate the systemic inflammatory response and may
prevent some post-TBI, non-brain end-organ injury. However, parasympathetic nervous system activation may
be maladaptive and result in dysregulation of alveolar macrophage and neutrophil immune function within the
lung. Our preliminary data reveal increased mortality after post-TBI pneumonia that is α7 nicotinic acetylcholine
receptor (α7nAChR)-dependent. α7nAChR activation inhibits Pseudomonas aeruginosa-induced release of
tumor necrosis factor-alpha (TNF-α) and nuclear factor-κβ (NF- κβ) activation in alveolar macrophages.
Additionally, α7nAChR activation inhibits phagocytosis of P. aeruginosa by alveolar macrophages.
Interestingly, female patients have a lower incidence of post-TBI lung infection compared to males with
equivalent TBI severity. Female mice have lower mortality and decreased lung bacterial burden after post-TBI
pneumonia compared to males. Oophorectomized females have a post-TBI P. aeruginosa-induced pneumonia
mortality rate similar to males and males that receive estrogen after TBI and just before onset of bacterial
pneumonia have improved survival. Finally, estrogen inhibits the effects of α7nAChR activation and restores
appropriate TNF-α release, NF- κβ activation and phagocytic function. Thus, the question of how estrogen
alleviates the α7nAChR-dependent maladaptive response and improves survival from secondary pneumonia in
TBI patients is of great clinical importance. Based on our preliminary data, we use a reverse translational
approach to hypothesize that parasympathetic-induced, α7nAChR-mediated dysregulation of alveolar
macrophage and neutrophil immune function leads to decreased lung bacterial clearance and survival
in post-TBI P. aeruginosa-induced lung infection and is alleviated by estrogen. To test this hypothesis,
we propose three specific aims: (Aim 1) α7nAChR activation leads to a dysregulated, maladaptive innate
immune response leading to decreased lung bacterial clearance and survival after post-TBI P. aeruginosa
infection; (Aim 2) Sex differences in parasympathetic-induced α7nAChR maladaptive signaling leading to lung
innate immune dysfunction are alleviated by estrogen; (Aim 3) Examine the sex differences in response to
α7nAChR activation of innate immune cells after TBI in humans. These findings will elucidate maladaptive
α7nAChR signaling and its molecular mechanisms leading to decreased lung innate immune function in post-
TBI bacterial pneumonia and...

## Key facts

- **NIH application ID:** 10468948
- **Project number:** 5R01GM127584-05
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Brant M Wagener
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $334,125
- **Award type:** 5
- **Project period:** 2018-09-21 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468948

## Citation

> US National Institutes of Health, RePORTER application 10468948, The Role of Sex Dimorphism in Post-TBI Bacterial Pneumonia (5R01GM127584-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10468948. Licensed CC0.

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