Estrogen Alleviates Sex-Dependent Differences in Lung Bacterial Clearance and Mortality Secondary to Bacterial Pneumonia after Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is the leading cause of injury-related death and disability in patients under the age of 46 years. Survivors of the initial injury often endure systemic complications such as pulmonary infection, and Pseudomonas aeruginosa is one of the most common causes of nosocomial pneumonia in intensive care units. Female patients are less likely to develop secondary pneumonia after TBI, and pre-clinical studies have revealed a salutary role for estrogen after trauma. Therefore, we hypothesized that female mice would experience less mortality after post-TBI pneumonia with P. aeruginosa. We employed a mouse model of TBI followed by P. aeruginosa pneumonia. Male mice had greater mortality and impaired lung bacterial clearance after post-TBI pneumonia compared with female mice. This was confirmed as a difference in sex hormones, as oophorectomized wild-type mice had mortality and lung bacterial clearance similar to male mice. There were differences in tumor necrosis factor-α secretion in male and female alveolar macrophages after P. aeruginosa infection. Finally, injection of male or oophorectomized wild-type female mice with estrogen restored lung bacterial clearance and prevented mortality. Our model of TBI followed by P. aeruginosa pneumonia is among the first to reveal sex dimorphism in secondary, long-term TBI complications.