The Role of Sex Dimorphism in Post-TBI Bacterial Pneumonia

性别二态性在 TBI 后细菌性肺炎中的作用

• 批准号: 10468948
• 负责人: Brant M Wagener
• 金额: $ 33.41万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-21 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468948
• 关键词: Age; Alveolar Macrophages; Attenuated; Bacterial Infections; Bacterial Pneumonia; Blood; Brain Injuries; Bronchoalveolar Lavage Fluid; Cell physiology; Cells; Chemotaxis; Clinical; Clinical Research; Data; Estrogen Receptors; Estrogen Therapy; Estrogens; Face; Female; Human; Immune; Immune System Diseases; Incidence; Infection; Innate Immune Response; Lead; Life; Lung; Lung infections; Mechanical ventilation; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Natural Immunity; Neutrophil Infiltration; Nuclear; Organ; Outcome; Parasympathetic Nervous System; Patients; Phagocytes; Phagocytosis; Pharmacologic Substance; Physiological; Play; Pneumonia; Postmenopause; Premenopause; Pseudomonas; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Pseudomonas aeruginosa pneumonia; Role; STAT3 gene; Severities; Sex Differences; Signal Transduction; Survivors; TNF gene; Testing; Traumatic Brain Injury; alpha-bungarotoxin receptor; base; immune function; improved; infection rate; injury-related death; innate immune function; macrophage; male; mortality; neutrophil; novel therapeutic intervention; organ injury; prevent; response; response to brain injury; sexual dimorphism; systemic inflammatory response; translational approach

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 may provide a novel therapeutic strategy to reverse these effects and improve post-TBI patient mortality and long-term outcomes during their most productive years of life.

项目摘要/摘要 创伤性脑损伤（TBI）是46岁以下患者损伤死亡的主要原因。 最初脑损伤的幸存者面临许多颅外并发症，这是主要的决定者 长期结局并阻碍他们最有生产力的生活。 TBI肺部感染率高 为50-60％，导致感染相关的死亡率约为30％。此外，在严重的TBI之后， 副交感神经系统被激活以减轻全身性炎症反应，可能 防止一些TBI后的非脑部最终器官损伤。但是，副交感神经系统激活可能 适应不良，导致肺泡巨噬细胞和中性粒细胞免疫功能失调 肺。我们的初步数据显示，TBI后肺炎（α7烟碱乙酰胆碱）死亡率增加 受体（α7NACHR）依赖性。 α7NACHR激活抑制铜绿假单胞菌诱导的释放 肺泡巨噬细胞中的肿瘤坏死因子-Alpha（TNF-α）和核因子-κβ（NF-κβ）活化。 另外，α7NACHR激活抑制肺泡巨噬细胞对铜绿假单胞菌的吞噬作用。 有趣的是，与男性相比 等效的TBI严重程度。 TBI后，雌性小鼠死亡率较低，肺细菌燃烧改善 肺炎与雄性相比。卵形切除症的雌性有TBI P.铜绿假单胞菌诱导的肺炎 死亡率类似于TBI之后和细菌发作之前接受雌激素的男性和男性的死亡率 肺炎改善了生存率。最后，雌激素抑制α7NACHR激活的作用并恢复 适当的TNF-α释放，NF-κβ激活和吞噬功能。那是雌激素如何的问题 减轻α7nAChR依赖性适应反应，并改善次级肺炎的生存率 TBI患者的临床重要性非常重要。根据我们的初步数据，我们使用反向翻译 假设副交感神经诱导的α7NACHR介导的肺泡失调的方法 巨噬细胞和中性粒细胞免疫功能可改善肺部细菌清除和存活率 在TBI P.铜绿诱导的肺部感染中，雌激素可以缓解。为了检验这一假设， 我们提出了三个特定目标：（目标1）α7nACHR激活导致失调，适应不良的先天性 免疫反应，导致肺炎后铜绿后肺细菌清除和存活率降低 感染; （AIM 2）副交感神经诱导的α7NACHR不良适应性信号传导的性别差异导致肺 雌激素可以减轻先天免疫功能障碍； （目标3）检查性别差异 人类TBI后先天免疫球的α7NACHR激活。这些发现将阐明适应不良的 α7NACHR信号传导及其分子机制导致肺先天免疫功能降低。 TBI细菌性肺炎，可能提供一种新型的热策略来扭转这些作用并改善 TBI后患者的死亡率和长期成果在其生命中最有生产力。

项目成果

Inflammation as a Source of Cardiac Injury After Subarachnoid Hemorrhage.

炎症是蛛网膜下腔出血后心脏损伤的一个原因。

• DOI: 10.1007/s12028-023-01893-0
• 发表时间: 2023
• 期刊: Neurocritical care
• 影响因子: 3.5
• 作者: Zhang,XiaoluLinda;Schaedel,JessicaF;Ahmad,Aftab;Wagener,BrantM
• 通讯作者: Wagener,BrantM

Autonomic nervous system activity and the risk of nosocomial infection in critically ill patients with brain injury.

• DOI: 10.1186/s40635-020-00359-3
• 发表时间: 2020-11-25
• 期刊: Intensive care medicine experimental
• 影响因子: 3.5
• 作者: Wirtz MR;Moekotte J;Balvers K;Admiraal MM;Pittet JF;Colombo J;Wagener BM;Goslings JC;Juffermans N
• 通讯作者: Juffermans N