Approximately 750,000 Americans each year experience a life-threatening episode of severe sepsis. Twenty five to 30% die acutely. The survivors will experience diminished cognitive function. Moreover, many will die within the next five years due to immunocompetence and infection. This research program will address these late sequelae of sepsis. The model we propose links these two impairments. Systemic inflammation leads to both brain inflammation and an altered splenic microenvironment. We ask whether systemic cytokines are necessary to sustain brain inflammation and whether impairment in the function of the efferent vagus nerve sustains the immunosuppression. In support of this model, and of obvious clinical significance, we have shown that intervening with cytokine blockade after apparent resolution of the acute event improves both brain and immune function. Three coordinated research projects, support by an administrative core and 3 scientific cores will explore the initiation and nature of brain inflammation, the nature and cause of persisting monocyte dysfunction and the optimal therapy to prevent the long term morbidity that is triggered by severe sepsis.
Following an episode of severe sepsis, individuals may develop impaired cognition and inadequate immune function, which contributes to poor long-term outcome. This research program will explore these persistent impairments, the links between them and therapeutic strategies for their prevention or reversal. These late sequelae have not been well studies, nor targeted therapeutically Project 1: Nervous system alterations in sepsis-surviving mice Project Leader (PL): Bruce Volpe DESCRIPTION (as provided by applicant): Survivors of sepsis often experience persistent cognitive impairment. Our preliminary data show that this can be ameliorated by reducing systemic inflammation at a time when acute, life-threatening immune activation has resolved. In this project, we will explore the brain inflammation that is triggered by an episode of sepsis and whether TNF, IL-1 or HMGB1, or some combination of these is 1) the critical cytokine in the circulation that initiates brain inflammation or 2) a key cytokine within the brain that contribute to histologic and functional damage. Further, we will explore how systemic inflammation is communicated to the brain: whether by neural circuitry or by activation of brain microvascular endothelial cells. These studies will identify pathways connecting brain inflammation to systemic inflammation and will dissect those components of brain inflammation that lead to a persistent cognitive deficit.
Individuals surviving sepsis often experience persistent cognitive impairment. This study will explore how systemic inflammation causes brain dysfunction.
| Pavlov, Valentin A; Chavan, Sangeeta S; Tracey, Kevin J (2018) Molecular and Functional Neuroscience in Immunity. Annu Rev Immunol 36:783-812 |
| Li, Wei; Bao, Guoqiang; Chen, Weiqiang et al. (2018) Connexin 43 Hemichannel as a Novel Mediator of Sterile and Infectious Inflammatory Diseases. Sci Rep 8:166 |
| Gunasekaran, Manojkumar; Chatterjee, Prodyot K; Shih, Andrew et al. (2018) Immunization Elicits Antigen-Specific Antibody Sequestration in Dorsal Root Ganglia Sensory Neurons. Front Immunol 9:638 |
| Zanos, Theodoros P; Silverman, Harold A; Levy, Todd et al. (2018) Identification of cytokine-specific sensory neural signals by decoding murine vagus nerve activity. Proc Natl Acad Sci U S A 115:E4843-E4852 |
| Chavan, Sangeeta S; Ma, Pingchuan; Chiu, Isaac M (2018) Neuro-immune interactions in inflammation and host defense: Implications for transplantation. Am J Transplant 18:556-563 |
| Rana, Minakshi; Fei-Bloom, Yurong; Son, Myoungsun et al. (2018) Constitutive Vagus Nerve Activation Modulates Immune Suppression in Sepsis Survivors. Front Immunol 9:2032 |
| Kim, Sook Young; Son, Myoungsun; Lee, Sang Eun et al. (2018) High-Mobility Group Box 1-Induced Complement Activation Causes Sterile Inflammation. Front Immunol 9:705 |
| Zaghloul, Nahla; Addorisio, Meghan E; Silverman, Harold A et al. (2017) Forebrain Cholinergic Dysfunction and Systemic and Brain Inflammation in Murine Sepsis Survivors. Front Immunol 8:1673 |
| Hirano, Yohei; Yang, Weng-Lang; Aziz, Monowar et al. (2017) MFG-E8-derived peptide attenuates adhesion and migration of immune cells to endothelial cells. J Leukoc Biol 101:1201-1209 |
| Chavan, Sangeeta S; Pavlov, Valentin A; Tracey, Kevin J (2017) Mechanisms and Therapeutic Relevance of Neuro-immune Communication. Immunity 46:927-942 |
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