Date of Award

Spring 5-20-2023

Embargo Period

4-25-2023

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD) in Health & Rehabilitation Science

College

College of Health Professions

First Advisor

Stephen Tomlinson

Second Advisor

Annie Simpson

Third Advisor

Silvia Guglietta

Fourth Advisor

Onder Albayram

Fifth Advisor

Azizul Haque

Abstract

Brain and neural injury are a non-specific disease category that includes traumatic brain injury (TBI) and stroke. Both TBI and stroke are common, costly, and leading causes of severe disability in adults. Both stroke and TBI are responsible for substantial disability in working age adults, with stroke being the second leading cause of death worldwide [1] and TBI a major cause of disability in people younger than their 40's [2]. The immune response after brain injury is multifactorial and involves both local and systemic events at the cellular and molecular level. The complement system is a component of both the innate and adaptive immune response and can be activated via one of three pathways: the classical, lectin, or alternative pathway. Studies by our lab and by others have established a prominent role for complement in propagating secondary injury after ischemic or traumatic insult to the brain [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13]. The complement system is recognized as an early and significant contributor to secondary insult after TBI by promoting neuronal loss, edema, and inflammatory cell infiltrate [14]. Clinical studies have shown that TBI patients have elevated levels of complement activation products (C3 and sC5b-9) in their cerebrospinal fluid and increased deposition of complement activation products in the perilesional brain [7], [15], [16], [17], [18]. The source of complement deposited after a TBI is a combined contribution of systemic complement, leaking to the brain after trauma-induced blood brain barrier dysfunction, and locally produced complement proteins by the brain parenchyma and infiltrating cells [7], [16], [17], [19]. A similar pattern of complement deposition is seen in experimental models of TBI that also implicate complement in the acute neuronal cell death, neutrophil extravasation, and worsening of outcomes after TBI [9], [10], [11], [12], [13], [20], [21], [22], [23], [24], [25]. 4 Complement is also a major mediator of acute pathology after stroke, and previous work from our lab and others have shown that complement serves as the recognition arm of the immune system to detect and respond to cellular stress in the penumbra leading to a robust neuroinflammatory response [26]. In addition, preclinical and clinical studies have shown significant complement activation in the ischemic penumbra, and elevated serum complement is associated with stroke outcomes [26]. We have also shown that complement increases acute neuronal loss, increases distal thrombosis, and promotes a chronic neuroinflammatory response after stroke leading to worsening of acute and chronic outcomes [14], [26]. A challenge in designing medical treatments for TBI and stroke is the location and multifactorial nature of the pathologies, which are complex and involve dysfunction of multiple homeostatic processes. Studies in animal models have greatly enhanced our understanding of the complex pathophysiology that underlies stroke and TBI and has enabled screening of over 1,000 novel therapeutic agents. A major concern in translational stroke research is that therapeutics that are deemed efficacious at the rodent level fail to show efficacy when moved to clinical trials. Reasons for failure of prior therapies include lack of assessment of chronic outcomes, lack of gender consideration, exclusion of age and other co-morbidities, administering therapeutics at time points not clinically relevant, failure to assess risk profile of novel therapies, and lack of significant motor and cognitive behavioral assessment. While it has long been recognized that neuroinflammation is injurious and represents a therapeutic reparative target, only more recently has it been recognized that neuroinflammation can also contribute to homeostatic and reparative mechanisms after brain injury. Consequently, an emerging paradigm is that systemic and complete 5 inhibition of neuroinflammation after brain injury is unlikely to be an optimal approach, and that localized and targeted inhibitory strategies, possibly of limited duration, will provide a better therapeutic approach. The goal of treatment has transitioned from symptomatic management to approaches for neuroprotection and regeneration [27]. The complement system is being discussed as a therapeutic target for TBI as well as stroke, due to data supporting a pivotal role for complement in supporting several downstream activities that promote neuroinflammation and degeneration [27]. An extensive understanding of the acute, subacute, and chronic consequences of complement activation is needed in both stroke and TBI and may lead to new therapeutic strategies, including the ability of targeting selective steps in the complement cascade.

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Copyright is held by the author. All rights reserved.

Supplemental Materials
HRS Dissertation Defense Approval Form(1).docx (190 kB)
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