Cerebral edema (CE) and resultant intracranial hypertension are associated with unfavorable prognosis in traumatic brain injury (TBI). CE is a leading cause of in-hospital mortality, occurring in ...>60% of patients with mass lesions, and ∼15% of those with normal initial computed tomography scans. After treatment of mass lesions in severe TBI, an important focus of acute neurocritical care is evaluating and managing the secondary injury process of CE and resultant intracranial hypertension. This review focuses on a contemporary understanding of various pathophysiologic pathways contributing to CE, with a subsequent description of potential targeted therapies. There is a discussion of identified cellular/cytotoxic contributors to CE, as well as mechanisms that influence blood-brain-barrier (BBB) disruption/vasogenic edema, with the caveat that this distinction may be somewhat artificial since molecular processes contributing to these pathways are interrelated. While an exhaustive discussion of all pathways with putative contributions to CE is beyond the scope of this review, the roles of some key contributors are highlighted, and references are provided for further details. Potential future molecular targets for treating CE are presented based on pathophysiologic mechanisms. We thus aim to provide a translational synopsis of present and future strategies targeting CE after TBI in the context of a paradigm shift towards precision medicine.
This article is part of the Special Issue entitled “Novel Treatments for Traumatic Brain Injury”.
•Brain swelling is a major contributor to adverse outcome in TBI.•It is due to combined mass effects of extravasated blood, cytotoxic & vasogenic edema and osmolyte-driven swelling.•Our understanding of molecular mechanisms of edema formation is in its infancy.•Here, we review 12 pathways implicated in edema formation and 11 drugs with potential benefit for targeting edema in TBI.
Molecular pathophysiology of cerebral edema Stokum, Jesse A; Gerzanich, Volodymyr; Simard, J Marc
Journal of Cerebral Blood Flow & Metabolism,
03/2016, Letnik:
36, Številka:
3
Book Review, Journal Article
Recenzirano
Odprti dostop
Advancements in molecular biology have led to a greater understanding of the individual proteins responsible for generating cerebral edema. In large part, the study of cerebral edema is the study of ...maladaptive ion transport. Following acute CNS injury, cells of the neurovascular unit, particularly brain endothelial cells and astrocytes, undergo a program of pre- and post-transcriptional changes in the activity of ion channels and transporters. These changes can result in maladaptive ion transport and the generation of abnormal osmotic forces that, ultimately, manifest as cerebral edema. This review discusses past models and current knowledge regarding the molecular and cellular pathophysiology of cerebral edema.
Hemorrhagic transformation is a major complication of ischemic stroke, is linked to matrix metalloproteinase-9 (MMP-9), and is exacerbated by tissue plasminogen activator (tPA). Cerebral ...ischemia/reperfusion is characterized by SUR1-TRPM4 (sulfonylurea receptor 1-transient receptor potential melastatin 4) channel upregulation in microvascular endothelium. In humans and rodents with cerebral ischemia/reperfusion (I/R), the SUR1 antagonist, glibenclamide, reduces hemorrhagic transformation and plasma MMP-9, but the mechanism is unknown. We hypothesized that tPA induces protease activated receptor 1 (PAR1)-mediated, Ca2+-dependent phasic secretion of MMP-9 from activated brain endothelium, and that SUR1-TRPM4 is required for this process.
Cerebral I/R, of 2 and 4 hours duration, respectively, was obtained using conventional middle cerebral artery occlusion. Immunolabeling was used to quantify p65 nuclear translocation. Murine and human brain endothelial cells (BEC) were studied in vitro, without and with NF-κB activation, using immunoblot, zymography and ELISA, patch clamp electrophysiology, and calcium imaging. Genetic and pharmacological manipulations were used to identify signaling pathways.
Cerebral I/R caused prominent nuclear translocation of p65 in microvascular endothelium. NF-κB-activation of BEC caused de novo expression of SUR1-TRPM4 channels. In NF-κB-activated BEC: (i) tPA caused opening of SUR1-TRPM4 channels in a plasmin-, PAR1-, TRPC3- and Ca2+-dependent manner; (ii) tPA caused PAR1-dependent secretion of MMP-9; (iii) tonic secretion of MMP-9 by activated BEC was not influenced by SUR1 inhibition; (iv) phasic secretion of MMP-9 induced by tPA or the PAR1-agonist, TFLLR, required functional SUR1-TRPM4 channels, with inhibition of SUR1 decreasing tPA-induced MMP-9 secretion.
tPA induces PAR1-mediated, SUR1-TRPM4-dependent, phasic secretion of MMP-9 from activated brain endothelium.
The sulfonylurea receptor 1 (Sur1)-regulated NCCa-ATP channel is a nonselective cation channel that is regulated by intracellular calcium and adenosine triphosphate. The channel is not constitutively ...expressed, but is transcriptionally upregulated de novo in all cells of the neurovascular unit, in many forms of central nervous system (CNS) injury, including cerebral ischemia, traumatic brain injury (TBI), spinal cord injury (SCI), and subarachnoid hemorrhage (SAH). The channel is linked to microvascular dysfunction that manifests as edema formation and delayed secondary hemorrhage. Also implicated in oncotic cell swelling and oncotic (necrotic) cell death, the channel is a major molecular mechanism of ‘accidental necrotic cell death’ in the CNS. In animal models of SCI, pharmacological inhibition of Sur1 by glibenclamide, as well as gene suppression of Abcc8, prevents delayed capillary fragmentation and tissue necrosis. In models of stroke and TBI, glibenclamide ameliorates edema, secondary hemorrhage, and tissue damage. In a model of SAH, glibenclamide attenuates the inflammatory response due to extravasated blood. Clinical trials of an intravenous formulation of glibenclamide in TBI and stroke underscore the importance of recent advances in understanding the role of the Sur1-regulated NCCa-ATP channel in acute ischemic, traumatic, and inflammatory injury to the CNS.
The ongoing SARS-CoV-2 pandemic has shocked the world due to its persistence, COVID-19-related morbidity and mortality, and the high mutability of the virus. One of the major concerns is the ...emergence of new viral variants that may increase viral transmission and disease severity. In addition to mutations of spike protein, mutations of viral proteins that affect virulence, such as ORF3a, also must be considered. The purpose of this article is to review the current literature on ORF3a, to summarize the molecular actions of SARS-CoV-2 ORF3a, and its role in viral pathogenesis and COVID-19. ORF3a is a polymorphic, multifunctional viral protein that is specific to SARS-CoV/SARS-CoV-2. It was acquired from β-CoV lineage and likely originated from bats through viral evolution. SARS-CoV-2 ORF3a is a viroporin that interferes with ion channel activities in host plasma and endomembranes. It is likely a virion-associated protein that exerts its effect on the viral life cycle during viral entry through endocytosis, endomembrane-associated viral transcription and replication, and viral release through exocytosis. ORF3a induces cellular innate and pro-inflammatory immune responses that can trigger a cytokine storm, especially under hypoxic conditions, by activating NLRP3 inflammasomes, HMGB1, and HIF-1α to promote the production of pro-inflammatory cytokines and chemokines. ORF3a induces cell death through apoptosis, necrosis, and pyroptosis, which leads to tissue damage that affects the severity of COVID-19. ORF3a continues to evolve along with spike and other viral proteins to adapt in the human cellular environment. How the emerging ORF3a mutations alter the function of SARS-CoV-2 ORF3a and its role in viral pathogenesis and COVID-19 is largely unknown. This review provides an in-depth analysis of ORF3a protein's structure, origin, evolution, and mutant variants, and how these characteristics affect its functional role in viral pathogenesis and COVID-19.
The magnitude of damage to cerebral tissues following head trauma is determined by the primary injury, caused by the kinetic energy delivered at the time of impact, plus numerous secondary injury ...responses that almost inevitably worsen the primary injury. When head trauma results in a cerebral contusion, the hemorrhagic lesion often progresses during the first several hours after impact, either expanding or developing new, non-contiguous hemorrhagic lesions, a phenomenon termed hemorrhagic progression of a contusion (HPC). Because a hemorrhagic contusion marks tissues with essentially total unrecoverable loss of function, and because blood is one of the most toxic substances to which the brain can be exposed, HPC is one of the most severe types of secondary injury encountered following traumatic brain injury (TBI). Historically, HPC has been attributed to continued bleeding of microvessels fractured at the time of primary injury. This concept has given rise to the notion that continued bleeding might be due to overt or latent coagulopathy, prompting attempts to normalize coagulation with agents such as recombinant factor VIIa. Recently, a novel mechanism was postulated to account for HPC that involves delayed, progressive microvascular failure initiated by the impact. Here we review the topic of HPC, we examine data relevant to the concept of a coagulopathy, and we detail emerging data elucidating the mechanism of progressive microvascular failure that predisposes to HPC after head trauma.
Summary Focal cerebral ischaemia and post-ischaemic reperfusion cause cerebral capillary dysfunction, resulting in oedema formation and haemorrhagic conversion. There are substantial gaps in ...understanding the pathophysiology, especially regarding early molecular participants. Here, we review physiological and molecular mechanisms involved. We reaffirm the central role of Starling's principle, which states that oedema formation is determined by the driving force and the capillary “permeability pore”. We emphasise that the movement of fluids is largely driven without new expenditure of energy by the ischaemic brain. We organise the progressive changes in osmotic and hydrostatic conductivity of abnormal capillaries into three phases: formation of ionic oedema, formation of vasogenic oedema, and catastrophic failure with haemorrhagic conversion. We suggest a new theory suggesting that ischaemia-induced capillary dysfunction can be attributed to de novo synthesis of a specific ensemble of proteins that determine osmotic and hydraulic conductivity in Starling's equation, and whose expression is driven by a distinct transcriptional program.
Brain swelling is one of the most robust predictors of outcome following brain injury, including ischemic, traumatic, hemorrhagic, metabolic or other injury. Depending on the specific type of insult, ...brain swelling can arise from the combined space-occupying effects of extravasated blood, extracellular edema fluid, cellular swelling, vascular engorgement and hydrocephalus. Of these, arguably the least well appreciated is cellular swelling. Here, we explore current knowledge regarding swelling of astrocytes, the most abundant cell type in the brain, and the one most likely to contribute to pathological brain swelling. We review the major molecular mechanisms identified to date that contribute to or mitigate astrocyte swelling via ion transport, and we touch upon the implications of astrocyte swelling in health and disease.
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