Traumatic Brain Injury and Blood–Brain Barrier (BBB): Underlying Pathophysiological Mechanisms and the Influence of Cigarette Smoking as a Premorbid Condition

Abstract

Traumatic brain injury (TBI) is among the most pressing global health issues and prevalent causes of cerebrovascular and neurological disorders all over the world. In addition to the brain injury, TBI may also alter the systemic immune response. Thus, TBI patients become vulnerable to infections, have worse neurological outcomes, and exhibit a higher rate of mortality and morbidity. It is well established that brain injury leads to impairments of the blood–brain barrier (BBB) integrity and function, contributing to the loss of neural tissue and affecting the response to neuroprotective drugs. Thus, stabilization/protection of the BBB after TBI could be a promising strategy to limit neuronal inflammation, secondary brain damage, and acute neurodegeneration. Herein, we present a review highlighting the significant post-traumatic effects of TBI on the cerebrovascular system. These include the loss of BBB integrity and selective permeability, impact on BBB transport mechanisms, post-traumatic cerebral edema formation, and significant pathophysiological factors that may further exacerbate post-traumatic BBB dysfunctions. Furthermore, we discuss the post-traumatic impacts of chronic smoking, which has been recently shown to act as a premorbid condition that impairs post-TBI recovery. Indeed, understanding the underlying molecular mechanisms associated with TBI damage is essential to better understand the pathogenesis and progression of post-traumatic secondary brain injury and the development of targeted treatments to improve outcomes and speed up the recovery process. Therapies aimed at restoring/protecting the BBB may reduce the post-traumatic burden of TBI by minimizing the impairment of brain homeostasis and help to restore an optimal microenvironment to support neuronal repair.

Cerebrovascular and Neurological Dysfunction under the Threat of COVID-19: Is There a Comorbid Role for Smoking and Vaping?

“…These diseases include, but are not limited to, lung cancer, chronic obstructive pulmonary disease (COPD), cardiovascular diseases, stroke, and decreased immune function [89]. Yearly, tobacco smoking (TS) kills around 6 million people in the world, and more than 0.48 million people in the USA alone [90]. Although the main addictive component of TS is nicotine, it also contains more than 4700 toxic compounds encompassing carcinogens, mutagens, stable and unstable free radicals as well as reactive oxygen species (ROS).…”

“…Although the main addictive component of TS is nicotine, it also contains more than 4700 toxic compounds encompassing carcinogens, mutagens, stable and unstable free radicals as well as reactive oxygen species (ROS). Different studies demonstrated the association between tobacco smoke and cerebrovascular-neurological dysfunction, including ischemic stroke, Alzheimer's diseases, multiple sclerosis, abnormal brain development, and vascular dementia [28,[90][91][92]. The mechanisms behind the toxic effects of smoking include, but are not limited to, inflammation, oxidative stress, atherosclerosis, disruption of the BBB, and hyperactive immune response [29,30].…”

“…Additionally, other scientific studies demonstrated the a7nAChR mediated alteration of the function of BBB Na + K + 2Clco-transporter by nicotine [104][105][106]. TS is also associated with the progression of atherosclerosis and angiogenesis [90]. Signal transducer and activator of transcription-3 (STAT-3) is an angiogenesis modulator that acts by IL-6/STAT-3 signaling mechanism and can be upregulated by TS [107].…”

“…Signal transducer and activator of transcription-3 (STAT-3) is an angiogenesis modulator that acts by IL-6/STAT-3 signaling mechanism and can be upregulated by TS [107]. TS may also upregulate Apo-lipoprotein E genes, which regulate the metabolism of lipoprotein and is related to increased cholesterol level [90]. This later can further elevate the risk of ischemic stroke and atherosclerosis.…”

Acute Traumatic Brain Injury-Induced Neuroinflammatory Response and Neurovascular Disorders in the Brain

“…Pericytes ensheath the capillary wall and are essential regulators of the stability and permeability of BBB (Bhowmick et al 2019). BBB breach is an early sign of cognitive disorder, and minimizing BBB dysfunction could reduce TBI severity (Nation et al 2019;Sivandzade et al 2020). BBB dysfunction has been reported as early as 3 min after concussion (Dinet et al 2019).…”