Toxicological impact of tobacco smoke exposure on blood brain barrier endothelium: Pathophysiological implications and cytoprotective mechanisms



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Despite the strong evidence for an association between tobacco smoke (TS) and vascular impairment, the impact of TS exposure on the blood brain barrier (BBB) endothelium has been only marginally addressed. Moreover, several reduced exposure cigarette products in the market claim to be safe without well substantiated toxicology studies. For this purpose, we tested the effect of whole soluble toxicants present in TS on BBB endothelium using cigarette smoke extracts (CSE) from conventional full flavor TS product in comparison with nicotine and reduced exposure products such as nicotine free (NF) and ultralow nicotine (ULN) cigarettes. Strikingly, reduced exposure products led to a similar (or even worse) outcome than 3R4F product. We demonstrated that TS toxicants from both type of products can severely impair BBB integrity via 1) disruption of tight junction (TJ) proteins such as ZO-1 and occludin, 2) increase in BBB permeability, 3) activation of pro-inflammatory response through enhanced translocation of NFκβ followed by release of IL-6, MMP-2 and up-regulation of adhesion molecules-VCAM-1, e-selectin and PECAM-1. Nrf2 based anti-oxidant response signaling triggered upregulation of several anti-oxidant and detoxifying enzymes (NQO-1, HMOX1, SLC7A11) in an effort to counteract TS-induced cellular oxidative stress. Further, we developed an in vivo model of smoke inhalation to study cerebrovascular impairments triggered by TS. In conclusion, this novel study demonstrated oxidative and inflammatory capacity of TS as a measure of its toxicity potential suggesting that LOWER NICOTINE does not imply LOWER TOXICITY.



Blood brain barrier, Toxicology, Cigarette smoke, Endothelium