title: Tobacco smoke: a critical etiological factor for vascular impairment at the blood-brain barrier.
abstract: Active and passive tobacco smoke are associated with the dysfunction of endothelial physiology and vascular impairment. Studies correlating the effects of smoking and the brain microvasculature at the blood-brain barrier (BBB) level have been largely limited to few selective compounds that are present in the tobacco smoke (TS) yet the pathophysiology of smoking has not been unveiled. For this purpose, we characterized the physiological response of isolated human brain microvascular endothelial cells (HBMEC) and monocytes to the exposure of whole soluble TS extract. With the use of a well established humanized flow-based in vitro blood-brain barrier model (DIV-BBB) we have also investigated the BBB physiological response to TS under both normal and impaired hemodynamic conditions simulating ischemia. Our results showed that TS selectively decreased endothelial viability only at very high concentrations while not significantly affecting that of astrocytes and monocytes. At lower concentrations, despite the absence of cytotoxicity, TS induced a strong vascular pro-inflammatory response. This included the upregulation of endothelial pro-inflammatory genes, a significant increase of the levels of pro-inflammatory cytokines, activated matrix metalloproteinase, and the differentiation of monocytes into macrophages. When flow-cessation/reperfusion was paired with TS exposure, the inflammatory response and the loss of BBB viability were significantly increased in comparison to sham-smoke condition. In conclusion, TS is a strong vascular inflammatory primer that can facilitate the loss of BBB function and viability in pathological settings involving a local transient loss of cerebral blood flow such as during ischemic insults.
authors.affiliation: Cerebrovascular Research, Cleveland Clinic Lerner College of Medicine, Cleveland, OH 44195, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hossain
authors.forename: T
authors.initials: T
authors.lastname: Sathe
authors.forename: V
authors.initials: V
authors.lastname: Fazio
authors.forename: P
authors.initials: P
authors.lastname: Mazzone
authors.forename: Babette
authors.initials: B
authors.lastname: Weksler
authors.forename: D
authors.initials: D
authors.lastname: Janigro
authors.forename: E
authors.initials: E
authors.lastname: Rapp
authors.forename: L
authors.initials: L
authors.lastname: Cucullo
mesh_terms: D001812:Blood-Brain Barrier / Q000473:pathology / Q000502:physiology / Q000503:physiopathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000473:pathology / Q000502:physiology / Q000503:physiopathology*; D006801:Humans; D055806:Microvessels / Q000473:pathology / Q000502:physiology / Q000503:physiopathology*; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D014652:Vascular Diseases / Q000209:etiology* / Q000503:physiopathology*
chemical_list: D014028:Tobacco Smoke Pollution