title: Oxidative and pro-inflammatory impact of regular and denicotinized cigarettes on blood brain barrier endothelial cells: is smoking reduced or nicotine-free products really safe?
abstract: BACKGROUND
  Both active and passive tobacco smoke (TS) potentially impair the vascular endothelial function in a causative and dose-dependent manner, largely related to the content of reactive oxygen species (ROS), nicotine, and pro-inflammatory activity. Together these factors can compromise the restrictive properties of the blood-brain barrier (BBB) and trigger the pathogenesis/progression of several neurological disorders including silent cerebral infarction, stroke, multiple sclerosis and Alzheimer's disease. Based on these premises, we analyzed and assessed the toxic impact of smoke extract from a range of tobacco products (with varying levels of nicotine) on brain microvascular endothelial cell line (hCMEC/D3), a well characterized human BBB model.
  
  
  RESULTS
  Initial profiling of TS showed a significant release of reactive oxygen (ROS) and reactive nitrogen species (RNS) in full flavor, nicotine-free (NF, "reduced-exposure" brand) and ultralow nicotine products. This release correlated with increased oxidative cell damage. In parallel, membrane expression of endothelial tight junction proteins ZO-1 and occludin were significantly down-regulated suggesting the impairment of barrier function. Expression of VE-cadherin and claudin-5 were also increased by the ultralow or nicotine free tobacco smoke extract. TS extract from these cigarettes also induced an inflammatory response in BBB ECs as demonstrated by increased IL-6 and MMP-2 levels and up-regulation of vascular adhesion molecules, such as VCAM-1 and PECAM-1.
  
  
  CONCLUSIONS
  In summary, our results indicate that NF and ultralow nicotine cigarettes are potentially more harmful to the BBB endothelium than regular tobacco products. In addition, this study demonstrates that the TS-induced toxicity at BBB ECs is strongly correlated to the TAR and NO levels in the cigarettes rather than the nicotine content.
authors.forename: Pooja
authors.initials: P
authors.lastname: Naik
authors.forename: Neel
authors.initials: N
authors.lastname: Fofaria
authors.forename: Shikha
authors.initials: S
authors.lastname: Prasad
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Sajja
authors.forename: Babette
authors.initials: B
authors.lastname: Weksler
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Couraud
authors.forename: Ignacio A
authors.initials: IA
authors.lastname: Romero
authors.affiliation: Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, School of Pharmacy, 1300 S, Coulter Street, Amarillo TX 79106, USA. luca.cucullo@ttuhsc.edu.
authors.forename: Luca
authors.initials: L
authors.lastname: Cucullo
mesh_terms: D001812:Blood-Brain Barrier / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D009538:Nicotine / Q000008:administration & dosage*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016540:Smoking Cessation; D062789:Tobacco Products / Q000032:analysis*
chemical_list: D018836:Inflammation Mediators; D017382:Reactive Oxygen Species; D009538:Nicotine
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