Tobacco smoke (TS) is considered a major public health challenge, responsible for more than 400,000 deaths each year in the United States alone. To reduce the risk of health damage caused by TS the tobacco industry is marketing and advertising a line of 'reduced-exposure' tobacco products (such as 'Advance' manufactured by Brown & Williamson Tobacco Corporation, 'Omni' and Quest 3 manufactured by Vector Group Ltd), which claim to have fewer toxins than the leading 'light' cigarette brands or reduce the nicotine dependence in smokers. However, the scientific evidence provided is insufficient to evaluate whether these products actually reduce the users' risk for tobacco-related diseases including those associated to impaired brain vascular endothelial function and loss of BBB integrity. Today, despite the strong evidence for an association between tobacco smoke and vascular impairment studies on the effects of smoking on the blood-brain barrier (BBB) have been limited to a few selective compounds. To address these critical issues, we will use a novel humanized dynamic in vitro BBB model (DIV-BBB), which relies on the use of hollow fibers to create capillary-like structures to support the adhesion of human BBB endothelial cells and astrocytes while simultaneously allowing for the circulation and extravasation upon activation of immune cells. This novel tool will provide a fully controllable environment to dissect the effect of tobacco smoke exposure on the BBB and to investigate the pro- inflammatory potential of regular and 'reduced exposure' tobacco brands. Given these premises we propose to: 1.Evaluate the effect of tobacco smoke from reduced-exposure, nicotine- free, and regular tobacco products on BBB function and the specific role of inflammation. Deterioration of BBB function following chronic exposure to the different soluble TS extracts will be evaluated in the dynamic in vitro BBB model. We will also investigate the role of peripheral blood mononuclear cells and platelet in the pathogenesis of BBB damage and assess whether the immune cells isolated from healthy chronic smokers are in a activated state and therefore, capable to provide a quicker and stronger inflammatory response when re-exposed to TS or other pro-inflammatory stimuli. 2. Assess the effect of TS exposure on BBB function and viability in synergism with rheological changes. The proposed study will elucidate whether and to what extent TS plays a role in the pathogenesis and progression of BBB damage associated with hemodynamic changes and the differential toxicity of regular and 'reduced exposure tobacco products. This is a relevant issue in people potentially at risk for vascular/cardiac disorders where a sudden impairment of blood flow can lead to BBB failure and the onset of secondary brain injuries.

Public Health Relevance

Active and passive tobacco smoke are associated with dysfunction of vascular endothelial physiology in a causative and dose dependent way. Despite the strong evidence for an association between tobacco smoke and vascular impairment studies on the effects of smoking on the blood-brain barrier (BBB) have been limited to a few selective compounds. To address these critical issues, we propose to use a novel humanized dynamic in vitro BBB model (DIV-BBB), which relies on the use of hollow fibers to create capillary-like structures to support the adhesion of human BBB endothelial cells and astrocytes while simultaneously allowing for the circulation and extravasation upon activation of immune cells. We propose to use this novel in vitro system to evaluate the effect of tobacco smoke from reduced-exposure, nicotine- free, and regular tobacco products on BBB function and the specific role of inflammation and to assess the effect of TS exposure on BBB function and viability in synergism with rheological changes. This proposal is in response to the PA-09-046. This program announcement specifically asks to explore the differential toxicity of various tobacco and nicotine products. In this respect, we believe that our application is significant.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
7R01DA029121-02
Application #
8394074
Study Section
Special Emphasis Panel (ZRG1-BDCN-T (02))
Program Officer
Purohit, Vishnudutt
Project Start
2011-03-01
Project End
2016-02-29
Budget Start
2011-07-01
Budget End
2012-02-29
Support Year
2
Fiscal Year
2011
Total Cost
$224,718
Indirect Cost
Name
Texas Tech University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
609980727
City
Lubbock
State
TX
Country
United States
Zip Code
79430
Kaisar, Mohammad A; Kallem, Raja Reddy; Sajja, Ravi K et al. (2017) A convenient UHPLC-MS/MS method for routine monitoring of plasma and brain levels of nicotine and cotinine as a tool to validate newly developed preclinical smoking model in mouse. BMC Neurosci 18:71
Festoff, Barry W; Sajja, Ravi K; Cucullo, Luca (2017) Proximate Mediators of Microvascular Dysfunction at the Blood-Brain Barrier: Neuroinflammatory Pathways to Neurodegeneration. Biomed Res Int 2017:1549194
Kaisar, Mohammad A; Sajja, Ravi K; Prasad, Shikha et al. (2017) New experimental models of the blood-brain barrier for CNS drug discovery. Expert Opin Drug Discov 12:89-103
Prasad, Shikha; Sajja, Ravi K; Kaisar, Mohammad Abul et al. (2017) Role of Nrf2 and protective effects of Metformin against tobacco smoke-induced cerebrovascular toxicity. Redox Biol 12:58-69
Prasad, Shikha; Kaisar, Mohammad Abul; Cucullo, Luca (2017) Unhealthy smokers: scopes for prophylactic intervention and clinical treatment. BMC Neurosci 18:70
Sajja, Ravi K; Prasad, Shikha; Tang, Suni et al. (2017) Blood-brain barrier disruption in diabetic mice is linked to Nrf2 signaling deficits: Role of ABCB10? Neurosci Lett 653:152-158
Kaisar, Mohammad A; Villalba, Heidi; Prasad, Shikha et al. (2017) Offsetting the impact of smoking and e-cigarette vaping on the cerebrovascular system and stroke injury: Is Metformin a viable countermeasure? Redox Biol 13:353-362
Cucullo, Luca; Liles, Taylor (2016) Membrane Transporters and Pharmacological Implications. J Pharmacovigil 4:
Sajja, Ravi K; Rahman, Shafiqur; Cucullo, Luca (2016) Drugs of abuse and blood-brain barrier endothelial dysfunction: A focus on the role of oxidative stress. J Cereb Blood Flow Metab 36:539-54
Prasad, Shikha; Sajja, Ravi K; Kaisar, Mohammad A et al. (2016) Hyperglycemia exacerbates antiretroviral drug combination induced blood-brain barrier endothelial toxicity. Neurotoxicology 56:1-6

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