title: Systems toxicology-based assessment of the candidate modified risk tobacco product THS2.2 for the adhesion of monocytic cells to human coronary arterial endothelial cells.
abstract: Alterations of endothelial adhesive properties by cigarette smoke (CS) can progressively favor the development of atherosclerosis which may cause cardiovascular disorders. Modified risk tobacco products (MRTPs) are tobacco products developed to reduce smoking-related risks. A systems biology/toxicology approach combined with a functional in vitro adhesion assay was used to assess the impact of a candidate heat-not-burn technology-based MRTP, Tobacco Heating System (THS) 2.2, on the adhesion of monocytic cells to human coronary arterial endothelial cells (HCAECs) compared with a reference cigarette (3R4F). HCAECs were treated for 4h with conditioned media of human monocytic Mono Mac 6 (MM6) cells preincubated with low or high concentrations of aqueous extracts from THS2.2 aerosol or 3R4F smoke for 2h (indirect treatment), unconditioned media (direct treatment), or fresh aqueous aerosol/smoke extracts (fresh direct treatment). Functional and molecular investigations revealed that aqueous 3R4F smoke extract promoted the adhesion of MM6 cells to HCAECs via distinct direct and indirect concentration-dependent mechanisms. Using the same approach, we identified significantly reduced effects of aqueous THS2.2 aerosol extract on MM6 cell-HCAEC adhesion, and reduced molecular changes in endothelial and monocytic cells. Ten- and 20-fold increased concentrations of aqueous THS2.2 aerosol extract were necessary to elicit similar effects to those measured with 3R4F in both fresh direct and indirect exposure modalities, respectively. Our systems toxicology study demonstrated reduced effects of an aqueous aerosol extract from the candidate MRTP, THS2.2, using the adhesion of monocytic cells to human coronary endothelial cells as a surrogate pathophysiologically relevant event in atherogenesis.
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland. Electronic address: Carine.Poussin@pmi.com.
authors.forename: Carine
authors.initials: C
authors.lastname: Poussin
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Laurent
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland.
authors.forename: Manuel C
authors.initials: MC
authors.lastname: Peitsch
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland.
authors.forename: Julia
authors.initials: J
authors.lastname: Hoeng
authors.affiliation: Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel, Switzerland.
authors.forename: Hector
authors.initials: H
authors.lastname: De Leon
mesh_terms: D000336:Aerosols; D050197:Atherosclerosis / Q000139:chemically induced / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects*; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects*; D016207:Cytokines / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects*; D006358:Hot Temperature; D006801:Humans; D066298:In Vitro Techniques; D009000:Monocytes / Q000187:drug effects*; D009538:Nicotine / Q000032:analysis; D050050:Protein Carbonylation / Q000187:drug effects; D012906:Smoke / Q000009:adverse effects* / Q000032:analysis; D014026:Nicotiana
chemical_list: D000336:Aerosols; D016207:Cytokines; D012906:Smoke; D009538:Nicotine
keywords: Adhesion; Atherosclerosis; Cigarette; Endothelial cell; Modified risk tobacco product; Monocyte