title: Proposed Mode of Action for Acrolein Respiratory Toxicity Associated with Inhaled Tobacco Smoke.
abstract: This article presents a mode of action (MOA) analysis that identifies key mechanisms in the respiratory toxicity of inhaled acrolein and proposes key acrolein-related toxic events resulting from the inhalation of tobacco smoke. Smoking causes chronic obstructive pulmonary disorder (COPD) and acrolein has been previously linked to the majority of smoking-induced noncancer respiratory toxicity. In contrast to previous MOA analyses for acrolein, this MOA focuses on the toxicity of acrolein in the lower respiratory system, reflecting the exposure that smokers experience upon tobacco smoke inhalation. The key mechanisms of acrolein toxicity identified in this proposed MOA include (1) acrolein chemical reactivity with proteins and other macromolecules of cells lining the respiratory tract, (2) cellular oxidative stress, including compromise of the important anti-oxidant glutathione, (3) chronic inflammation, (4) necrotic cell death leading to a feedback loop where necrosis-induced inflammation leads to more necrosis and oxidative damage and vice versa, (5) tissue remodeling and destruction, and (6) loss of lung elasticity and enlarged lung airspaces. From these mechanisms, the proposed MOA analysis identifies the key cellular processes in acrolein respiratory toxicity that consistently occur with the development of COPD: inflammation and necrosis in the middle and lower regions of the respiratory tract. Moreover, the acrolein exposures that occur as a result of smoking are well above exposures that induce both inflammation and necrosis in laboratory animals, highlighting the importance of the role of acrolein in smoking-related respiratory disease.
authors.affiliation: *Division of Nonclinical Science, Center for Tobacco Products, US Food and Drug Administration, Silver Spring, Maryland 20993;
authors.forename: R Philip
authors.initials: RP
authors.lastname: Yeager
authors.affiliation: *Division of Nonclinical Science, Center for Tobacco Products, US Food and Drug Administration, Silver Spring, Maryland 20993;
authors.forename: Mary
authors.initials: M
authors.lastname: Kushman
authors.affiliation: *Division of Nonclinical Science, Center for Tobacco Products, US Food and Drug Administration, Silver Spring, Maryland 20993;
authors.forename: Susan
authors.initials: S
authors.lastname: Chemerynski
authors.affiliation: *Division of Nonclinical Science, Center for Tobacco Products, US Food and Drug Administration, Silver Spring, Maryland 20993;
authors.forename: Roxana
authors.initials: R
authors.lastname: Weil
authors.affiliation: *Division of Nonclinical Science, Center for Tobacco Products, US Food and Drug Administration, Silver Spring, Maryland 20993;
authors.forename: Xin
authors.initials: X
authors.lastname: Fu
authors.affiliation: Division of Regulatory Project Management, Center for Tobacco Products, US Food and Drug Administration, Silver Spring, Maryland 20993; and.
authors.forename: Marcella
authors.initials: M
authors.lastname: White
authors.affiliation: Division of Individual Health Science, Center for Tobacco Products, US Food and Drug Administration, Silver Spring, Maryland 20993.
authors.forename: Priscilla
authors.initials: P
authors.lastname: Callahan-Lyon
authors.affiliation: *Division of Nonclinical Science, Center for Tobacco Products, US Food and Drug Administration, Silver Spring, Maryland 20993; *Division of Nonclinical Science, Center for Tobacco Products, US Food and Drug Administration, Silver Spring, Maryland 20993; hans.rosenfeldt@fda.hhs.gov.
authors.forename: Hans
authors.initials: H
authors.lastname: Rosenfeldt
mesh_terms: D000171:Acrolein / Q000009:adverse effects*; D056151:Airway Remodeling; D000818:Animals; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D019570:Inhalation Exposure / Q000009:adverse effects*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009336:Necrosis; D018384:Oxidative Stress / Q000187:drug effects; D011014:Pneumonia / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D018570:Risk Assessment; D012907:Smoking / Q000009:adverse effects*
chemical_list: D018836:Inflammation Mediators; D017382:Reactive Oxygen Species; D000171:Acrolein
keywords: acrolein; inhalation; mode of action; respiratory toxicity.; tobacco smoke