title: IL-17A and serum amyloid A are elevated in a cigarette smoke cessation model associated with the persistence of pigmented macrophages, neutrophils and activated NK cells.
abstract: While global success in cessation advocacy has seen smoking rates fall in many developed countries, persistent lung inflammation in ex-smokers is an increasingly important clinical problem whose mechanistic basis remains poorly understood. In this study, candidate effector mechanisms were assessed in mice exposed to cigarette smoke (CS) for 4 months following cessation from long term CS exposure. BALF neutrophils, CD4+ and CD8+ T cells and lung innate NK cells remained significantly elevated following smoking cessation. Analysis of neutrophil mobilization markers showed a transition from acute mediators (MIP-2α, KC and G-CSF) to sustained drivers of neutrophil and macrophage recruitment and activation (IL-17A and Serum Amyoid A (SAA)). Follicle-like lymphoid aggregates formed with CS exposure and persisted with cessation, where they were in close anatomical proximity to pigmented macrophages, whose number actually increased 3-fold following CS cessation. This was associated with the elastolytic protease, MMP-12 (macrophage metallo-elastase) which remained significantly elevated post-cessation. Both GM-CSF and CSF-1 were significantly increased in the CS cessation group relative to the control group. In conclusion, we show that smoking cessation mediates a transition to accumulation of pigmented macrophages, which may contribute to the expanded macrophage population observed in COPD. These macrophages together with IL-17A, SAA and innate NK cells are identified here as candidate persistence determinants and, we suggest, may represent specific targets for therapies directed towards the amelioration of chronic airway inflammation.
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, The University of Melbourne, Victoria, Australia.
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Hansen
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, The University of Melbourne, Victoria, Australia.
authors.forename: Sheau Pyng J
authors.initials: SP
authors.lastname: Chan
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, The University of Melbourne, Victoria, Australia.
authors.forename: Shenna Y
authors.initials: SY
authors.lastname: Langenbach
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, The University of Melbourne, Victoria, Australia.
authors.forename: Lovisa F
authors.initials: LF
authors.lastname: Dousha
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, The University of Melbourne, Victoria, Australia.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Jones
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, The University of Melbourne, Victoria, Australia.
authors.forename: Selcuk
authors.initials: S
authors.lastname: Yatmaz
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, The University of Melbourne, Victoria, Australia.
authors.forename: Huei Jiunn
authors.initials: HJ
authors.lastname: Seow
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, The University of Melbourne, Victoria, Australia.
authors.forename: Ross
authors.initials: R
authors.lastname: Vlahos
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, The University of Melbourne, Victoria, Australia.
authors.forename: Gary P
authors.initials: GP
authors.lastname: Anderson
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, The University of Melbourne, Victoria, Australia.
authors.forename: Steven
authors.initials: S
authors.lastname: Bozinovski
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D005434:Flow Cytometry; D020381:Interleukin-17 / Q000097:blood*; D007694:Killer Cells, Natural / Q000473:pathology / Q000502:physiology*; D016676:Macrophages, Alveolar / Q000473:pathology / Q000502:physiology*; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D009504:Neutrophils / Q000473:pathology / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D000685:Serum Amyloid A Protein / Q000378:metabolism*; D016540:Smoking Cessation; D014028:Tobacco Smoke Pollution / Q000009:adverse effects
chemical_list: D020381:Interleukin-17; D000685:Serum Amyloid A Protein; D014028:Tobacco Smoke Pollution; D053508:Matrix Metalloproteinase 12