title: Neu-164 and Neu-107, two novel antioxidant and anti-myeloperoxidase compounds, inhibit acute cigarette smoke-induced lung inflammation.
abstract: Cigarette smoke is a profound proinflammatory stimulus that causes acute lung inflammation and chronic lung disease, including chronic obstructive pulmonary disease (COPD, emphysema, and chronic bronchitis), via a variety of mechanisms, including oxidative stress. Cigarette smoke contains high levels of free radicals, whereas inflammatory cells, including macrophages and neutrophils, express enzymes, including NADPH oxidase, nitric oxide synthase, and myeloperoxidase, that generate reactive oxygen species in situ and contribute to inflammation and tissue damage. Neu-164 and Neu-107 are small-molecule inhibitors of myeloperoxidase, as well as potent antioxidants. We hypothesized that Neu-164 and Neu-107 would inhibit acute cigarette smoke-induced inflammation. Adult C57BL/6J mice were exposed to mainstream cigarette smoke for 3 days to induce acute inflammation and were treated daily by inhalation with Neu-164, Neu-107, or dexamethasone as a control. Inflammatory cells and cytokines were assessed by bronchoalveolar lavage and histology. mRNA levels of endogenous antioxidant genes heme oxygenase-1 and glutamate-cysteine ligase modifier subunit were determined by qPCR. Cigarette smoke exposure induced acute lung inflammation with accumulation of neutrophils and upregulation of proinflammatory cytokines, including IL-6, macrophage inflammatory protein-2, and keratinocyte-derived cytokine. Both Neu-164 and Neu-107 significantly reduced the accumulation of inflammatory cells and the expression of inflammatory cytokines as effectively as dexamethasone. Upregulation of endogenous antioxidant genes was dampened. Neu-164 and Neu-107 inhibit acute cigarette smoke-induced inflammation by scavenging reactive oxygen species in cigarette smoke and by inhibiting further oxidative stress caused by inflammatory cells. These compounds may have promise in preventing or treating lung disease associated with chronic smoke exposure, including COPD.
authors.affiliation: Department of Medicine, University of Rochester, Rochester, NY 14642, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Thatcher
authors.forename: Hsi-Min
authors.initials: HM
authors.lastname: Hsiao
authors.forename: Elhanan
authors.initials: E
authors.lastname: Pinner
authors.forename: Moshe
authors.initials: M
authors.lastname: Laudon
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Pollock
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Sime
authors.forename: Richard P
authors.initials: RP
authors.lastname: Phipps
mesh_terms: D000328:Adult; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002109:Caffeic Acids / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008168:Lung / Q000201:enzymology* / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*; D009195:Peroxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011014:Pneumonia / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D012907:Smoking / Q000009:adverse effects*; D014028:Tobacco Smoke Pollution / Q000009:adverse effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000975:Antioxidants; D002109:Caffeic Acids; D016207:Cytokines; D004791:Enzyme Inhibitors; D007211:Indoles; D008565:Membrane Proteins; C583642:Neu-107; C583641:Neu-164; D012333:RNA, Messenger; D014028:Tobacco Smoke Pollution; D009195:Peroxidase; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
keywords: anti-inflammatory; antioxidants; chronic obstructive pulmonary disease; cigarette smoke; inflammation