title: Alpha-1-antitrypsin inhibits nitric oxide production.
abstract: NO is an endogenously produced gas that regulates inflammation, vascular tone, neurotransmission, and immunity. NO production can be increased by exposing cells to several endogenous and exogenous proinflammatory mediators, including IFN-γ, TNF-α, IL-1β, and LPS. As AAT has been shown to inhibit cell activation and suppress cytokine production associated with proinflammatory stimulation, we examined AAT for NO-suppressive function. In RAW 264.7 murine macrophagic cells, physiological AAT concentrations significantly inhibited combined LPS- and IFN-γ-induced NO synthesis, and NO synthesis inhibition was associated with decreased expression of iNOS, suppressed NF-κB activation, and reduced translocation of extracellular AAT into the interior of RAW 264.7 cells. CE-2072, a synthetic inhibitor of serine proteases, also suppressed NO production, iNOS expression, and NF-κB activation. However, AAT did not alter activation of intracellular MAPKs. In subjects with genetic AAT deficiency, exhaled NO was increased significantly compared with exhaled NO in healthy controls. These in vitro and in vivo studies suggest that AAT is an endogenous inhibitor of NO production. Administering AAT or AAT-like molecules may have use as a treatment for diseases associated with excessive NO production.
authors.affiliation: Division of Pulmonary Medicine, Veterans Affairs Medical Center, Denver, CO, USA.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Chan
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Pott
authors.forename: Philip E
authors.initials: PE
authors.lastname: Silkoff
authors.forename: Annemarie H
authors.initials: AH
authors.lastname: Ralston
authors.forename: Courtney L
authors.initials: CL
authors.lastname: Bryan
authors.forename: Leland
authors.initials: L
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000515:alpha 1-Antitrypsin / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D016328:NF-kappa B; D000515:alpha 1-Antitrypsin; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D020928:Mitogen-Activated Protein Kinases