title: Dysregulated Nox4 ubiquitination contributes to redox imbalance and age-related severity of acute lung injury.
abstract: Acute respiratory distress syndrome (ARDS) is a devastating critical illness disproportionately affecting the elderly population, with both higher incidence and mortality. The integrity of the lung endothelial cell (EC) monolayer is critical for preservation of lung function. However, mechanisms mediating EC barrier regulation in the context of aging remain unclear. We assessed the severity of acute lung injury (ALI) in young (2 mo) and aged (18 mo) mice using a two-hit preclinical model. Compared with young cohorts, aged mice exhibited increased ALI severity, with greater vascular permeability characterized by elevated albumin influx and levels of bronchoalveolar lavage (BAL) cells (neutrophils) and protein. Aged/injured mice also demonstrated elevated levels of reactive oxygen species (ROS) in the BAL, which was associated with upregulation of the ROS-generating enzyme, Nox4. We evaluated the role of aging in human lung EC barrier regulation utilizing a cellular model of replicative senescence. Senescent EC populations were defined by increases in β-galactosidase activity and p16 levels. In response to lipopolysaccharide (LPS) challenge, senescent ECs demonstrate exacerbated permeability responses compared with control "young" ECs. LPS challenge led to a rapid induction of Nox4 expression in both control and senescent ECs, which was posttranslationally mediated via the proteasome/ubiquitin system. However, senescent ECs demonstrated deficient Nox4 ubiquitination, resulting in sustained expression of Nox4 and alterations in cellular redox homeostasis. Pharmacological inhibition of Nox4 in senescent ECs reduced LPS-induced alterations in permeability. These studies provide insight into the roles of Nox4/senescence in EC barrier responses and offer a mechanistic link to the increased incidence and mortality of ARDS associated with aging.
authors.affiliation: College of Medicine, University of Arizona, Tucson, Arizona; and.
authors.forename: Sunmi
authors.initials: S
authors.lastname: Palumbo
authors.affiliation: College of Medicine, University of Arizona, Tucson, Arizona; and.
authors.forename: Yoon-Joo
authors.initials: YJ
authors.lastname: Shin
authors.affiliation: College of Medicine, University of Arizona, Tucson, Arizona; and.
authors.forename: Kareem
authors.initials: K
authors.lastname: Ahmad
authors.affiliation: College of Medicine, University of Arizona, Tucson, Arizona; and.
authors.forename: Ankit A
authors.initials: AA
authors.lastname: Desai
authors.affiliation: College of Medicine, University of Arizona, Tucson, Arizona; and.
authors.forename: Hector
authors.initials: H
authors.lastname: Quijada
authors.affiliation: College of Medicine, University of Arizona, Tucson, Arizona; and.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Mohamed
authors.affiliation: College of Medicine, University of Arizona, Tucson, Arizona; and.
authors.forename: Adam
authors.initials: A
authors.lastname: Knox
authors.affiliation: College of Medicine, University of Arizona, Tucson, Arizona; and.
authors.forename: Saad
authors.initials: S
authors.lastname: Sammani
authors.affiliation: College of Medicine, University of Arizona, Tucson, Arizona; and.
authors.forename: Brett A
authors.initials: BA
authors.lastname: Colson
authors.affiliation: College of Medicine, University of Arizona, Tucson, Arizona; and.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: College of Medicine, University of Arizona, Tucson, Arizona; and.
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
authors.affiliation: College of Medicine, University of Arizona, Tucson, Arizona; and lhecker@email.arizona.edu.|Southern Arizona VA Health Care System (SAVAHCS), Tucson, Arizona.
authors.forename: Louise
authors.initials: L
authors.lastname: Hecker
mesh_terms: D055371:Acute Lung Injury / Q000378:metabolism* / Q000473:pathology*; D000375:Aging / Q000378:metabolism*; D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D004198:Disease Susceptibility; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D025801:Ubiquitin; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D046988:Proteasome Endopeptidase Complex
keywords: Nox4; oxidative stress; reactive oxygen species; senescence