Dysregulated Nox4 ubiquitination contributes to redox imbalance and age-related severity of acute lung injury.

TitleDysregulated Nox4 ubiquitination contributes to redox imbalance and age-related severity of acute lung injury.
Publication TypeJournal Article
Year of Publication2017
AuthorsPalumbo S, Shin Y-J, Ahmad K, Desai AA, Quijada H, Mohamed M, Knox A, Sammani S, Colson BA, Wang T, Garcia JGN, Hecker L
JournalAm J Physiol Lung Cell Mol Physiol
Volume312
Issue3
PaginationL297-L308
Date Published2017 Mar 01
ISSN Number1522-1504
Abstract

<p>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.</p>

DOI10.1152/ajplung.00305.2016
Alternate JournalAm. J. Physiol. Lung Cell Mol. Physiol.
PubMed ID28062482
PubMed Central IDPMC5374302
Grant ListR01 HL136603 / HL / NHLBI NIH HHS / United States