Early induction of uncoupling protein-2 in pulmonary macrophages in hyperoxia-associated lung injury

Jay Steer, Tracy Mann, S.Z.Y. Lo, Julia Inglis, Huey Yap, Peter Henry, David Joyce

Research output: Contribution to journalArticle

7 Citations (Scopus)
396 Downloads (Pure)

Abstract

Context: High concentrations of inspired oxygen contribute to the pathogenesis of neonatal bronchopulmonary dysplasia and adult acute respiratory distress syndrome. Animal models of hyperoxia-associated lung injury (HALI) are characterized by enhanced generation of reactive oxygen species (ROS) and an adaptive antioxidant response. ROS contribute to pathogenesis, partly through enhancing pro-inflammatory activity in macrophages. Uncoupling protein-2 (UCP2) is an inner mitochondrial membrane protein whose expression lowers mitochondrial superoxide (O2 ̇-) production. UCP2, therefore, has potential to contribute to antioxidant response. It is inducible in macrophages. Objectives and methods: We hypothesized that induction of UCP2 occurred in response to pulmonary hyperoxia in vivo and that expression localized to pulmonary macrophages. We then investigated mechanisms of UCP2 regulation in hyperoxia-exposed macrophages in vitro and correlated changing UCP2 expression with mitochondrial membrane potential (Δψm) and O2 ̇- production. Results: UCP2 is induced in lungs of mice within 1 h of hyperoxia exposure. Induction occurs in pulmonary alveolar macrophages in vivo, and can be replicated in vitro in isolated macrophages. UCP2 mRNA does not change. UCP2 increases quickly after the first hyperoxia-induced burst of mitochondrial O2 ̇- generation. Suppression of Δψm and mitochondrial O2 ̇- production follow and persist while UCP2 is elevated. Discussion and conclusions: Induction of UCP2 is an early response to hyperoxia in pulmonary macrophages. The mechanism is post-transcriptional. UCP2 induction follows a transient rise in mitochondrial ROS generation. The subsequent falls in Δψm and mitochondrial O2 ̇- support the notion that regulable UCP2 expression in macrophages acts to contain mitochondrial ROS generation. That, in turn, may limit inappropriate pro-inflammatory activation in HALI. © 2013 Informa Healthcare USA, Inc.
Original languageEnglish
Pages (from-to)544-552
JournalInhalation Toxicology
Volume25
Issue number9
Early online date30 Jul 2013
DOIs
Publication statusPublished - Aug 2013

Fingerprint Dive into the research topics of 'Early induction of uncoupling protein-2 in pulmonary macrophages in hyperoxia-associated lung injury'. Together they form a unique fingerprint.

Cite this