title: Proapoptotic Noxa is required for particulate matter-induced cell death and lung inflammation.
abstract: Elevated ambient levels of particulate matter air pollution are associated with excess daily mortality, largely attributable to increased rates of cardiovascular events. We have previously reported that particulate matter induces p53-dependent apoptosis in primary human alveolar epithelial cells. Activation of the intrinsic apoptotic pathway by p53 often requires the transcription of the proapoptotic Bcl-2 proteins Noxa, Puma, or both. In this study, we exposed alveolar epithelial cells in culture and mice to fine particulate matter <2.5 microm in diameter (PM(2.5)) collected from the ambient air in Washington, D. C. Exposure to PM(2.5) induced apoptosis in primary alveolar epithelial cells from wild-type but not Noxa(-/-) mice. Twenty-four hours after the intratracheal instillation of PM(2.5), wild-type mice showed increased apoptosis in the lung and increased levels of mRNA encoding Noxa but not Puma. These changes were associated with increased permeability of the alveolar-capillary membrane and inflammation. All of these findings were absent or attenuated in Noxa(-/-) animals. We conclude that PM(2.5)-induced cell death requires Noxa both in vitro and in vivo and that Noxa-dependent cell death might contribute to PM-induced alveolar epithelial dysfunction and the resulting inflammatory response.
authors.affiliation: Feinberg School of Medicine, Northwestern University, Division of Pulmonary and Critical Care Medicine, 240 E. Huron, Chicago, IL 60611, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Urich
authors.forename: Saul
authors.initials: S
authors.lastname: Soberanes
authors.forename: Zach
authors.initials: Z
authors.lastname: Burgess
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Chiarella
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Ghio
authors.forename: Karen M
authors.initials: KM
authors.lastname: Ridge
authors.forename: David W
authors.initials: DW
authors.lastname: Kamp
authors.forename: Navdeep S
authors.initials: NS
authors.lastname: Chandel
authors.forename: Gökhan M
authors.initials: GM
authors.lastname: Mutlu
authors.forename: G R Scott
authors.initials: GR
authors.lastname: Budinger
mesh_terms: D000393:Air Pollutants / Q000009:adverse effects*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D016923:Cell Death; D007249:Inflammation / Q000139:chemically induced*; D008171:Lung Diseases / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D010316:Particle Size; D052638:Particulate Matter / Q000009:adverse effects*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D025521:Tumor Suppressor Proteins / Q000032:analysis; D015854:Up-Regulation
chemical_list: D000393:Air Pollutants; D051017:Apoptosis Regulatory Proteins; C488588:PUMA protein, mouse; D052638:Particulate Matter; C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins