title: Repression of the equilibrative nucleoside transporters dampens inflammatory lung injury.
abstract: Acute lung injury (ALI) is a devastating disorder of the lung that is characterized by hypoxemia, overwhelming pulmonary inflammation, and a high mortality in the critically ill. Adenosine has been implicated as an anti-inflammatory signaling molecule, and previous studies showed that extracellular adenosine concentrations are increased in inflamed tissues. Adenosine signaling is terminated by the uptake of adenosine from the extracellular into the intracellular compartment via equilibrative nucleoside transporters (ENTs). However, their role in controlling adenosine signaling during pulmonary inflammation remains unknown. After inflammatory in vitro experiments, we observed a repression of ENT1 and ENT2 that was associated with an attenuation of extracellular adenosine uptake. Experiments using short, interfering RNA silencing confirmed a significant contribution of ENT repression in elevating extracellular adenosine concentrations during inflammation. Furthermore, an examination of the ENT2 promoter implicated NF-κB as a key regulator for the observed ENT repression. Additional in vivo experiments using a murine model of inflammatory lung injury showed that the pharmacological inhibition of ENT1 and ENT2 resulted in improved pulmonary barrier function and reduced signs of acute inflammation of the lung. Whereas experiments on Ent1(-/-) or Ent2(-/-) mice revealed lung protection in LPS-induced lung injury, an examination of bone marrow chimeras for ENTs pointed to the nonhematopoetic expression of ENTs as the underlying cause of dampened pulmonary inflammation during ALI. Taken together, these findings reveal the transcriptional repression of ENTs as an innate protective response during acute pulmonary inflammation. The inhibition of ENTs could be pursued as a therapeutic option to ameliorate inflammatory lung injury.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Eberhard Karls University and Tübingen University Hospital, Tübingen, Germany.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Morote-Garcia
authors.forename: David
authors.initials: D
authors.lastname: Köhler
authors.forename: Judith M
authors.initials: JM
authors.lastname: Roth
authors.forename: Valbona
authors.initials: V
authors.lastname: Mirakaj
authors.forename: Therese
authors.initials: T
authors.lastname: Eldh
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
authors.forename: Peter
authors.initials: P
authors.lastname: Rosenberger
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002460:Cell Line; D033721:Equilibrative Nucleoside Transporter 1 / Q000096:biosynthesis* / Q000235:genetics; D033722:Equilibrative-Nucleoside Transporter 2 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D033721:Equilibrative Nucleoside Transporter 1; D033722:Equilibrative-Nucleoside Transporter 2; D016328:NF-kappa B; C438649:SLC29A1 protein, human; C498476:SLC29A1 protein, mouse; C438654:SLC29A2 protein, human; C486681:Slc29a2 protein, mouse