title: Protein phosphatase 2A activation attenuates inflammation in murine models of acute lung injury.
abstract: Acute respiratory distress syndrome (ARDS) remains a leading cause of morbidity and mortality in both adult and pediatric intensive care units. A key event in the development of ARDS is neutrophil recruitment into the lungs leading to tissue damage and destruction. Interleukin-8 (IL-8) is the major human chemokine responsible for neutrophil recruitment into the lungs. Protein phosphatase 2A (PP2A) has been shown to be a key regulator of the mitogen-activated protein kinase (MAPK) cascades, which control the production of IL-8. Previously, our laboratory employed an in vitro model to show that inhibition of PP2A results in an increase in IL-8 production in human alveolar epithelial cells. The objective of this study was to determine whether PP2A regulated this response in vivo by investigating the impact of pharmacologic activation of PP2A on chemokine production and activation of the MAPK cascade and lung injury using endotoxin- and bacterial-challenge models of ARDS in mice. N6-cyclopentyladenosine (N6-CPA) increased PP2A activity and inhibited endotoxin-induced cytokine production in a murine alveolar macrophage cell line. N6-CPA pretreatment in mice challenged with intratracheal endotoxin decreased chemokine production, reduced neutrophil infiltration, and attenuated lung injury. Following initiation of lung injury with live Pseudomonas aeruginosa, mice that received N6-CPA 4 h following bacterial challenge showed attenuated chemokine production and reduced neutrophil infiltration compared with control mice. Pharmacologic PP2A activation both limited and prevented inflammation and tissue injury in two direct injury models of ARDS. These results suggest modulation of PP2A activity as a therapeutic target in ARDS.
authors.affiliation: Division of Pediatric Critical Care Medicine, Department of Pediatrics and Communicable Diseases, University of Michigan School of Medicine, and C. S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan.
authors.forename: Walker M
authors.initials: WM
authors.lastname: McHugh
authors.affiliation: Division of Pediatric Critical Care Medicine, Department of Pediatrics and Communicable Diseases, University of Michigan School of Medicine, and C. S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan.
authors.forename: William W
authors.initials: WW
authors.lastname: Russell
authors.affiliation: Division of Pediatric Critical Care Medicine, Department of Pediatrics and Communicable Diseases, University of Michigan School of Medicine, and C. S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Fleszar
authors.affiliation: Division of Pediatric Critical Care Medicine, Department of Pediatrics and Communicable Diseases, University of Michigan School of Medicine, and C. S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Rodenhouse
authors.affiliation: Division of Pediatric Critical Care Medicine, Department of Pediatrics and Communicable Diseases, University of Michigan School of Medicine, and C. S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan.
authors.forename: Skyler P
authors.initials: SP
authors.lastname: Rietberg
authors.affiliation: Division of Pediatric Critical Care Medicine, Department of Pediatrics and Communicable Diseases, University of Michigan School of Medicine, and C. S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan.
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
authors.affiliation: Division of Pediatric Critical Care Medicine, Department of Pediatrics and Communicable Diseases, University of Michigan School of Medicine, and C. S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Shanley
authors.affiliation: Division of Pediatric Critical Care Medicine, Department of Pediatrics and Communicable Diseases, University of Michigan School of Medicine, and C. S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan ttcornel@med.umich.edu.
authors.forename: Timothy T
authors.initials: TT
authors.lastname: Cornell
mesh_terms: D055371:Acute Lung Injury / Q000201:enzymology* / Q000473:pathology; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D018925:Chemokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004731:Endotoxins; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D012128:Respiratory Distress Syndrome / Q000201:enzymology / Q000473:pathology
chemical_list: D018925:Chemokines; D004731:Endotoxins; C048599:N(6)-cyclopentyladenosine; D048031:JNK Mitogen-Activated Protein Kinases; D054648:Protein Phosphatase 2; D000241:Adenosine
keywords: acute respiratory distress syndrome; lung inflammation; murine acute lung injury model; neutrophil recruitment; protein phosphatase 2A