Protein phosphatase 2A activation attenuates inflammation in murine models of acute lung injury

Walker M. McHugh, William W. Russell, Andrew J. Fleszar, Paul E. Rodenhouse, Skyler P. Rietberg, Lei Sun, Thomas P. Shanley, Timothy T. Cornell*

*Corresponding author for this work

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 (N 6 -CPA) increased PP2A activity and inhibited endotoxin-induced cytokine production in a murine alveolar macrophage cell line. N 6 -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 N 6 -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.

Original languageEnglish (US)
Pages (from-to)L903-L912
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume311
Issue number5
DOIs
StatePublished - Jan 1 2016

Fingerprint

Protein Phosphatase 2
Acute Lung Injury
Adult Respiratory Distress Syndrome
Inflammation
Neutrophil Infiltration
Chemokines
Lung Injury
Interleukin-8
Endotoxins
Alveolar Epithelial Cells
Mitogen-Activated Protein Kinases
Lung
Pediatric Intensive Care Units
Wounds and Injuries
Alveolar Macrophages
Pseudomonas aeruginosa
Cytokines
Morbidity
Cell Line
Mortality

Keywords

  • Acute respiratory distress syndrome
  • Lung inflammation
  • Murine acute lung injury model
  • Neutrophil recruitment
  • Protein phosphatase 2A

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Cite this

McHugh, W. M., Russell, W. W., Fleszar, A. J., Rodenhouse, P. E., Rietberg, S. P., Sun, L., ... Cornell, T. T. (2016). Protein phosphatase 2A activation attenuates inflammation in murine models of acute lung injury. American Journal of Physiology - Lung Cellular and Molecular Physiology, 311(5), L903-L912. https://doi.org/10.1152/ajplung.00007.2016
McHugh, Walker M. ; Russell, William W. ; Fleszar, Andrew J. ; Rodenhouse, Paul E. ; Rietberg, Skyler P. ; Sun, Lei ; Shanley, Thomas P. ; Cornell, Timothy T. / Protein phosphatase 2A activation attenuates inflammation in murine models of acute lung injury. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2016 ; Vol. 311, No. 5. pp. L903-L912.
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Protein phosphatase 2A activation attenuates inflammation in murine models of acute lung injury. / McHugh, Walker M.; Russell, William W.; Fleszar, Andrew J.; Rodenhouse, Paul E.; Rietberg, Skyler P.; Sun, Lei; Shanley, Thomas P.; Cornell, Timothy T.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 311, No. 5, 01.01.2016, p. L903-L912.

Research output: Contribution to journalArticle

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T1 - Protein phosphatase 2A activation attenuates inflammation in murine models of acute lung injury

AU - McHugh, Walker M.

AU - Russell, William W.

AU - Fleszar, Andrew J.

AU - Rodenhouse, Paul E.

AU - Rietberg, Skyler P.

AU - Sun, Lei

AU - Shanley, Thomas P.

AU - Cornell, Timothy T.

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AB - 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 (N 6 -CPA) increased PP2A activity and inhibited endotoxin-induced cytokine production in a murine alveolar macrophage cell line. N 6 -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 N 6 -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.

KW - Acute respiratory distress syndrome

KW - Lung inflammation

KW - Murine acute lung injury model

KW - Neutrophil recruitment

KW - Protein phosphatase 2A

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