Protective role of PI3-kinase/Akt/eNOS signaling in mechanical stress through inhibition of p38 mitogen-activated protein kinase in mouse lung

Xin Qi Peng, Mahendra Damarla, Jarrett Skirball, Stephanie Nonas, Xiao Ying Wang, Eugenia J. Han, Emile J. Hasan, Xuan Cao, Adel Boueiz, Rachel Damico, Rubin M. Tuder, Alfred M. Sciuto, Dana R. Anderson, Joe GN Garcia, David A. Kass, Paul M. Hassoun, Jun Tian Zhang

Research output: Contribution to journalArticle

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Abstract

Aim: To test the hypothesis that PI3K/Akt/eNOS signaling has a protective role in a murine model of ventilation associated lung injury (VALI) through down-regulation of p38 MAPK signaling. Methods: Male C57BL/J6 (wild-type, WT) or eNOS knockout mice (eNOS-/-) were exposed to mechanical ventilation (MV) with low (LV T, 7 mL/kg) and high tidal volume (HVT, 20 mL/kg) for 0-4 h. A subset of WT mice was administered the specific inhibitors of PI3K (100 nmol/L Wortmannin [Wort], ip) or of p38 MAPK (SB203580, 2 mg/kg, ip) 1 h before MV. Cultured type II alveolar epithelial cells C10 were exposed to 18% cyclic stretch for 2 h with or without 20 nmol/L Wort pretreatment. At the end of the experiment, the capillary leakage in vivo was assessed by extravasation of Evans blue dye (EBD), wet/dry weight ratio and lung lavage protein concentration. The lung tissue and cell lysate were also collected for protein and histological review. Results: MV decreased PI3K/Akt phosphorylation and eNOS expression but increased phospho-p38 MAPK expression along with a lung leakage of EBD. Inhibitions of phospho-Akt by Wort worsen the lung edema, whereas inhibition of p38 MAPK kinase restored activation of Akt together with alleviated capillary leakage. eNOS-/- mice showed an exacerbated lung edema and injury. The stretched C10 cells demonstrated that Wort diminished the activation of Akt, but potentiated phosphorylation of MAPK p38. Conclusion: Our results indicate that PI-3K/Akt/eNOS pathway has significant protective effects in VALI by preventing capillary leakage, and that there is a cross-talk between PI3K/Akt and p38 MAPK pathways in vascular barrier dysfunction resulting from VALI.

Original languageEnglish (US)
Pages (from-to)175-183
Number of pages9
JournalActa Pharmacologica Sinica
Volume31
Issue number2
DOIs
StatePublished - Feb 2010
Externally publishedYes

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Mechanical Stress
p38 Mitogen-Activated Protein Kinases
Phosphatidylinositol 3-Kinases
Lung Injury
Lung
Artificial Respiration
Ventilation
Evans Blue
Edema
Coloring Agents
Phosphorylation
Alveolar Epithelial Cells
Tidal Volume
Mitogen-Activated Protein Kinase Kinases
Bronchoalveolar Lavage
Knockout Mice
Blood Vessels
Proteins
Down-Regulation
Weights and Measures

Keywords

  • Mechanical stress
  • P38 MAPK signalings
  • PI3K/Akt/eNOS
  • Pulmonary capillary leakage
  • Pulmonary edema
  • Signals cross-talk
  • Ventilator-associated lung injury
  • Wortmannin

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Protective role of PI3-kinase/Akt/eNOS signaling in mechanical stress through inhibition of p38 mitogen-activated protein kinase in mouse lung. / Peng, Xin Qi; Damarla, Mahendra; Skirball, Jarrett; Nonas, Stephanie; Wang, Xiao Ying; Han, Eugenia J.; Hasan, Emile J.; Cao, Xuan; Boueiz, Adel; Damico, Rachel; Tuder, Rubin M.; Sciuto, Alfred M.; Anderson, Dana R.; Garcia, Joe GN; Kass, David A.; Hassoun, Paul M.; Zhang, Jun Tian.

In: Acta Pharmacologica Sinica, Vol. 31, No. 2, 02.2010, p. 175-183.

Research output: Contribution to journalArticle

Peng, XQ, Damarla, M, Skirball, J, Nonas, S, Wang, XY, Han, EJ, Hasan, EJ, Cao, X, Boueiz, A, Damico, R, Tuder, RM, Sciuto, AM, Anderson, DR, Garcia, JGN, Kass, DA, Hassoun, PM & Zhang, JT 2010, 'Protective role of PI3-kinase/Akt/eNOS signaling in mechanical stress through inhibition of p38 mitogen-activated protein kinase in mouse lung', Acta Pharmacologica Sinica, vol. 31, no. 2, pp. 175-183. https://doi.org/10.1038/aps.2009.190
Peng, Xin Qi ; Damarla, Mahendra ; Skirball, Jarrett ; Nonas, Stephanie ; Wang, Xiao Ying ; Han, Eugenia J. ; Hasan, Emile J. ; Cao, Xuan ; Boueiz, Adel ; Damico, Rachel ; Tuder, Rubin M. ; Sciuto, Alfred M. ; Anderson, Dana R. ; Garcia, Joe GN ; Kass, David A. ; Hassoun, Paul M. ; Zhang, Jun Tian. / Protective role of PI3-kinase/Akt/eNOS signaling in mechanical stress through inhibition of p38 mitogen-activated protein kinase in mouse lung. In: Acta Pharmacologica Sinica. 2010 ; Vol. 31, No. 2. pp. 175-183.
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abstract = "Aim: To test the hypothesis that PI3K/Akt/eNOS signaling has a protective role in a murine model of ventilation associated lung injury (VALI) through down-regulation of p38 MAPK signaling. Methods: Male C57BL/J6 (wild-type, WT) or eNOS knockout mice (eNOS-/-) were exposed to mechanical ventilation (MV) with low (LV T, 7 mL/kg) and high tidal volume (HVT, 20 mL/kg) for 0-4 h. A subset of WT mice was administered the specific inhibitors of PI3K (100 nmol/L Wortmannin [Wort], ip) or of p38 MAPK (SB203580, 2 mg/kg, ip) 1 h before MV. Cultured type II alveolar epithelial cells C10 were exposed to 18{\%} cyclic stretch for 2 h with or without 20 nmol/L Wort pretreatment. At the end of the experiment, the capillary leakage in vivo was assessed by extravasation of Evans blue dye (EBD), wet/dry weight ratio and lung lavage protein concentration. The lung tissue and cell lysate were also collected for protein and histological review. Results: MV decreased PI3K/Akt phosphorylation and eNOS expression but increased phospho-p38 MAPK expression along with a lung leakage of EBD. Inhibitions of phospho-Akt by Wort worsen the lung edema, whereas inhibition of p38 MAPK kinase restored activation of Akt together with alleviated capillary leakage. eNOS-/- mice showed an exacerbated lung edema and injury. The stretched C10 cells demonstrated that Wort diminished the activation of Akt, but potentiated phosphorylation of MAPK p38. Conclusion: Our results indicate that PI-3K/Akt/eNOS pathway has significant protective effects in VALI by preventing capillary leakage, and that there is a cross-talk between PI3K/Akt and p38 MAPK pathways in vascular barrier dysfunction resulting from VALI.",
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T1 - Protective role of PI3-kinase/Akt/eNOS signaling in mechanical stress through inhibition of p38 mitogen-activated protein kinase in mouse lung

AU - Peng, Xin Qi

AU - Damarla, Mahendra

AU - Skirball, Jarrett

AU - Nonas, Stephanie

AU - Wang, Xiao Ying

AU - Han, Eugenia J.

AU - Hasan, Emile J.

AU - Cao, Xuan

AU - Boueiz, Adel

AU - Damico, Rachel

AU - Tuder, Rubin M.

AU - Sciuto, Alfred M.

AU - Anderson, Dana R.

AU - Garcia, Joe GN

AU - Kass, David A.

AU - Hassoun, Paul M.

AU - Zhang, Jun Tian

PY - 2010/2

Y1 - 2010/2

N2 - Aim: To test the hypothesis that PI3K/Akt/eNOS signaling has a protective role in a murine model of ventilation associated lung injury (VALI) through down-regulation of p38 MAPK signaling. Methods: Male C57BL/J6 (wild-type, WT) or eNOS knockout mice (eNOS-/-) were exposed to mechanical ventilation (MV) with low (LV T, 7 mL/kg) and high tidal volume (HVT, 20 mL/kg) for 0-4 h. A subset of WT mice was administered the specific inhibitors of PI3K (100 nmol/L Wortmannin [Wort], ip) or of p38 MAPK (SB203580, 2 mg/kg, ip) 1 h before MV. Cultured type II alveolar epithelial cells C10 were exposed to 18% cyclic stretch for 2 h with or without 20 nmol/L Wort pretreatment. At the end of the experiment, the capillary leakage in vivo was assessed by extravasation of Evans blue dye (EBD), wet/dry weight ratio and lung lavage protein concentration. The lung tissue and cell lysate were also collected for protein and histological review. Results: MV decreased PI3K/Akt phosphorylation and eNOS expression but increased phospho-p38 MAPK expression along with a lung leakage of EBD. Inhibitions of phospho-Akt by Wort worsen the lung edema, whereas inhibition of p38 MAPK kinase restored activation of Akt together with alleviated capillary leakage. eNOS-/- mice showed an exacerbated lung edema and injury. The stretched C10 cells demonstrated that Wort diminished the activation of Akt, but potentiated phosphorylation of MAPK p38. Conclusion: Our results indicate that PI-3K/Akt/eNOS pathway has significant protective effects in VALI by preventing capillary leakage, and that there is a cross-talk between PI3K/Akt and p38 MAPK pathways in vascular barrier dysfunction resulting from VALI.

AB - Aim: To test the hypothesis that PI3K/Akt/eNOS signaling has a protective role in a murine model of ventilation associated lung injury (VALI) through down-regulation of p38 MAPK signaling. Methods: Male C57BL/J6 (wild-type, WT) or eNOS knockout mice (eNOS-/-) were exposed to mechanical ventilation (MV) with low (LV T, 7 mL/kg) and high tidal volume (HVT, 20 mL/kg) for 0-4 h. A subset of WT mice was administered the specific inhibitors of PI3K (100 nmol/L Wortmannin [Wort], ip) or of p38 MAPK (SB203580, 2 mg/kg, ip) 1 h before MV. Cultured type II alveolar epithelial cells C10 were exposed to 18% cyclic stretch for 2 h with or without 20 nmol/L Wort pretreatment. At the end of the experiment, the capillary leakage in vivo was assessed by extravasation of Evans blue dye (EBD), wet/dry weight ratio and lung lavage protein concentration. The lung tissue and cell lysate were also collected for protein and histological review. Results: MV decreased PI3K/Akt phosphorylation and eNOS expression but increased phospho-p38 MAPK expression along with a lung leakage of EBD. Inhibitions of phospho-Akt by Wort worsen the lung edema, whereas inhibition of p38 MAPK kinase restored activation of Akt together with alleviated capillary leakage. eNOS-/- mice showed an exacerbated lung edema and injury. The stretched C10 cells demonstrated that Wort diminished the activation of Akt, but potentiated phosphorylation of MAPK p38. Conclusion: Our results indicate that PI-3K/Akt/eNOS pathway has significant protective effects in VALI by preventing capillary leakage, and that there is a cross-talk between PI3K/Akt and p38 MAPK pathways in vascular barrier dysfunction resulting from VALI.

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KW - PI3K/Akt/eNOS

KW - Pulmonary capillary leakage

KW - Pulmonary edema

KW - Signals cross-talk

KW - Ventilator-associated lung injury

KW - Wortmannin

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