Liver damage and systemic inflammatory responses are exacerbated by the genetic deletion of CD39 in total hepatic ischemia

Xiaofeng Sun, Masato Imai, Martina Nowak-Machen, Olaf Guckelberger, Keiichi Enjyoji, Yan Wu, Zain I Khalpey, Pascal Berberat, Jeeva Munasinghe, Simon Christopher Robson

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Liver ischemia reperfusion injury is associated with both local damage to the hepatic vasculature and systemic inflammatory responses. CD39 is the dominant vascular endothelial cell ectonucleotidase and rapidly hydrolyses both adenosine triphosphate (ATP) and adenosine diphosphate to adenosine monophosphate. These biochemical properties, in tandem with 5′-nucleotidases, generate adenosine and potentially illicit inflammatory vascular responses and thrombosis. We have evaluated the role of CD39 in total hepatic ischemia reperfusion injury (IRI). Wildtype mice, Cd39-hemizygous mice (+/-) and matched Cd39-null mice (-/-); (n = 25 per group) underwent 45 min of total warm ischemia with full inflow occlusion necessitating partial hepatectomy. Soluble nucleoside triphosphate diphosphohydrolase (NTPDases) or adenosine/amrinone were administered to wildtype (n = 6) and Cd39-null mice (n = 6) in order to study protective effects in vivo. Parameters of liver injury, systemic inflammation, hepatic ATP determinations by P31-NMR and parameters of lung injury were obtained. All wildtype mice survived up to 7 days with minimal biochemical disturbances and minor evidence for injury. In contrast, 64% of Cd39+/- and 84% of Cd39-null mice required euthanasia or died within 4 h post-reperfusion with liver damage and systemic inflammation associated with hypercytokinemia. Hepatic ATP depletion was pronounced in Cd39-null mice posthepatic IRI. Soluble NTPDase or adenosine administration protected Cd39-deficient mice from acute reperfusion injury. We conclude that CD39 is protective in hepatic IRI preventing local injury and systemic inflammation in an adenosine dependent manner. Our data indicate that vascular CD39 expression has an essential protective role in hepatic IRI.

Original languageEnglish (US)
Pages (from-to)427-434
Number of pages8
JournalPurinergic Signalling
Volume7
Issue number4
DOIs
StatePublished - Dec 2011
Externally publishedYes

Fingerprint

Ischemia
Reperfusion Injury
Liver
Adenosine
Adenosine Triphosphate
Inflammation
Blood Vessels
Wounds and Injuries
Amrinone
Warm Ischemia
5'-Nucleotidase
Euthanasia
Hepatectomy
Lung Injury
Nucleosides
Reperfusion
Thrombosis
Endothelial Cells

Keywords

  • CD39
  • Hepatic ischemia reperfusion
  • Vascular endothelium

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Cellular and Molecular Neuroscience

Cite this

Liver damage and systemic inflammatory responses are exacerbated by the genetic deletion of CD39 in total hepatic ischemia. / Sun, Xiaofeng; Imai, Masato; Nowak-Machen, Martina; Guckelberger, Olaf; Enjyoji, Keiichi; Wu, Yan; Khalpey, Zain I; Berberat, Pascal; Munasinghe, Jeeva; Robson, Simon Christopher.

In: Purinergic Signalling, Vol. 7, No. 4, 12.2011, p. 427-434.

Research output: Contribution to journalArticle

Sun, X, Imai, M, Nowak-Machen, M, Guckelberger, O, Enjyoji, K, Wu, Y, Khalpey, ZI, Berberat, P, Munasinghe, J & Robson, SC 2011, 'Liver damage and systemic inflammatory responses are exacerbated by the genetic deletion of CD39 in total hepatic ischemia', Purinergic Signalling, vol. 7, no. 4, pp. 427-434. https://doi.org/10.1007/s11302-011-9239-6
Sun, Xiaofeng ; Imai, Masato ; Nowak-Machen, Martina ; Guckelberger, Olaf ; Enjyoji, Keiichi ; Wu, Yan ; Khalpey, Zain I ; Berberat, Pascal ; Munasinghe, Jeeva ; Robson, Simon Christopher. / Liver damage and systemic inflammatory responses are exacerbated by the genetic deletion of CD39 in total hepatic ischemia. In: Purinergic Signalling. 2011 ; Vol. 7, No. 4. pp. 427-434.
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T1 - Liver damage and systemic inflammatory responses are exacerbated by the genetic deletion of CD39 in total hepatic ischemia

AU - Sun, Xiaofeng

AU - Imai, Masato

AU - Nowak-Machen, Martina

AU - Guckelberger, Olaf

AU - Enjyoji, Keiichi

AU - Wu, Yan

AU - Khalpey, Zain I

AU - Berberat, Pascal

AU - Munasinghe, Jeeva

AU - Robson, Simon Christopher

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N2 - Liver ischemia reperfusion injury is associated with both local damage to the hepatic vasculature and systemic inflammatory responses. CD39 is the dominant vascular endothelial cell ectonucleotidase and rapidly hydrolyses both adenosine triphosphate (ATP) and adenosine diphosphate to adenosine monophosphate. These biochemical properties, in tandem with 5′-nucleotidases, generate adenosine and potentially illicit inflammatory vascular responses and thrombosis. We have evaluated the role of CD39 in total hepatic ischemia reperfusion injury (IRI). Wildtype mice, Cd39-hemizygous mice (+/-) and matched Cd39-null mice (-/-); (n = 25 per group) underwent 45 min of total warm ischemia with full inflow occlusion necessitating partial hepatectomy. Soluble nucleoside triphosphate diphosphohydrolase (NTPDases) or adenosine/amrinone were administered to wildtype (n = 6) and Cd39-null mice (n = 6) in order to study protective effects in vivo. Parameters of liver injury, systemic inflammation, hepatic ATP determinations by P31-NMR and parameters of lung injury were obtained. All wildtype mice survived up to 7 days with minimal biochemical disturbances and minor evidence for injury. In contrast, 64% of Cd39+/- and 84% of Cd39-null mice required euthanasia or died within 4 h post-reperfusion with liver damage and systemic inflammation associated with hypercytokinemia. Hepatic ATP depletion was pronounced in Cd39-null mice posthepatic IRI. Soluble NTPDase or adenosine administration protected Cd39-deficient mice from acute reperfusion injury. We conclude that CD39 is protective in hepatic IRI preventing local injury and systemic inflammation in an adenosine dependent manner. Our data indicate that vascular CD39 expression has an essential protective role in hepatic IRI.

AB - Liver ischemia reperfusion injury is associated with both local damage to the hepatic vasculature and systemic inflammatory responses. CD39 is the dominant vascular endothelial cell ectonucleotidase and rapidly hydrolyses both adenosine triphosphate (ATP) and adenosine diphosphate to adenosine monophosphate. These biochemical properties, in tandem with 5′-nucleotidases, generate adenosine and potentially illicit inflammatory vascular responses and thrombosis. We have evaluated the role of CD39 in total hepatic ischemia reperfusion injury (IRI). Wildtype mice, Cd39-hemizygous mice (+/-) and matched Cd39-null mice (-/-); (n = 25 per group) underwent 45 min of total warm ischemia with full inflow occlusion necessitating partial hepatectomy. Soluble nucleoside triphosphate diphosphohydrolase (NTPDases) or adenosine/amrinone were administered to wildtype (n = 6) and Cd39-null mice (n = 6) in order to study protective effects in vivo. Parameters of liver injury, systemic inflammation, hepatic ATP determinations by P31-NMR and parameters of lung injury were obtained. All wildtype mice survived up to 7 days with minimal biochemical disturbances and minor evidence for injury. In contrast, 64% of Cd39+/- and 84% of Cd39-null mice required euthanasia or died within 4 h post-reperfusion with liver damage and systemic inflammation associated with hypercytokinemia. Hepatic ATP depletion was pronounced in Cd39-null mice posthepatic IRI. Soluble NTPDase or adenosine administration protected Cd39-deficient mice from acute reperfusion injury. We conclude that CD39 is protective in hepatic IRI preventing local injury and systemic inflammation in an adenosine dependent manner. Our data indicate that vascular CD39 expression has an essential protective role in hepatic IRI.

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KW - Hepatic ischemia reperfusion

KW - Vascular endothelium

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