Ketone and pyruvate Ringer's solutions decrease pulmonary apoptosis in a rat model of severe hemorrhagic shock and resuscitation

Elena Koustova, Peter M Rhee, Timothy Hancock, Huazhen Chen, Ryan Inocencio, Amin Jaskille, William Hanes, C. Robert Valeri, Hasan B. Alam

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Background. Resuscitation fluids containing β-hydroxybutyrate (BHB) have been shown to decrease cellular injury after hemorrhagic shock and resuscitation through an unknown mechanism. We tested whether this effect was related to BHB-induced metabolic modulations. Methods. Male Sprague Dawley rats (n=30) were subjected to volume-controlled hemorrhage (27 mL/kg during 10 minutes followed by 75 minutes of shock during which another 8 mL/kg of blood was withdrawn). Experimental groups included the following: (1) sham, (2) no resuscitation (NR), (3) racemic lactated Ringer's (DL-LR) solution, (4) LR containing L-isomer only (L-LR), (5) ketone Ringer's solution with lactate substituted by BHB (KR), and (6) pyruvate Ringer's solution with lactate substituted by pyruvate (PR). The resuscitation fluids were infused during 45 minutes simultaneously with additional hemorrhage of 8 mL/kg. Hemodynamic and physiologic parameters and the plasma levels of BHB were serially measured. The animals were killed 2 hours after resuscitation, and tissues were frozen instantaneously for cellular adenylate extraction and adenosine triphosphate (ATP) and adenosine diphosphate analysis. Pulmonary apoptosis was studied using Western blotting, immunohistochemistry, and reverse transcriptases-polymerase chain reaction. Expression of enzymes involved in ketogenesis and ketolysis was analyzed by reverse transcriptases-polymerase chain reaction. Results. NR and resuscitation with DL-LR increased the expression of apoptotic markers, whereas resuscitation with KR and PR significantly decreased the expression of apoptotic markers in rat lungs. Resuscitation with KR was followed by a profound increase in plasma BHB levels; however, the expression levels of ketolytic enzymes were essentially unaffected. KR infusion did not induce significant improvements in tissue ATP levels. Conclusion. Resuscitation with KR and PR protects against pulmonary apoptosis without improving tissue ATP content. Therefore, metabolic modulation is unlikely to be the major mechanism by which BHB exerts its protective effects during reperfusion.

Original languageEnglish (US)
Pages (from-to)267-274
Number of pages8
JournalSurgery
Volume134
Issue number2
DOIs
StatePublished - Aug 1 2003
Externally publishedYes

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Hemorrhagic Shock
Ketones
Pyruvic Acid
Resuscitation
Apoptosis
Lung
Adenosine Triphosphate
Reverse Transcriptase Polymerase Chain Reaction
Lactic Acid
Ringer's solution
Hemorrhage
Hydroxybutyrates
Enzymes
Adenosine Diphosphate
Reperfusion
Sprague Dawley Rats
Shock
Hemodynamics
Western Blotting
Immunohistochemistry

ASJC Scopus subject areas

  • Surgery

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Ketone and pyruvate Ringer's solutions decrease pulmonary apoptosis in a rat model of severe hemorrhagic shock and resuscitation. / Koustova, Elena; Rhee, Peter M; Hancock, Timothy; Chen, Huazhen; Inocencio, Ryan; Jaskille, Amin; Hanes, William; Valeri, C. Robert; Alam, Hasan B.

In: Surgery, Vol. 134, No. 2, 01.08.2003, p. 267-274.

Research output: Contribution to journalArticle

Koustova, E, Rhee, PM, Hancock, T, Chen, H, Inocencio, R, Jaskille, A, Hanes, W, Valeri, CR & Alam, HB 2003, 'Ketone and pyruvate Ringer's solutions decrease pulmonary apoptosis in a rat model of severe hemorrhagic shock and resuscitation', Surgery, vol. 134, no. 2, pp. 267-274. https://doi.org/10.1067/msy.2003.245
Koustova, Elena ; Rhee, Peter M ; Hancock, Timothy ; Chen, Huazhen ; Inocencio, Ryan ; Jaskille, Amin ; Hanes, William ; Valeri, C. Robert ; Alam, Hasan B. / Ketone and pyruvate Ringer's solutions decrease pulmonary apoptosis in a rat model of severe hemorrhagic shock and resuscitation. In: Surgery. 2003 ; Vol. 134, No. 2. pp. 267-274.
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abstract = "Background. Resuscitation fluids containing β-hydroxybutyrate (BHB) have been shown to decrease cellular injury after hemorrhagic shock and resuscitation through an unknown mechanism. We tested whether this effect was related to BHB-induced metabolic modulations. Methods. Male Sprague Dawley rats (n=30) were subjected to volume-controlled hemorrhage (27 mL/kg during 10 minutes followed by 75 minutes of shock during which another 8 mL/kg of blood was withdrawn). Experimental groups included the following: (1) sham, (2) no resuscitation (NR), (3) racemic lactated Ringer's (DL-LR) solution, (4) LR containing L-isomer only (L-LR), (5) ketone Ringer's solution with lactate substituted by BHB (KR), and (6) pyruvate Ringer's solution with lactate substituted by pyruvate (PR). The resuscitation fluids were infused during 45 minutes simultaneously with additional hemorrhage of 8 mL/kg. Hemodynamic and physiologic parameters and the plasma levels of BHB were serially measured. The animals were killed 2 hours after resuscitation, and tissues were frozen instantaneously for cellular adenylate extraction and adenosine triphosphate (ATP) and adenosine diphosphate analysis. Pulmonary apoptosis was studied using Western blotting, immunohistochemistry, and reverse transcriptases-polymerase chain reaction. Expression of enzymes involved in ketogenesis and ketolysis was analyzed by reverse transcriptases-polymerase chain reaction. Results. NR and resuscitation with DL-LR increased the expression of apoptotic markers, whereas resuscitation with KR and PR significantly decreased the expression of apoptotic markers in rat lungs. Resuscitation with KR was followed by a profound increase in plasma BHB levels; however, the expression levels of ketolytic enzymes were essentially unaffected. KR infusion did not induce significant improvements in tissue ATP levels. Conclusion. Resuscitation with KR and PR protects against pulmonary apoptosis without improving tissue ATP content. Therefore, metabolic modulation is unlikely to be the major mechanism by which BHB exerts its protective effects during reperfusion.",
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T1 - Ketone and pyruvate Ringer's solutions decrease pulmonary apoptosis in a rat model of severe hemorrhagic shock and resuscitation

AU - Koustova, Elena

AU - Rhee, Peter M

AU - Hancock, Timothy

AU - Chen, Huazhen

AU - Inocencio, Ryan

AU - Jaskille, Amin

AU - Hanes, William

AU - Valeri, C. Robert

AU - Alam, Hasan B.

PY - 2003/8/1

Y1 - 2003/8/1

N2 - Background. Resuscitation fluids containing β-hydroxybutyrate (BHB) have been shown to decrease cellular injury after hemorrhagic shock and resuscitation through an unknown mechanism. We tested whether this effect was related to BHB-induced metabolic modulations. Methods. Male Sprague Dawley rats (n=30) were subjected to volume-controlled hemorrhage (27 mL/kg during 10 minutes followed by 75 minutes of shock during which another 8 mL/kg of blood was withdrawn). Experimental groups included the following: (1) sham, (2) no resuscitation (NR), (3) racemic lactated Ringer's (DL-LR) solution, (4) LR containing L-isomer only (L-LR), (5) ketone Ringer's solution with lactate substituted by BHB (KR), and (6) pyruvate Ringer's solution with lactate substituted by pyruvate (PR). The resuscitation fluids were infused during 45 minutes simultaneously with additional hemorrhage of 8 mL/kg. Hemodynamic and physiologic parameters and the plasma levels of BHB were serially measured. The animals were killed 2 hours after resuscitation, and tissues were frozen instantaneously for cellular adenylate extraction and adenosine triphosphate (ATP) and adenosine diphosphate analysis. Pulmonary apoptosis was studied using Western blotting, immunohistochemistry, and reverse transcriptases-polymerase chain reaction. Expression of enzymes involved in ketogenesis and ketolysis was analyzed by reverse transcriptases-polymerase chain reaction. Results. NR and resuscitation with DL-LR increased the expression of apoptotic markers, whereas resuscitation with KR and PR significantly decreased the expression of apoptotic markers in rat lungs. Resuscitation with KR was followed by a profound increase in plasma BHB levels; however, the expression levels of ketolytic enzymes were essentially unaffected. KR infusion did not induce significant improvements in tissue ATP levels. Conclusion. Resuscitation with KR and PR protects against pulmonary apoptosis without improving tissue ATP content. Therefore, metabolic modulation is unlikely to be the major mechanism by which BHB exerts its protective effects during reperfusion.

AB - Background. Resuscitation fluids containing β-hydroxybutyrate (BHB) have been shown to decrease cellular injury after hemorrhagic shock and resuscitation through an unknown mechanism. We tested whether this effect was related to BHB-induced metabolic modulations. Methods. Male Sprague Dawley rats (n=30) were subjected to volume-controlled hemorrhage (27 mL/kg during 10 minutes followed by 75 minutes of shock during which another 8 mL/kg of blood was withdrawn). Experimental groups included the following: (1) sham, (2) no resuscitation (NR), (3) racemic lactated Ringer's (DL-LR) solution, (4) LR containing L-isomer only (L-LR), (5) ketone Ringer's solution with lactate substituted by BHB (KR), and (6) pyruvate Ringer's solution with lactate substituted by pyruvate (PR). The resuscitation fluids were infused during 45 minutes simultaneously with additional hemorrhage of 8 mL/kg. Hemodynamic and physiologic parameters and the plasma levels of BHB were serially measured. The animals were killed 2 hours after resuscitation, and tissues were frozen instantaneously for cellular adenylate extraction and adenosine triphosphate (ATP) and adenosine diphosphate analysis. Pulmonary apoptosis was studied using Western blotting, immunohistochemistry, and reverse transcriptases-polymerase chain reaction. Expression of enzymes involved in ketogenesis and ketolysis was analyzed by reverse transcriptases-polymerase chain reaction. Results. NR and resuscitation with DL-LR increased the expression of apoptotic markers, whereas resuscitation with KR and PR significantly decreased the expression of apoptotic markers in rat lungs. Resuscitation with KR was followed by a profound increase in plasma BHB levels; however, the expression levels of ketolytic enzymes were essentially unaffected. KR infusion did not induce significant improvements in tissue ATP levels. Conclusion. Resuscitation with KR and PR protects against pulmonary apoptosis without improving tissue ATP content. Therefore, metabolic modulation is unlikely to be the major mechanism by which BHB exerts its protective effects during reperfusion.

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