Abstract
Introduction: The treatment of septic conditions in critically ill patients is still one of medicine's major challenges. Cyclic nucleotides, adenosine and its receptors play a pivotal role in the regulation of inflammatory responses and in limiting inflammatory tissue destruction. The aim of this study was to verify the hypothesis that adenosine deaminase-1 and cyclic guanosine monophosphate-stimulated phosphodiesterase inhibition by erythro-9-[2-hydroxyl-3-nonyl]-adenine could be beneficial in experimental endotoxicosis/sepsis. Method: We used two established animal models for endotoxicosis and sepsis. Twenty-four male Wistar rats that had been given intravenous endotoxin (Escherichia coli lipopolysaccharide) were treated with either erythro-9-[2-hydroxyl-3-nonyl]-adenine infusion or 0.9% saline during a study length of 120 minutes. Sepsis in 84 female C57BL/6 mice was induced by caecal ligation and puncture. Animals were treated with repeated erythro-9-[2-hydroxyl-3-nonyl]-adenine injections after 0, 12 and 24 hours or 4, 12 and 24 hours for delayed treatment. Results: In endotoxaemic rats, intestinal production of hypoxanthine increased from 9.8 +/- 90.2 μmol/l at baseline to 411.4 +/- 124.6 μmol/l and uric acid formation increased from 1.5 +/- 2.3 mmol/l to 13.1 +/- 2.7 mmol/l after 120 minutes. In endotoxaemic animals treated with erythro-9-[2-hydroxyl-3-nonyl]-adenine, we found no elevation of adenosine metabolites. The lactulose/L-rhamnose ratio (14.3 versus 4.2 in control animals; p = 2.5 × 10-7) reflects a highly permeable small intestine and through the application of erythro-9-[2-hydroxyl-3-nonyl]-adenine, intestinal permeability could be re-established. The lipopolysaccharide animals had decreased L-rhamnose/ 3-O-methyl-D-glucose urine excretion ratios. Erythro-9-[2-hydroxyl-3-nonyl]-adenine reduced this effect. The mucosa damage score of the septic animals was higher compared with control and therapy animals (p <0.05). Septic shock induction by caecal ligation and puncture resulted in a 160-hour survival rate of about 25%. In contrast, direct adenosine deaminase-1 inhibition resulted in a survival rate of about 75% (p = 0.0018). A protective effect was still present when erythro-9-[2-hydroxyl-3-nonyl]-adenine treatment was delayed for four hours (55%, p = 0.029). Conclusions: We present further evidence of the beneficial effects achieved by administering erythro-9-[2-hydroxyl-3-nonyl]-adenine, an adenosine deaminase-1 and cyclic guanosine monophosphate-stimulated phosphodiesterase inhibitor, in an endotoxicosis and sepsis animal model. This suggests a potential therapeutic option in the treatment of septic conditions.
| Original language | English (US) |
|---|---|
| Article number | R125 |
| Journal | Critical Care |
| Volume | 12 |
| Issue number | 5 |
| DOIs | |
| State | Published - Oct 13 2008 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Critical Care and Intensive Care Medicine
- Medicine(all)
Cite this
The adenosine deaminase inhibitor erythro-9-[2-hydroxyl-3-nonyl]-adenine decreases intestinal permeability and protects against experimental sepsis : A prospective, randomised laboratory investigation. / Kayhan, Nalan; Funke, Benjamin; Conzelmann, Lars Oliver; Winkler, Harald; Hofer, Stefan; Steppan, Jochen; Bardenheuer, Hubert; Vahl, Christian Friedrich; Weigand, Markus A.
In: Critical Care, Vol. 12, No. 5, R125, 13.10.2008.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The adenosine deaminase inhibitor erythro-9-[2-hydroxyl-3-nonyl]-adenine decreases intestinal permeability and protects against experimental sepsis
T2 - A prospective, randomised laboratory investigation
AU - Kayhan, Nalan
AU - Funke, Benjamin
AU - Conzelmann, Lars Oliver
AU - Winkler, Harald
AU - Hofer, Stefan
AU - Steppan, Jochen
AU - Bardenheuer, Hubert
AU - Vahl, Christian Friedrich
AU - Weigand, Markus A.
PY - 2008/10/13
Y1 - 2008/10/13
N2 - Introduction: The treatment of septic conditions in critically ill patients is still one of medicine's major challenges. Cyclic nucleotides, adenosine and its receptors play a pivotal role in the regulation of inflammatory responses and in limiting inflammatory tissue destruction. The aim of this study was to verify the hypothesis that adenosine deaminase-1 and cyclic guanosine monophosphate-stimulated phosphodiesterase inhibition by erythro-9-[2-hydroxyl-3-nonyl]-adenine could be beneficial in experimental endotoxicosis/sepsis. Method: We used two established animal models for endotoxicosis and sepsis. Twenty-four male Wistar rats that had been given intravenous endotoxin (Escherichia coli lipopolysaccharide) were treated with either erythro-9-[2-hydroxyl-3-nonyl]-adenine infusion or 0.9% saline during a study length of 120 minutes. Sepsis in 84 female C57BL/6 mice was induced by caecal ligation and puncture. Animals were treated with repeated erythro-9-[2-hydroxyl-3-nonyl]-adenine injections after 0, 12 and 24 hours or 4, 12 and 24 hours for delayed treatment. Results: In endotoxaemic rats, intestinal production of hypoxanthine increased from 9.8 +/- 90.2 μmol/l at baseline to 411.4 +/- 124.6 μmol/l and uric acid formation increased from 1.5 +/- 2.3 mmol/l to 13.1 +/- 2.7 mmol/l after 120 minutes. In endotoxaemic animals treated with erythro-9-[2-hydroxyl-3-nonyl]-adenine, we found no elevation of adenosine metabolites. The lactulose/L-rhamnose ratio (14.3 versus 4.2 in control animals; p = 2.5 × 10-7) reflects a highly permeable small intestine and through the application of erythro-9-[2-hydroxyl-3-nonyl]-adenine, intestinal permeability could be re-established. The lipopolysaccharide animals had decreased L-rhamnose/ 3-O-methyl-D-glucose urine excretion ratios. Erythro-9-[2-hydroxyl-3-nonyl]-adenine reduced this effect. The mucosa damage score of the septic animals was higher compared with control and therapy animals (p <0.05). Septic shock induction by caecal ligation and puncture resulted in a 160-hour survival rate of about 25%. In contrast, direct adenosine deaminase-1 inhibition resulted in a survival rate of about 75% (p = 0.0018). A protective effect was still present when erythro-9-[2-hydroxyl-3-nonyl]-adenine treatment was delayed for four hours (55%, p = 0.029). Conclusions: We present further evidence of the beneficial effects achieved by administering erythro-9-[2-hydroxyl-3-nonyl]-adenine, an adenosine deaminase-1 and cyclic guanosine monophosphate-stimulated phosphodiesterase inhibitor, in an endotoxicosis and sepsis animal model. This suggests a potential therapeutic option in the treatment of septic conditions.
AB - Introduction: The treatment of septic conditions in critically ill patients is still one of medicine's major challenges. Cyclic nucleotides, adenosine and its receptors play a pivotal role in the regulation of inflammatory responses and in limiting inflammatory tissue destruction. The aim of this study was to verify the hypothesis that adenosine deaminase-1 and cyclic guanosine monophosphate-stimulated phosphodiesterase inhibition by erythro-9-[2-hydroxyl-3-nonyl]-adenine could be beneficial in experimental endotoxicosis/sepsis. Method: We used two established animal models for endotoxicosis and sepsis. Twenty-four male Wistar rats that had been given intravenous endotoxin (Escherichia coli lipopolysaccharide) were treated with either erythro-9-[2-hydroxyl-3-nonyl]-adenine infusion or 0.9% saline during a study length of 120 minutes. Sepsis in 84 female C57BL/6 mice was induced by caecal ligation and puncture. Animals were treated with repeated erythro-9-[2-hydroxyl-3-nonyl]-adenine injections after 0, 12 and 24 hours or 4, 12 and 24 hours for delayed treatment. Results: In endotoxaemic rats, intestinal production of hypoxanthine increased from 9.8 +/- 90.2 μmol/l at baseline to 411.4 +/- 124.6 μmol/l and uric acid formation increased from 1.5 +/- 2.3 mmol/l to 13.1 +/- 2.7 mmol/l after 120 minutes. In endotoxaemic animals treated with erythro-9-[2-hydroxyl-3-nonyl]-adenine, we found no elevation of adenosine metabolites. The lactulose/L-rhamnose ratio (14.3 versus 4.2 in control animals; p = 2.5 × 10-7) reflects a highly permeable small intestine and through the application of erythro-9-[2-hydroxyl-3-nonyl]-adenine, intestinal permeability could be re-established. The lipopolysaccharide animals had decreased L-rhamnose/ 3-O-methyl-D-glucose urine excretion ratios. Erythro-9-[2-hydroxyl-3-nonyl]-adenine reduced this effect. The mucosa damage score of the septic animals was higher compared with control and therapy animals (p <0.05). Septic shock induction by caecal ligation and puncture resulted in a 160-hour survival rate of about 25%. In contrast, direct adenosine deaminase-1 inhibition resulted in a survival rate of about 75% (p = 0.0018). A protective effect was still present when erythro-9-[2-hydroxyl-3-nonyl]-adenine treatment was delayed for four hours (55%, p = 0.029). Conclusions: We present further evidence of the beneficial effects achieved by administering erythro-9-[2-hydroxyl-3-nonyl]-adenine, an adenosine deaminase-1 and cyclic guanosine monophosphate-stimulated phosphodiesterase inhibitor, in an endotoxicosis and sepsis animal model. This suggests a potential therapeutic option in the treatment of septic conditions.
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U2 - 10.1186/cc7033
DO - 10.1186/cc7033
M3 - Article
VL - 12
JO - Critical Care
JF - Critical Care
SN - 1364-8535
IS - 5
M1 - R125
ER -