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Cytokines induce small intestine and liver injury after renal ischemia or nephrectomy.

Park SW, Chen SW, Kim M, Brown KM, Kolls JK, D'Agati VD, Lee HT - Lab. Invest. (2010)

Bottom Line: Small intestine histology after AKI showed profound villous lacteal capillary endothelial apoptosis, disruption of vascular permeability and epithelial necrosis.Small intestine appears to be the source of IL-17A, as IL-17A levels were higher in the portal circulation and small intestine compared with the levels measured from the systemic circulation and liver.Modulation of the inflammatory response and cytokine release in the small intestine after AKI may have important therapeutic implications in reducing complications arising from AKI.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, NY 10032-3784, USA.

ABSTRACT
Patients with acute kidney injury (AKI) frequently suffer from extra-renal complications including hepatic dysfunction and systemic inflammation. We aimed to determine the mechanisms of AKI-induced hepatic dysfunction and systemic inflammation. Mice subjected to AKI (renal ischemia reperfusion (IR) or nephrectomy) rapidly developed acute hepatic dysfunction and suffered significantly worse hepatic IR injury. After AKI, rapid peri-portal hepatocyte necrosis, vacuolization, neutrophil infiltration and pro-inflammatory mRNA upregulation were observed suggesting an intestinal source of hepatic injury. Small intestine histology after AKI showed profound villous lacteal capillary endothelial apoptosis, disruption of vascular permeability and epithelial necrosis. After ischemic or non-ischemic AKI, plasma TNF-α, IL-17A and IL-6 increased significantly. Small intestine appears to be the source of IL-17A, as IL-17A levels were higher in the portal circulation and small intestine compared with the levels measured from the systemic circulation and liver. Wild-type mice treated with neutralizing antibodies against TNF-α, IL-17A or IL-6 or mice deficient in TNF-α, IL-17A, IL-17A receptor or IL-6 were protected against hepatic and small intestine injury because of ischemic or non-ischemic AKI. For the first time, we implicate the increased release of IL-17A from small intestine together with induction of TNF-α and IL-6 as a cause of small intestine and liver injury after ischemic or non-ischemic AKI. Modulation of the inflammatory response and cytokine release in the small intestine after AKI may have important therapeutic implications in reducing complications arising from AKI.

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Increased hepatic vascular permeability after ischemic or non-ischemic AKI(Left) Representative photographs of liver isolated from mice subjected to sham-operation or to bilateral nephrectomy (BNx) 5 hrs prior and injected with Evans blue dye (EBD). (Right) Quantification of liver EBD extravasations in mice subjected to sham-operation (N=6), bilateral nephrectomy (BNx) or 30 min. renal IR (RIR). Five hrs after surgery, EBD was extracted in formamide and the amount of extravasated EBD in the liver was calculated against a standard curve. *P<0.05 vs. sham-operated mice. Error bars represent 1 SEM.
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Figure 4: Increased hepatic vascular permeability after ischemic or non-ischemic AKI(Left) Representative photographs of liver isolated from mice subjected to sham-operation or to bilateral nephrectomy (BNx) 5 hrs prior and injected with Evans blue dye (EBD). (Right) Quantification of liver EBD extravasations in mice subjected to sham-operation (N=6), bilateral nephrectomy (BNx) or 30 min. renal IR (RIR). Five hrs after surgery, EBD was extracted in formamide and the amount of extravasated EBD in the liver was calculated against a standard curve. *P<0.05 vs. sham-operated mice. Error bars represent 1 SEM.

Mentions: We also observed increased number of apoptotic nuclei in the liver of mice subjected to 30 min. renal IR (TUNEL positive cells, Supplemental Figure 1) or bilateral nephrectomy (data not shown). TUNEL positive cells were heavily localized to the peri-portal area. DNA laddering experiments confirmed increased apoptosis in the liver after 30 min. renal IR or bilateral nephrectomy (Supplemental Figure 2). We also measured liver vascular permeability after 30 min. renal IR or bilateral nephrectomy with EBD injection. EBD binds to plasma proteins and its appearance in extravascular tissues reflects an increase in vascular permeability. Analysis demonstrating increased EBD extravasations in livers of mice subjected to ischemic (30 min. renal IR) or non-ischemic (bilateral nephrectomy) AKI is shown in Figure 4.


Cytokines induce small intestine and liver injury after renal ischemia or nephrectomy.

Park SW, Chen SW, Kim M, Brown KM, Kolls JK, D'Agati VD, Lee HT - Lab. Invest. (2010)

Increased hepatic vascular permeability after ischemic or non-ischemic AKI(Left) Representative photographs of liver isolated from mice subjected to sham-operation or to bilateral nephrectomy (BNx) 5 hrs prior and injected with Evans blue dye (EBD). (Right) Quantification of liver EBD extravasations in mice subjected to sham-operation (N=6), bilateral nephrectomy (BNx) or 30 min. renal IR (RIR). Five hrs after surgery, EBD was extracted in formamide and the amount of extravasated EBD in the liver was calculated against a standard curve. *P<0.05 vs. sham-operated mice. Error bars represent 1 SEM.
© Copyright Policy
Related In: Results  -  Collection

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Figure 4: Increased hepatic vascular permeability after ischemic or non-ischemic AKI(Left) Representative photographs of liver isolated from mice subjected to sham-operation or to bilateral nephrectomy (BNx) 5 hrs prior and injected with Evans blue dye (EBD). (Right) Quantification of liver EBD extravasations in mice subjected to sham-operation (N=6), bilateral nephrectomy (BNx) or 30 min. renal IR (RIR). Five hrs after surgery, EBD was extracted in formamide and the amount of extravasated EBD in the liver was calculated against a standard curve. *P<0.05 vs. sham-operated mice. Error bars represent 1 SEM.
Mentions: We also observed increased number of apoptotic nuclei in the liver of mice subjected to 30 min. renal IR (TUNEL positive cells, Supplemental Figure 1) or bilateral nephrectomy (data not shown). TUNEL positive cells were heavily localized to the peri-portal area. DNA laddering experiments confirmed increased apoptosis in the liver after 30 min. renal IR or bilateral nephrectomy (Supplemental Figure 2). We also measured liver vascular permeability after 30 min. renal IR or bilateral nephrectomy with EBD injection. EBD binds to plasma proteins and its appearance in extravascular tissues reflects an increase in vascular permeability. Analysis demonstrating increased EBD extravasations in livers of mice subjected to ischemic (30 min. renal IR) or non-ischemic (bilateral nephrectomy) AKI is shown in Figure 4.

Bottom Line: Small intestine histology after AKI showed profound villous lacteal capillary endothelial apoptosis, disruption of vascular permeability and epithelial necrosis.Small intestine appears to be the source of IL-17A, as IL-17A levels were higher in the portal circulation and small intestine compared with the levels measured from the systemic circulation and liver.Modulation of the inflammatory response and cytokine release in the small intestine after AKI may have important therapeutic implications in reducing complications arising from AKI.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, NY 10032-3784, USA.

ABSTRACT
Patients with acute kidney injury (AKI) frequently suffer from extra-renal complications including hepatic dysfunction and systemic inflammation. We aimed to determine the mechanisms of AKI-induced hepatic dysfunction and systemic inflammation. Mice subjected to AKI (renal ischemia reperfusion (IR) or nephrectomy) rapidly developed acute hepatic dysfunction and suffered significantly worse hepatic IR injury. After AKI, rapid peri-portal hepatocyte necrosis, vacuolization, neutrophil infiltration and pro-inflammatory mRNA upregulation were observed suggesting an intestinal source of hepatic injury. Small intestine histology after AKI showed profound villous lacteal capillary endothelial apoptosis, disruption of vascular permeability and epithelial necrosis. After ischemic or non-ischemic AKI, plasma TNF-α, IL-17A and IL-6 increased significantly. Small intestine appears to be the source of IL-17A, as IL-17A levels were higher in the portal circulation and small intestine compared with the levels measured from the systemic circulation and liver. Wild-type mice treated with neutralizing antibodies against TNF-α, IL-17A or IL-6 or mice deficient in TNF-α, IL-17A, IL-17A receptor or IL-6 were protected against hepatic and small intestine injury because of ischemic or non-ischemic AKI. For the first time, we implicate the increased release of IL-17A from small intestine together with induction of TNF-α and IL-6 as a cause of small intestine and liver injury after ischemic or non-ischemic AKI. Modulation of the inflammatory response and cytokine release in the small intestine after AKI may have important therapeutic implications in reducing complications arising from AKI.

Show MeSH
Related in: MedlinePlus