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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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Exacerbated hepatic IR injury (necrosis, apoptosis and inflammation) after ischemic or non-ischemic AKIA. Plasma alanine aminotransferase (ALT) levels in mice subjected to sham-operation (Sham, N=4), 45 min. hepatic ischemia and reperfusion (HIR, N=6), HIR coupled with unilateral nephrectomy (UNx+HIR, N=6), HIR coupled with bilateral nephrectomy (BNx+HIR, N=6) or HIR coupled with 20 min. renal ischemia and reperfusion (RIR+HIR, N=8) 24 hrs prior. *P<0.05 vs. HIR mice. Error bars represent 1 SEM. B. Representative hematoxylin and eosin staining photomicrographs in liver sections (magnification X40) in mice subjected to sham-operation, 45 min. hepatic ischemia and reperfusion (HIR), HIR coupled with bilateral nephrectomy or HIR coupled with 20 min. renal ischemia and reperfusion 24 hrs prior. Necrotic hepatic tissue appears as light pink. Arrows indicate vascular congestion and inflammation. C. Representative fluorescence photomicrographs (of 4 experiments) of liver sections illustrating apoptotic nuclei [terminal deoxynucleotidyl transferase biotin-dUTP nick end-labeling (TUNEL) fluorescence staining, 100X] from mice subjected to 45 min. hepatic ischemia and reperfusion (HIR) or HIR coupled with 20 min. renal ischemia and reperfusion 24 hrs prior. D. Representative gel images (top) and band intensity quantifications (bottom) of semi-quantitative RT-PCR of the pro-inflammatory markers ICAM-1, IL-6 and MCP-1 from liver tissues of mice subjected to sham-operation (Sham), 20 min. renal ischemia and reperfusion (RIR), 45 min hepatic ischemia and reperfusion (HIR) or 20 min RIR plus HIR. Liver tissues were harvested 5 hrs after sham-operation or AKI induction. *P<0.05 vs. sham-operated mice. Error bars represent 1 SEM. #P<0.01 vs. HIR mice.
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Figure 5: Exacerbated hepatic IR injury (necrosis, apoptosis and inflammation) after ischemic or non-ischemic AKIA. Plasma alanine aminotransferase (ALT) levels in mice subjected to sham-operation (Sham, N=4), 45 min. hepatic ischemia and reperfusion (HIR, N=6), HIR coupled with unilateral nephrectomy (UNx+HIR, N=6), HIR coupled with bilateral nephrectomy (BNx+HIR, N=6) or HIR coupled with 20 min. renal ischemia and reperfusion (RIR+HIR, N=8) 24 hrs prior. *P<0.05 vs. HIR mice. Error bars represent 1 SEM. B. Representative hematoxylin and eosin staining photomicrographs in liver sections (magnification X40) in mice subjected to sham-operation, 45 min. hepatic ischemia and reperfusion (HIR), HIR coupled with bilateral nephrectomy or HIR coupled with 20 min. renal ischemia and reperfusion 24 hrs prior. Necrotic hepatic tissue appears as light pink. Arrows indicate vascular congestion and inflammation. C. Representative fluorescence photomicrographs (of 4 experiments) of liver sections illustrating apoptotic nuclei [terminal deoxynucleotidyl transferase biotin-dUTP nick end-labeling (TUNEL) fluorescence staining, 100X] from mice subjected to 45 min. hepatic ischemia and reperfusion (HIR) or HIR coupled with 20 min. renal ischemia and reperfusion 24 hrs prior. D. Representative gel images (top) and band intensity quantifications (bottom) of semi-quantitative RT-PCR of the pro-inflammatory markers ICAM-1, IL-6 and MCP-1 from liver tissues of mice subjected to sham-operation (Sham), 20 min. renal ischemia and reperfusion (RIR), 45 min hepatic ischemia and reperfusion (HIR) or 20 min RIR plus HIR. Liver tissues were harvested 5 hrs after sham-operation or AKI induction. *P<0.05 vs. sham-operated mice. Error bars represent 1 SEM. #P<0.01 vs. HIR mice.

Mentions: We also induced liver IR injury in mice subjected to sham-operation, unilateral or bilateral nephrectomy or 20 min. renal IR injury. We determined that mice subjected to hepatic IR together with ischemic (20 min. renal IR) or non-ischemic (unilateral or bilateral nephrectomy) AKI developed significantly exacerbated hepatic injury with significant higher plasma ALT at 24 hrs after liver IR (Figure 5A). Exacerbation of hepatic injury (20 min. renal IR) or non-ischemic (bilateral nephrectomy) AKI was associated the increased hepatic necrosis (Figure 5B), apoptosis (Figure 5C) and inflammation (Figure 5D) compared to mice subjected to hepatic IR alone.


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)

Exacerbated hepatic IR injury (necrosis, apoptosis and inflammation) after ischemic or non-ischemic AKIA. Plasma alanine aminotransferase (ALT) levels in mice subjected to sham-operation (Sham, N=4), 45 min. hepatic ischemia and reperfusion (HIR, N=6), HIR coupled with unilateral nephrectomy (UNx+HIR, N=6), HIR coupled with bilateral nephrectomy (BNx+HIR, N=6) or HIR coupled with 20 min. renal ischemia and reperfusion (RIR+HIR, N=8) 24 hrs prior. *P<0.05 vs. HIR mice. Error bars represent 1 SEM. B. Representative hematoxylin and eosin staining photomicrographs in liver sections (magnification X40) in mice subjected to sham-operation, 45 min. hepatic ischemia and reperfusion (HIR), HIR coupled with bilateral nephrectomy or HIR coupled with 20 min. renal ischemia and reperfusion 24 hrs prior. Necrotic hepatic tissue appears as light pink. Arrows indicate vascular congestion and inflammation. C. Representative fluorescence photomicrographs (of 4 experiments) of liver sections illustrating apoptotic nuclei [terminal deoxynucleotidyl transferase biotin-dUTP nick end-labeling (TUNEL) fluorescence staining, 100X] from mice subjected to 45 min. hepatic ischemia and reperfusion (HIR) or HIR coupled with 20 min. renal ischemia and reperfusion 24 hrs prior. D. Representative gel images (top) and band intensity quantifications (bottom) of semi-quantitative RT-PCR of the pro-inflammatory markers ICAM-1, IL-6 and MCP-1 from liver tissues of mice subjected to sham-operation (Sham), 20 min. renal ischemia and reperfusion (RIR), 45 min hepatic ischemia and reperfusion (HIR) or 20 min RIR plus HIR. Liver tissues were harvested 5 hrs after sham-operation or AKI induction. *P<0.05 vs. sham-operated mice. Error bars represent 1 SEM. #P<0.01 vs. HIR mice.
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Related In: Results  -  Collection

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Figure 5: Exacerbated hepatic IR injury (necrosis, apoptosis and inflammation) after ischemic or non-ischemic AKIA. Plasma alanine aminotransferase (ALT) levels in mice subjected to sham-operation (Sham, N=4), 45 min. hepatic ischemia and reperfusion (HIR, N=6), HIR coupled with unilateral nephrectomy (UNx+HIR, N=6), HIR coupled with bilateral nephrectomy (BNx+HIR, N=6) or HIR coupled with 20 min. renal ischemia and reperfusion (RIR+HIR, N=8) 24 hrs prior. *P<0.05 vs. HIR mice. Error bars represent 1 SEM. B. Representative hematoxylin and eosin staining photomicrographs in liver sections (magnification X40) in mice subjected to sham-operation, 45 min. hepatic ischemia and reperfusion (HIR), HIR coupled with bilateral nephrectomy or HIR coupled with 20 min. renal ischemia and reperfusion 24 hrs prior. Necrotic hepatic tissue appears as light pink. Arrows indicate vascular congestion and inflammation. C. Representative fluorescence photomicrographs (of 4 experiments) of liver sections illustrating apoptotic nuclei [terminal deoxynucleotidyl transferase biotin-dUTP nick end-labeling (TUNEL) fluorescence staining, 100X] from mice subjected to 45 min. hepatic ischemia and reperfusion (HIR) or HIR coupled with 20 min. renal ischemia and reperfusion 24 hrs prior. D. Representative gel images (top) and band intensity quantifications (bottom) of semi-quantitative RT-PCR of the pro-inflammatory markers ICAM-1, IL-6 and MCP-1 from liver tissues of mice subjected to sham-operation (Sham), 20 min. renal ischemia and reperfusion (RIR), 45 min hepatic ischemia and reperfusion (HIR) or 20 min RIR plus HIR. Liver tissues were harvested 5 hrs after sham-operation or AKI induction. *P<0.05 vs. sham-operated mice. Error bars represent 1 SEM. #P<0.01 vs. HIR mice.
Mentions: We also induced liver IR injury in mice subjected to sham-operation, unilateral or bilateral nephrectomy or 20 min. renal IR injury. We determined that mice subjected to hepatic IR together with ischemic (20 min. renal IR) or non-ischemic (unilateral or bilateral nephrectomy) AKI developed significantly exacerbated hepatic injury with significant higher plasma ALT at 24 hrs after liver IR (Figure 5A). Exacerbation of hepatic injury (20 min. renal IR) or non-ischemic (bilateral nephrectomy) AKI was associated the increased hepatic necrosis (Figure 5B), apoptosis (Figure 5C) and inflammation (Figure 5D) compared to mice subjected to hepatic IR alone.

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