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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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A. Representative gel images (top) and band intensity quantifications (bottom) of semi-quantitative RT-PCR of the pro-inflammatory markers ICAM-1, TNF-α, IL-6, KC, MCP-1 and MIP-2 from ileum of C57BL/6 (WT) mice subjected to sham-operation (Sham) or bilateral nephrectomy (BNx) compared to pro-inflammatory gene expression from the ileum of TNF-α, IL-6 or IL-17A deficient (KO) mice. Tissues were harvested 5 hrs after sham-operation or AKI induction. *P<0.05 vs. sham-operated mice. #P<0.05 vs. WT mice subjected to BNx. Error bars represent 1 SEM. B-D. Representative photomicrographs of ileum of hematoxylin and eosin staining (magnification 200X and 400X) of WT, TNF-α, IL-6 or IL-17A KO mice subjected to BNx 5 hrs prior (B), WT mice treated with isotype control IgG, TNF-α, IL-6 or IL-17A neutralizing antibody (Ab) and subjected to RIR 24 hrs prior (C) and WT mice treated with a combination of recombinant mouse TNF-α, IL-6 plus IL-17A in lieu of AKI 5 hrs prior (D). Cytokine deficient mice or WT mice treated with cytokine neutralizing antibodies (single antibody)were protected against small intestine injury whereas WT mice treated with cytokine cocktails demonstrate severe injury (*). Representative of 4 experiments.
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Figure 7: A. Representative gel images (top) and band intensity quantifications (bottom) of semi-quantitative RT-PCR of the pro-inflammatory markers ICAM-1, TNF-α, IL-6, KC, MCP-1 and MIP-2 from ileum of C57BL/6 (WT) mice subjected to sham-operation (Sham) or bilateral nephrectomy (BNx) compared to pro-inflammatory gene expression from the ileum of TNF-α, IL-6 or IL-17A deficient (KO) mice. Tissues were harvested 5 hrs after sham-operation or AKI induction. *P<0.05 vs. sham-operated mice. #P<0.05 vs. WT mice subjected to BNx. Error bars represent 1 SEM. B-D. Representative photomicrographs of ileum of hematoxylin and eosin staining (magnification 200X and 400X) of WT, TNF-α, IL-6 or IL-17A KO mice subjected to BNx 5 hrs prior (B), WT mice treated with isotype control IgG, TNF-α, IL-6 or IL-17A neutralizing antibody (Ab) and subjected to RIR 24 hrs prior (C) and WT mice treated with a combination of recombinant mouse TNF-α, IL-6 plus IL-17A in lieu of AKI 5 hrs prior (D). Cytokine deficient mice or WT mice treated with cytokine neutralizing antibodies (single antibody)were protected against small intestine injury whereas WT mice treated with cytokine cocktails demonstrate severe injury (*). Representative of 4 experiments.

Mentions: We determined whether the increased pro-inflammatory cytokines TNF-α, IL-17A and/or IL-6 play a critical role in hepatic and intestine injury after ischemic or non-ischemic AKI. Mice genetically deficient for TNF-α, IL-17A, IL-17R or IL-6 were significantly protected against hepatic (Table 3) and small intestine (Figure 7A) injury after ischemic (30 min. renal IR, data not shown) or non-ischemic AKI (bilateral nephrectomy, Figure 7B). We complemented our knockout mice studies by treating the wild type mice with specific neutralizing antibody for TNF-α, IL-17A or IL-6. Each neutralizing antibody treatment was very effective in protecting against hepatic (Table 3) and small intestine injury after ischemic (30 min. renal IR, Figure 7C) or non-ischemic (bilateral nephrectomy, data not shown) AKI. Furthermore, TNF-α, IL-17A or IL-6 antibody treatment also significantly attenuated the exacerbation of hepatic injury due to ischemic (30 min. renal IR) or non-ischemic (bilateral nephrectomy) AKI (Table 3). Finally, mice injected with a combination of recombinant mouse TNF-α, IL-6 plus IL-17A in lieu of AKI induction developed acute hepatic (ALT=368±67 U/L, N=5, P<0.001 vs. sham) and intestine dysfunction (Figure 7D).


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)

A. Representative gel images (top) and band intensity quantifications (bottom) of semi-quantitative RT-PCR of the pro-inflammatory markers ICAM-1, TNF-α, IL-6, KC, MCP-1 and MIP-2 from ileum of C57BL/6 (WT) mice subjected to sham-operation (Sham) or bilateral nephrectomy (BNx) compared to pro-inflammatory gene expression from the ileum of TNF-α, IL-6 or IL-17A deficient (KO) mice. Tissues were harvested 5 hrs after sham-operation or AKI induction. *P<0.05 vs. sham-operated mice. #P<0.05 vs. WT mice subjected to BNx. Error bars represent 1 SEM. B-D. Representative photomicrographs of ileum of hematoxylin and eosin staining (magnification 200X and 400X) of WT, TNF-α, IL-6 or IL-17A KO mice subjected to BNx 5 hrs prior (B), WT mice treated with isotype control IgG, TNF-α, IL-6 or IL-17A neutralizing antibody (Ab) and subjected to RIR 24 hrs prior (C) and WT mice treated with a combination of recombinant mouse TNF-α, IL-6 plus IL-17A in lieu of AKI 5 hrs prior (D). Cytokine deficient mice or WT mice treated with cytokine neutralizing antibodies (single antibody)were protected against small intestine injury whereas WT mice treated with cytokine cocktails demonstrate severe injury (*). Representative of 4 experiments.
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Figure 7: A. Representative gel images (top) and band intensity quantifications (bottom) of semi-quantitative RT-PCR of the pro-inflammatory markers ICAM-1, TNF-α, IL-6, KC, MCP-1 and MIP-2 from ileum of C57BL/6 (WT) mice subjected to sham-operation (Sham) or bilateral nephrectomy (BNx) compared to pro-inflammatory gene expression from the ileum of TNF-α, IL-6 or IL-17A deficient (KO) mice. Tissues were harvested 5 hrs after sham-operation or AKI induction. *P<0.05 vs. sham-operated mice. #P<0.05 vs. WT mice subjected to BNx. Error bars represent 1 SEM. B-D. Representative photomicrographs of ileum of hematoxylin and eosin staining (magnification 200X and 400X) of WT, TNF-α, IL-6 or IL-17A KO mice subjected to BNx 5 hrs prior (B), WT mice treated with isotype control IgG, TNF-α, IL-6 or IL-17A neutralizing antibody (Ab) and subjected to RIR 24 hrs prior (C) and WT mice treated with a combination of recombinant mouse TNF-α, IL-6 plus IL-17A in lieu of AKI 5 hrs prior (D). Cytokine deficient mice or WT mice treated with cytokine neutralizing antibodies (single antibody)were protected against small intestine injury whereas WT mice treated with cytokine cocktails demonstrate severe injury (*). Representative of 4 experiments.
Mentions: We determined whether the increased pro-inflammatory cytokines TNF-α, IL-17A and/or IL-6 play a critical role in hepatic and intestine injury after ischemic or non-ischemic AKI. Mice genetically deficient for TNF-α, IL-17A, IL-17R or IL-6 were significantly protected against hepatic (Table 3) and small intestine (Figure 7A) injury after ischemic (30 min. renal IR, data not shown) or non-ischemic AKI (bilateral nephrectomy, Figure 7B). We complemented our knockout mice studies by treating the wild type mice with specific neutralizing antibody for TNF-α, IL-17A or IL-6. Each neutralizing antibody treatment was very effective in protecting against hepatic (Table 3) and small intestine injury after ischemic (30 min. renal IR, Figure 7C) or non-ischemic (bilateral nephrectomy, data not shown) AKI. Furthermore, TNF-α, IL-17A or IL-6 antibody treatment also significantly attenuated the exacerbation of hepatic injury due to ischemic (30 min. renal IR) or non-ischemic (bilateral nephrectomy) AKI (Table 3). Finally, mice injected with a combination of recombinant mouse TNF-α, IL-6 plus IL-17A in lieu of AKI induction developed acute hepatic (ALT=368±67 U/L, N=5, P<0.001 vs. sham) and intestine dysfunction (Figure 7D).

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