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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 inflammation after ischemic or non-ischemic AKIA. Representative gel images and band intensity quantifications of semi-quantitative RT-PCR of the pro-inflammatory markers ICAM-1, TNF-α, IL-6, IL-17A, KC, MCP-1 and MIP-2 from liver tissues of mice subjected to sham-operation (Sham), bilateral nephrectomy (BNx) or 30 min. renal IR (RIR). Liver tissues were harvested 5 hrs after sham-operation or AKI induction. *P<0.05 vs. sham-operated mice. Error bars represent 1 SEM. B. Representative photomicrographs (200X and 400X) of 4 experiments of immunohistochemistry for neutrophil infiltration (dark brown stain) in the liver tissues harvested from mice subjected to sham-operation (Sham) or to bilateral nephrectomy (BNx) 5 hrs prior.
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Figure 3: Increased hepatic inflammation after ischemic or non-ischemic AKIA. Representative gel images and band intensity quantifications of semi-quantitative RT-PCR of the pro-inflammatory markers ICAM-1, TNF-α, IL-6, IL-17A, KC, MCP-1 and MIP-2 from liver tissues of mice subjected to sham-operation (Sham), bilateral nephrectomy (BNx) or 30 min. renal IR (RIR). Liver tissues were harvested 5 hrs after sham-operation or AKI induction. *P<0.05 vs. sham-operated mice. Error bars represent 1 SEM. B. Representative photomicrographs (200X and 400X) of 4 experiments of immunohistochemistry for neutrophil infiltration (dark brown stain) in the liver tissues harvested from mice subjected to sham-operation (Sham) or to bilateral nephrectomy (BNx) 5 hrs prior.

Mentions: Hepatic as well as intestinal inflammation, apoptosis and vascular permeability were assessed at 5 hr after ischemic or non-ischemic AKI since plasma ALT and bilirubin levels were significantly elevated at this time point. With RTPCR, we measured the expression of pro-inflammatory cytokine mRNAs in the liver 5 hrs after 30 min. renal IR or bilateral nephrectomy (Figure 3A). We demonstrate significant upregulation of all of the pro-inflammatory mRNAs examined (ICAM-1, TNF-α, IL-6, IL-17A, KC, MCP-1 and MIP-2) in the liver 5 hrs after 30 min. renal IR or bilateral nephrectomy. We also show significantly increased PMN infiltration (dark brown stain, especially near the portal venous drainage) in mice subjected to 30 min. renal IR or bilateral nephrectomy (Figure 3B). In sham-operated mice, we were unable to detect any neutrophils in liver. Five hrs after unilateral (13±3 neutrophils/field, 200X magnification, N=5) or bilateral (24±4 neutrophils/field, 200X magnification, N=5) nephrectomy, increased neutrophil infiltration occurred. Similarly, we observed increased neutrophil infiltration into the liver 5 hrs after 20 min. (23±6 neutrophils/field, 200X magnification, N=5) or 30 min. (28±6 neutrophils/field, 200X magnification, N=5) renal IR. In contrast, we failed to observe increased T-lymphocyte (CD3) or macrophage (F4/80) infiltration after ischemic or non-ischemic AKI compared to sham-operated animals (data not shown).


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 inflammation after ischemic or non-ischemic AKIA. Representative gel images and band intensity quantifications of semi-quantitative RT-PCR of the pro-inflammatory markers ICAM-1, TNF-α, IL-6, IL-17A, KC, MCP-1 and MIP-2 from liver tissues of mice subjected to sham-operation (Sham), bilateral nephrectomy (BNx) or 30 min. renal IR (RIR). Liver tissues were harvested 5 hrs after sham-operation or AKI induction. *P<0.05 vs. sham-operated mice. Error bars represent 1 SEM. B. Representative photomicrographs (200X and 400X) of 4 experiments of immunohistochemistry for neutrophil infiltration (dark brown stain) in the liver tissues harvested from mice subjected to sham-operation (Sham) or to bilateral nephrectomy (BNx) 5 hrs prior.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2991383&req=5

Figure 3: Increased hepatic inflammation after ischemic or non-ischemic AKIA. Representative gel images and band intensity quantifications of semi-quantitative RT-PCR of the pro-inflammatory markers ICAM-1, TNF-α, IL-6, IL-17A, KC, MCP-1 and MIP-2 from liver tissues of mice subjected to sham-operation (Sham), bilateral nephrectomy (BNx) or 30 min. renal IR (RIR). Liver tissues were harvested 5 hrs after sham-operation or AKI induction. *P<0.05 vs. sham-operated mice. Error bars represent 1 SEM. B. Representative photomicrographs (200X and 400X) of 4 experiments of immunohistochemistry for neutrophil infiltration (dark brown stain) in the liver tissues harvested from mice subjected to sham-operation (Sham) or to bilateral nephrectomy (BNx) 5 hrs prior.
Mentions: Hepatic as well as intestinal inflammation, apoptosis and vascular permeability were assessed at 5 hr after ischemic or non-ischemic AKI since plasma ALT and bilirubin levels were significantly elevated at this time point. With RTPCR, we measured the expression of pro-inflammatory cytokine mRNAs in the liver 5 hrs after 30 min. renal IR or bilateral nephrectomy (Figure 3A). We demonstrate significant upregulation of all of the pro-inflammatory mRNAs examined (ICAM-1, TNF-α, IL-6, IL-17A, KC, MCP-1 and MIP-2) in the liver 5 hrs after 30 min. renal IR or bilateral nephrectomy. We also show significantly increased PMN infiltration (dark brown stain, especially near the portal venous drainage) in mice subjected to 30 min. renal IR or bilateral nephrectomy (Figure 3B). In sham-operated mice, we were unable to detect any neutrophils in liver. Five hrs after unilateral (13±3 neutrophils/field, 200X magnification, N=5) or bilateral (24±4 neutrophils/field, 200X magnification, N=5) nephrectomy, increased neutrophil infiltration occurred. Similarly, we observed increased neutrophil infiltration into the liver 5 hrs after 20 min. (23±6 neutrophils/field, 200X magnification, N=5) or 30 min. (28±6 neutrophils/field, 200X magnification, N=5) renal IR. In contrast, we failed to observe increased T-lymphocyte (CD3) or macrophage (F4/80) infiltration after ischemic or non-ischemic AKI compared to sham-operated animals (data not shown).

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