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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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Acute hepatic injury with increased hepatic necrosis and vacuolization after ischemic AKIRepresentative photomicrographs of liver from 6 experiments (hematoxylin and eosin staining, magnification 600X) of mice subjected to sham-operation (Sham) or to 30 min. renal ischemia and 5 hrs of reperfusion (30 min. renal IR). Sham operated animals show normal-appearing hepatocyte parenchyma (A). Five hours after 30 min. renal IR (B, C), nuclear and cytoplasmic degenerative changes, centrilobular necrosis (B, arrows), marked hepatocyte vacuolization (C) and congestion were observed.
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Figure 2: Acute hepatic injury with increased hepatic necrosis and vacuolization after ischemic AKIRepresentative photomicrographs of liver from 6 experiments (hematoxylin and eosin staining, magnification 600X) of mice subjected to sham-operation (Sham) or to 30 min. renal ischemia and 5 hrs of reperfusion (30 min. renal IR). Sham operated animals show normal-appearing hepatocyte parenchyma (A). Five hours after 30 min. renal IR (B, C), nuclear and cytoplasmic degenerative changes, centrilobular necrosis (B, arrows), marked hepatocyte vacuolization (C) and congestion were observed.

Mentions: Liver histology was also assessed by H&E staining of liver sections. As shown in Figure 2A, sham-operated mice had normal liver histology. Five hours after 30 min. renal IR, nuclear and cytoplasmic degenerative changes, cellular vacuolization, leukocyte infiltration and congestion were observed (Figures 2B and 2C). Similar hepatic injury was observed 5 hrs after 20 min. renal IR, unilateral or bilateral nephrectomy (data not shown). The severity of tissue injury was increased at 24 hrs after 30 min. renal IR (as reflected in plasma ALT) as manifested by the extent of cellular degenerative changes including individual hepatocyte necrosis and focal apoptotic, pyknotic nuclei. Some degree of centrilobular necrosis was observed in this group. At 24 hrs after bilateral nephrectomy, the severity of injury was milder relative to 5 hrs although areas of congestion could be detected. Vascular congestion and leukocyte (mainly neutrophil) infiltration were also detected after bilateral nephrectomy or 30 min. renal IR.


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)

Acute hepatic injury with increased hepatic necrosis and vacuolization after ischemic AKIRepresentative photomicrographs of liver from 6 experiments (hematoxylin and eosin staining, magnification 600X) of mice subjected to sham-operation (Sham) or to 30 min. renal ischemia and 5 hrs of reperfusion (30 min. renal IR). Sham operated animals show normal-appearing hepatocyte parenchyma (A). Five hours after 30 min. renal IR (B, C), nuclear and cytoplasmic degenerative changes, centrilobular necrosis (B, arrows), marked hepatocyte vacuolization (C) and congestion were observed.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2991383&req=5

Figure 2: Acute hepatic injury with increased hepatic necrosis and vacuolization after ischemic AKIRepresentative photomicrographs of liver from 6 experiments (hematoxylin and eosin staining, magnification 600X) of mice subjected to sham-operation (Sham) or to 30 min. renal ischemia and 5 hrs of reperfusion (30 min. renal IR). Sham operated animals show normal-appearing hepatocyte parenchyma (A). Five hours after 30 min. renal IR (B, C), nuclear and cytoplasmic degenerative changes, centrilobular necrosis (B, arrows), marked hepatocyte vacuolization (C) and congestion were observed.
Mentions: Liver histology was also assessed by H&E staining of liver sections. As shown in Figure 2A, sham-operated mice had normal liver histology. Five hours after 30 min. renal IR, nuclear and cytoplasmic degenerative changes, cellular vacuolization, leukocyte infiltration and congestion were observed (Figures 2B and 2C). Similar hepatic injury was observed 5 hrs after 20 min. renal IR, unilateral or bilateral nephrectomy (data not shown). The severity of tissue injury was increased at 24 hrs after 30 min. renal IR (as reflected in plasma ALT) as manifested by the extent of cellular degenerative changes including individual hepatocyte necrosis and focal apoptotic, pyknotic nuclei. Some degree of centrilobular necrosis was observed in this group. At 24 hrs after bilateral nephrectomy, the severity of injury was milder relative to 5 hrs although areas of congestion could be detected. Vascular congestion and leukocyte (mainly neutrophil) infiltration were also detected after bilateral nephrectomy or 30 min. renal IR.

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