The Important Role of the Gut in Initiating the Hyperdynamic Response during Early Sepsis

Yang, Shaolong; Koo, Douglas J.; Chaudry, Irshad H.; Wang, Haichao

doi:10.1006/jsre.1999.5807

Cited by 23 publications

(10 citation statements)

References 41 publications

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“…29 Hepatic dysfunction after AKI has been described 30 and we recently identified Paneth cells, located in small intestinal crypts, as the source of the inflammatory mediator, IL-17A, seen in mice following AKI. 31 Release of IL-17A from Paneth cells led to hepatic dysfunction and a cascade of inflammation, including generation of TNF-α and IL-6.…”

Section: Discussionmentioning

confidence: 98%

Isoflurane Activates Intestinal Sphingosine Kinase to Protect against Renal Ischemia–Reperfusion-induced Liver and Intestine Injury

Kim

Park

Kim³

et al. 2011

Anesthesiology

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Background Renal ischemia–reperfusion injury (IRI) is a major cause of acute kidney injury and often leads to multi-organ dysfunction and systemic inflammation. Volatile anesthetics have potent antiinflammatory effects and we aimed to determine whether the representative volatile anesthetic isoflurane protects against acute kidney injury-induced liver and intestinal injury and the mechanisms involved in this protection. Methods Mice were anesthetized with pentobarbital and subjected to 30 min of left renal ischemia after right nephrectomy followed by exposure to 4 h of equi-anesthetic doses of pentobarbital or isoflurane. Five hrs after renal IRI, plasma creatinine and alanine aminotransferase were measured. Liver and intestine tissues were analyzed for pro-inflammatory mRNAs, histology, sphingosine kinase-1 (SK1) immunoblotting, SK1 activity, and sphingosine-1-phosphate levels. Results Renal IRI with pentobarbital led to severe renal, hepatic, and intestinal injury with focused peri-portal hepatocyte vacuolization, small intestinal apoptosis and pro-inflammatory mRNA upregulation. Isoflurane protected against renal IRI and reduced hepatic and intestinal injury via induction of small intestinal crypt SK1 mRNA, protein and enzyme activity and increase in S1P. We confirmed the importance of SK1 as mice treated with a selective SK inhibitor (SKI-II) or mice deficient in SK1 enzyme were not protected against hepatic and intestinal dysfunction with isoflurane. Conclusions Taken together, we demonstrate that isoflurane protects against multi-organ injury after renal IRI via induction of the SK1/sphingosine-1-phosphate pathway. Our findings may help to unravel the cellular signaling pathways of volatile anesthetic-mediated hepatic and intestinal protection and lead to new therapeutic applications of volatile anesthetics during the perioperative period.

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Section: Discussionmentioning

confidence: 98%

Isoflurane Activates Intestinal Sphingosine Kinase to Protect against Renal Ischemia–Reperfusion-induced Liver and Intestine Injury

Kim

Park

Kim³

et al. 2011

Anesthesiology

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show abstract

“…Therefore, after ischemic and non-ischemic AKI, it appears that intestinal endothelial and epithelial apoptosis and necrosis occur rapidly with subsequent intestine barrier and vascular disruption. Since the small intestinal dysfunction with barrier interruption has been implicated as the source of multi-organ dysfunction, cytokine generation and sepsis (32), increased incidence of systemic inflammation and sepsis after AKI may be due to the injury to the small intestine. Interestingly, we observed greater increases in pro-inflammatory mRNA expression in the ileum compared to jejunum after bilateral nephrectomy.…”

Section: Discussionmentioning

confidence: 99%

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

Park

Chen

Kim

et al. 2011

Laboratory Investigation

156

154

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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 demonstrated 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 to 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 due to 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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“…In addition, we demonstrated massive small intestinal injury (apoptosis, inflammation, and necrosis) after ischemic or nonischemic AKI (46). The gut has long been suspected to play a key role in initiating the early hyperdynamic response to sepsis (58), and recently we demonstrated that the inflammatory mediator IL-17A was released by small intestinal crypt Paneth cells after AKI in mice (47). IL-17A released from Paneth cells caused hepatic injury and a proinflammatory cascade, including upregulation of TNF-␣ and IL-6.…”

Section: Discussionmentioning

confidence: 81%

Isoflurane activates intestinal sphingosine kinase to protect against bilateral nephrectomy-induced liver and intestine dysfunction

Kim¹,

Park²,

Kim³

et al. 2011

American Journal of Physiology-Renal Physiology

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The Important Role of the Gut in Initiating the Hyperdynamic Response during Early Sepsis

Cited by 23 publications

References 41 publications

Isoflurane Activates Intestinal Sphingosine Kinase to Protect against Renal Ischemia–Reperfusion-induced Liver and Intestine Injury

Isoflurane Activates Intestinal Sphingosine Kinase to Protect against Renal Ischemia–Reperfusion-induced Liver and Intestine Injury

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

Isoflurane activates intestinal sphingosine kinase to protect against bilateral nephrectomy-induced liver and intestine dysfunction

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