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CXC chemokines function as a rheostat for hepatocyte proliferation and liver regeneration.

Wilson GC, Kuboki S, Freeman CM, Nojima H, Schuster RM, Edwards MJ, Lentsch AB - PLoS ONE (2015)

Bottom Line: Our previous in vitro studies have demonstrated dose-dependent effects of CXCR2 ligands on hepatocyte cell death and proliferation.Interestingly, the same pattern of expression was found in ischemic versus non-ischemic liver lobes following I/R injury with expression significantly greater in the ischemic liver lobes.Mice receiving the "high" dose had reduced levels of hepatocyte proliferation and regeneration whereas the "low" dose promoted hepatocyte proliferation and regeneration.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.

ABSTRACT

Background: Our previous in vitro studies have demonstrated dose-dependent effects of CXCR2 ligands on hepatocyte cell death and proliferation. In the current study, we sought to determine if CXCR2 ligand concentration is responsible for the divergent effects of these mediators on liver regeneration after ischemia/reperfusion injury and partial hepatectomy.

Methods: Murine models of partial ischemia/reperfusion injury and hepatectomy were used to study the effect of CXCR2 ligands on liver regeneration.

Results: We found that hepatic expression of the CXCR2 ligands, macrophage inflammatory protein-2 (MIP-2) and keratinocyte-derived chemokine (KC), was significantly increased after both I/R injury and partial hepatectomy. However, expression of these ligands after I/R injury was 30-100-fold greater than after hepatectomy. Interestingly, the same pattern of expression was found in ischemic versus non-ischemic liver lobes following I/R injury with expression significantly greater in the ischemic liver lobes. In both systems, lower ligand expression was associated with increased hepatocyte proliferation and liver regeneration in a CXCR2-dependent fashion. To confirm that these effects were related to ligand concentration, we administered exogenous MIP-2 and KC to mice undergoing partial hepatectomy. Mice received a "high" dose that replicated serum levels found after I/R injury and a "low" dose that was similar to that found after hepatectomy. Mice receiving the "high" dose had reduced levels of hepatocyte proliferation and regeneration whereas the "low" dose promoted hepatocyte proliferation and regeneration.

Conclusions: Together, these data demonstrate that concentrations of CXC chemokines regulate the hepatic proliferative response and subsequent liver regeneration.

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Related in: MedlinePlus

Differential hepatic expression of CXC chemokines in I/R injury and hepatectomy.Expression of MIP-2 and KC in the remnant liver after partial hepatectomy or ischemic and non-ischemic lobes after I/R injury. Data are mean ± SEM with n = 3–6 per group. *P<0.05 compared to sham group. **P<0.05 compared to ischemic liver.
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pone.0120092.g001: Differential hepatic expression of CXC chemokines in I/R injury and hepatectomy.Expression of MIP-2 and KC in the remnant liver after partial hepatectomy or ischemic and non-ischemic lobes after I/R injury. Data are mean ± SEM with n = 3–6 per group. *P<0.05 compared to sham group. **P<0.05 compared to ischemic liver.

Mentions: Because it has been previously shown that the roles of CXC chemokines in the regenerative responses after hepatic I/R injury and partial hepatectomy are opposite in nature, we examined the tissue expression of CXC chemokines after hepatectomy and I/R to see if levels of these mediators were related to the observed biological effects. We examined chemokines 48 hours after the insult, as this is a time in both models when hepatocytes begin to actively proliferate. We found that levels of MIP-2 and KC in the livers of mice undergoing partial hepatectomy were significantly increased several fold, compared to sham mice (Fig. 1). However, after I/R injury, expression of MIP-2 and KC proteins in the ischemic lobes were increased hundreds- to thousands-fold over control (Fig. 1). These findings are consistent with the concept of relative “low” and “high” ligand concentrations, respectively.


CXC chemokines function as a rheostat for hepatocyte proliferation and liver regeneration.

Wilson GC, Kuboki S, Freeman CM, Nojima H, Schuster RM, Edwards MJ, Lentsch AB - PLoS ONE (2015)

Differential hepatic expression of CXC chemokines in I/R injury and hepatectomy.Expression of MIP-2 and KC in the remnant liver after partial hepatectomy or ischemic and non-ischemic lobes after I/R injury. Data are mean ± SEM with n = 3–6 per group. *P<0.05 compared to sham group. **P<0.05 compared to ischemic liver.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4355613&req=5

pone.0120092.g001: Differential hepatic expression of CXC chemokines in I/R injury and hepatectomy.Expression of MIP-2 and KC in the remnant liver after partial hepatectomy or ischemic and non-ischemic lobes after I/R injury. Data are mean ± SEM with n = 3–6 per group. *P<0.05 compared to sham group. **P<0.05 compared to ischemic liver.
Mentions: Because it has been previously shown that the roles of CXC chemokines in the regenerative responses after hepatic I/R injury and partial hepatectomy are opposite in nature, we examined the tissue expression of CXC chemokines after hepatectomy and I/R to see if levels of these mediators were related to the observed biological effects. We examined chemokines 48 hours after the insult, as this is a time in both models when hepatocytes begin to actively proliferate. We found that levels of MIP-2 and KC in the livers of mice undergoing partial hepatectomy were significantly increased several fold, compared to sham mice (Fig. 1). However, after I/R injury, expression of MIP-2 and KC proteins in the ischemic lobes were increased hundreds- to thousands-fold over control (Fig. 1). These findings are consistent with the concept of relative “low” and “high” ligand concentrations, respectively.

Bottom Line: Our previous in vitro studies have demonstrated dose-dependent effects of CXCR2 ligands on hepatocyte cell death and proliferation.Interestingly, the same pattern of expression was found in ischemic versus non-ischemic liver lobes following I/R injury with expression significantly greater in the ischemic liver lobes.Mice receiving the "high" dose had reduced levels of hepatocyte proliferation and regeneration whereas the "low" dose promoted hepatocyte proliferation and regeneration.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.

ABSTRACT

Background: Our previous in vitro studies have demonstrated dose-dependent effects of CXCR2 ligands on hepatocyte cell death and proliferation. In the current study, we sought to determine if CXCR2 ligand concentration is responsible for the divergent effects of these mediators on liver regeneration after ischemia/reperfusion injury and partial hepatectomy.

Methods: Murine models of partial ischemia/reperfusion injury and hepatectomy were used to study the effect of CXCR2 ligands on liver regeneration.

Results: We found that hepatic expression of the CXCR2 ligands, macrophage inflammatory protein-2 (MIP-2) and keratinocyte-derived chemokine (KC), was significantly increased after both I/R injury and partial hepatectomy. However, expression of these ligands after I/R injury was 30-100-fold greater than after hepatectomy. Interestingly, the same pattern of expression was found in ischemic versus non-ischemic liver lobes following I/R injury with expression significantly greater in the ischemic liver lobes. In both systems, lower ligand expression was associated with increased hepatocyte proliferation and liver regeneration in a CXCR2-dependent fashion. To confirm that these effects were related to ligand concentration, we administered exogenous MIP-2 and KC to mice undergoing partial hepatectomy. Mice received a "high" dose that replicated serum levels found after I/R injury and a "low" dose that was similar to that found after hepatectomy. Mice receiving the "high" dose had reduced levels of hepatocyte proliferation and regeneration whereas the "low" dose promoted hepatocyte proliferation and regeneration.

Conclusions: Together, these data demonstrate that concentrations of CXC chemokines regulate the hepatic proliferative response and subsequent liver regeneration.

Show MeSH
Related in: MedlinePlus