Prostaglandins are required for CREB activation and cellular proliferation during liver regeneration

Abstract

The liver responds to multiple types of injury with an extraordinarily well orchestrated and tightly regulated form of regeneration. The response to partial hepatectomy has been used as a model system to elucidate the molecular basis of this regenerative response. In this study, we used cyclooxygenase (COX)-selective antagonists and -null mice to determine the role of prostaglandin signaling in the response of liver to partial hepatectomy. The results show that liver regeneration is markedly impaired when both COX-1 and COX-2 are inhibited by indocin or by a combination of the COX-1 selective antagonist, SC-560, and the COX-2 selective antagonist, SC-236. Inhibition of COX-2 alone partially inhibits regeneration whereas inhibition of COX-1 alone tends to delay regeneration. Neither the rise in IL-6 nor the activation of signal transducer and activator of transcription-3 (STAT3) that is seen during liver regeneration is inhibited by indocin or the selective COX antagonists. In contrast, indocin treatment prevents the activation of CREB by phosphorylation that occurs during hepatic regeneration. These data indicate that prostaglandin signaling is required during liver regeneration, that COX-2 plays a particularly important role but COX-1 is also involved, and implicate the activation of CREB rather than STAT3 as the mediator of prostaglandin signaling during liver regeneration.

Evidence for non-traditional activation of complement factor C3 during murine liver regeneration

“…One mg of the inhibitory monoclonal anti-factor B antibody mAb 1379 was administered by intraperitoneal injection once daily beginning 12 hours prior to partial hepatectomy. This is within the dosing range reported to neutralize factor B activity in models of murine inflammation (Leinhase et Two to three month old male mice, maintained on 12 h dark-light cycles and standard mouse chow, were subjected to partial hepatectomy, allowed to recover, and then sacrificed for plasma and tissue harvest as previously described (Rudnick et al 2001;Shteyer et al 2004;Liao et al 2004). Briefly, mice were sedated with inhaled Isoflurane (VEDCO, Inc., St. Joseph, MO) delivered via an anesthesia cart, then subjected to mid-ventral laparotomy with exposure of the left and median hepatic lobes, which was followed by sequential ligation and resection of the median and left lobes and closure of the peritoneal and skin wounds.…”

“…Analyses using the rodent partial hepatectomy model (Higgins and Anderson 1931) show that following partial hepatectomy, the proliferation of normally quiescent hepatocytes is rapidly induced, proceeds until the original liver mass is restored, and is then precisely terminated (Fausto 2000;Diehl and Rai 1999;Michalopoulos and DeFrances 1997). The molecular mechanisms that control this carefully orchestrated response include activation of TNFα-IL6 signaling (Akerman et al 1992; Yamada et al 1997;Cressman et al 1996), generation of mitochondrial reactive oxygen species (Lee et al 1999) and prostaglandins (Rudnick et al 2001), and activation of stress-and mitogen-activated-protein kinase cascades (Talarmin et al 1999). These events promote activation of NFκB, STAT3, AP1 and other transcription factors (Cressman et al 1994;Cressman et al 1995;, which direct an immediate-early gene expression program (Haber et al 1993) culminating in growth factor-dependent, hepatocellular re-entry into and progression through the cell cycle, and restoration of normal hepatic mass.…”

Disruption of hepatic adipogenesis is associated with impaired liver regeneration in mice

“…Partial hepatectomy or sham surgery was performed as previously described. 4,9 For analysis of hepatocellular proliferation, at the time of partial hepatectomy mice also underwent intraperitoneal implantation of a bromodeoxyuridine (BrdU)-containing sustained-release osmotic pump (Alza, Newark, DE) delivering a flow rate of 20 g/h of BrdU. For leptin supplementation experiments, mice were treated daily with 1 mg/kg recombinant mouse leptin (Alpha Diagnostics, San Antonio, TX) delivered by subcutaneous injection beginning 3 days prior to partial hepatectomy and continuing until the time of animal sacrifice.…”

“…4 Analyses of genetically and pharmacologically manipulated mice using this model have begun to identify the coordinated signaling events that regulate hepatic regeneration. These signals include activation of tumor necrosis factor ␣ (TNF␣) interleukin (IL)-6 signaling, 5-7 generation of mitochondrial reactive oxygen species 8 and prostaglandins 9 , and activation of stress-and mitogenactivated-protein kinase cascades. 10 These signals lead to activation of nuclear factor B (NF B) and other transcription factors, which direct an immediate early gene expression program culminating in growth factor-dependent hepatocellular reentry into and progression through the cell cycle [11][12][13] .…”

Interplay among cardiotrophin-1, prostaglandins, and vascular endothelial growth factor in rat liver regeneration

“…[6][7][8] COX-2 and PGE 2 synthesis are upregulated soon after partial hepatectomy (PH), with peaks at 3 and 10 hours after operation. 3,9 Recently, liver regenerative response after PH in rodents was reported to be blocked by administration of a COX-2-specific inhibitor, 10,11 indicating the critical role of PGs during the early phase of liver regeneration. PGs display hepatoprotective activities and are also able to modulate the expression of cytokines and growth factors in other tissue systems.…”