Compensatory hepatic regeneration after mild, but not fulminant, intraperitoneal sepsis in rats

Abstract

Sepsis is the leading cause of death in surgical intensive care units. Although both mild sepsis secondary to cecal ligation and single puncture (CLP) and fulminant, double puncture CLP (2CLP) may provoke hepatocyte death, we hypothesize that regeneration compensates for cell death after CLP but not 2CLP. In male Sprague-Dawley rats, hepatic necrosis, as determined by serum alpha-glutathione S-transferase (alpha-GST) levels, was significantly but equally elevated over time after both CLP and 2CLP. Apoptosis, evaluated using both terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and morphological examination, was minimal after both CLP and 2CLP. Regeneration, assayed by staining tissue for incorporation of exogenously administered bromodeoxyuridine, was present after CLP but not after 2CLP. To further substantiate impaired regeneration, steady-state levels of mRNAs encoding JunB, LRF-1, and cyclin D1 were determined. After 2CLP, the absence of JunB, LRF-1, and cyclin D1 mRNAs confirmed failed activation of the mitogen-activated protein kinase-linked proliferative pathway and progression through the cell cycle. Therefore, failed hepatocyte regeneration may be a manifestation of hepatic dysfunction in fulminant sepsis.

First-Generation Adenovirus Vectors Shorten Survival Time in a Murine Model of Sepsis

“…2A). CLP surgery alone did not produce apoptosis in the liver, which is consistent with previous reports (13,14). Interestingly, a limited degree of hepatic apoptosis was observed in Ad-infected sham operated animals.…”

“…Liver has been shown to be an important target organ in the CLP model of murine sepsis (14,27). Kupffer cells are the resident macrophages of the liver and play an essential role in the outcome of sepsis (28).…”

Role of Interleukin-6 in Mortality from and Physiologic Response to Sepsis

“…Over 6 years ago it was reported that plasma IL-6 levels are significantly higher in the acute phase (first 10 h) in those animals with a more severe infection (1) and these IL-6 levels play an important role in the hepatic response to sepsis (40). The IL-6 controversy revolves around whether or not, in sepsis, IL-6 represents a marker of inflammation, an inducer of altered physiology, or a mediator of organ injury.…”

Intraabdominal bacterial infections significantly alter regeneration and function of the liver in a rat model of major hepatectomy

“…It is known, that cecal ligation and puncture (CLP)-a commonly used experimental model of abdominal infection and sepsiscauses hepatocellular dysfunction [9] and impaired regeneration capacity of the liver in experimental settings without PH [10]. In addition, regeneration might be inhibited by increased liberation of pro-inflammatory cytokines like tumor necrosis factory-alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6 during septic reactions.…”