Abstract
Pre-induction of heme oxygenase (HO)-1, which is regarded as an effective method of “organ preconditioning”, exerts beneficial effects during hemorrhagic shock (HS). However, the available HO-1 inducers exhibit disadvantages such as toxicity or complex technical requirements. Therefore, a safe and convenient HO-1 inducer would be promising and could be exploited in the treatment of foreseeable hemorrhaging, such as prior to major surgery. Here we investigated the effect of vitamin C (VitC), a common antioxidant, on intestinal HO-1 expression and examined whether VitC pretreatment prevented HS related intestinal tissue injuries after HO-1 induction. First, we conducted an in vitro study and found that HO-1 expression in rat intestinal epithelial cells (IEC-6) was induced by non-toxic VitC in a time and concentration dependent manner, and the mechanism was related to the activation of extracellular signal-regulated kinase 1/2 (ERK1/2). Next, we conducted an in vivo study and found that VitC induced intestinal HO-1 protein expression (mainly observed in the intestinal epithelial cells) and HO-1 activity in normal SD rats, and that these HO-1 levels were further enhanced by VitC in a rat model of HS. The HS related intestinal injuries, including histological damage, pro-inflammatory cytokine levels (tumor necrosis factor and interleukin-6), neutrophil infiltration and apoptosis decreased after VitC pretreatment, and this alleviating of organ injuries was abrogated after the inhibition of HO-1 activity by zinc protoporphyrin-IX. It was of note that VitC did little histological damage to the intestine of the sham rats. These data suggested that VitC might be applied as a safe inducer of intestinal HO-1 and that VitC pretreatment attenuated HS related intestinal injuries via the induction of HO-1.
Highlights
50% of trauma mortality occurs in the age of 5 to 44 years globally [1]
We reported here that vitamin C (VitC) led to the profound induction of heme oxygenase (HO)-1 in intestinal epithelial cells, and the specific molecular mechanism of induction is related to the activation of extracellular signal-regulated kinase 1/2 (ERK1/2)
Our results showed a significant increase in the number of TdT-mediated dUTP nick end-labeling (TUNEL) positive cells (Fig. 9A) and the apoptosis index (Fig. 9B) in Hemorrhagic shock (HS) group compared to sham rats treated with NS (Sham) group, which was reduced at 24 hours after VitC pretreatment in HSV group
Summary
50% of trauma mortality occurs in the age of 5 to 44 years globally [1]. Hemorrhagic shock (HS) is reported to be the leading cause of death in trauma patients [2]. HS and subsequent resuscitation is regarded as a systemic ischemic/reperfusion (I/R) injury, during which the intestine acts as a site of endorgan, and a generator of inflammatory mediators via bacterial translocation. Pre-exposure of the intestine to temporary sub-lethal stress, known as ‘‘organ preconditioning’’, has been shown to increase tolerance to I/R injuries [4]. Several methods for ‘‘organ preconditioning’’ have been described, including brief ischemia followed by reperfusion [5], whole-body hyperthermia [6], and chemical induction of a heat shock protein [7]
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