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Background Gut barrier failure has been implicated in the progression from single organ injury to multiple organ failure. The unstirred mucus layer is a major component of the physiological gut barrier, its role in acute pancreatitis(AP) is not clearly defined. Study Design Rats underwent biliopancreatic duct ligation-induced AP; two controls were used: biliopancreatic duct ligation with drainage and sham duct ligation. After 4.5 hours, serum and ascitic amylase activity was measured. Mucus was analyzed for reactive nitrogen intermediates(RNI)-mediated damage, reactive oxygen species(ROS)-induced damage, and total antioxidant capacity. Mucus coverage and villous injury was assessed histologically. Ileum permeability was measured by diffusion of a fluorescent dextran probe. Histology and morphology of the mucus layer were validated in a mouse AP model (intraductal taurocholate plus caerulein). Results Biliopancreatic duct ligation increased serum α-amylase, ascitic volume, and ascitic α-amylase. Intestinal permeability was increased, which was associated with loss of the unstirred mucus layer but not villous injury. These changes correlated with increased ROS-and-RNI-mediated mucus damage as well as decreased mucus total antioxidant capacity but were not present in the two control groups. Using a different model of AP in mice, the finding of mucus layer disruption was recapitulated at 6 hours after AP, but by 24 hours, rebound hypersecretion of inspissated mucus was seen. Conclusions These results support the hypothesis that damage to the unstirred mucus layer with evidence of oxidative stress occurs during AP-induced gut barrier failure.

Structured Abstract Objective To test whether the mucus layer, luminal digestive enzymes, and intestinal mast cells are critical components in the pathogenesis of trauma-shock-induced gut and lung injury. Summary Background Data Gut-origin sepsis studies have highlighted the importance of the systemic component (ischemia-repefusion) of gut injury while the intraluminal component is less well studied. Methods In rats subjected to trauma-hemorrhagic shock (T/HS) or sham-shock (T/SS), the role of pancreatic enzymes in gut injury was tested by diversion of pancreatic enzymes via pancreatic duct exteriorization (PDE), while the role of the mucus layer was tested via the enteral administration of a mucus surrogate. Additionally the role of mast cells was assessed by measuring mast cell activation and the ability of pharmacologic inhibition of mast cells to abrogate gut and lung injury. Gut and mucus injury was characterized functionally, morphologically and chemically. Results PDE abrogated T/HS-induced gut barrier loss and limited chemical mucus changes. The mucus surrogate prevented both T/HS-induced gut and lung injury. Lastly, pancreatic enzyme-induced gut and lung injury appears to involve mast cell activation, since T/HS activates mast cells and pharmacologic inhibition of intestinal mast cells prevented T/HS-induced gut and lung injury. Conclusions These results indicate that gut and gut-induced lung injury after T/HS involves a complex process consisting of intraluminal digestive enzymes, the unstirred mucus layer, and a systemic ischemic-reperfusion injury. This suggests the possibility of intraluminal therapeutic strategies.

Oxidative modification of the intestinal mucus layer is a critical but unrecognized component of trauma hemorrhagic shock-induced gut barrier failure. Am J Physiol Gastrointest Liver Physiol 304: G57-G63, 2013. First published November 1, 2012; doi:10.1152/ajpgi.00170.2012.-Recent studies demonstrate that mechanisms underlying gut barrier failure include systemic processes and less studied luminal processes. We thus tested the hypothesis that mucus layer oxidation is a component of trauma/hemorrhagic shock-induced gut injury and dysfunction. Male Sprague-Dawley rats underwent trauma/hemorrhagic shock. Controls underwent trauma only. Mucus from the terminal 30 cm of the ileum was collected, processed, and analyzed for reactive nitrogen intermediates (RNI)-mediated damage, reactive oxygen species (ROS)-induced damage, and total antioxidant capacity. The distal ileum was stained to quantify the mucus layer; gut permeability was assessed physiologically. A time course study was conducted to determine the temporal sequence of mucus layer damage. The role of free radicalmediated damage to the gut barrier was investigated by the effect of the free radical scavenger dimethyl sulfoxide on trauma/hemorrhagic shock-induced changes on the mucus and on gut permeability. Trauma/hemorrhagic shock increased intestinal permeability, which was associated with evidence of loss of the unstirred mucus layer. These changes correlated with increased ROS-and RNI-mediated mucus damage and loss of mucus total antioxidant capacity. Based on the time course study, ROS-mediated mucus damage and loss of total antioxidant capacity were present immediately following shock, whereas RNI-mediated damage was delayed for 3 h. Dimethyl sulfoxide ameliorated gut barrier loss, ROS-mediated changes to the mucus layer, and loss of total antioxidant capacity. There was no change in RNI-induced changes to the mucus layer. These results support the hypothesis that trauma/hemorrhagic shock leads to mucus damage and gut dysfunction through the generation of free radical species.intestinal mucus layer; gut-mediated sepsis IN CERTAIN CLINICAL SCENARIOS, including major trauma and hemorrhage, gut injury and the subsequent loss of the gut barrier function have been implicated in the development of the acute respiratory distress syndrome, systemic inflammatory response syndrome, and multiple organ dysfunction syndrome (8). Thus prevention or amelioration of gut injury in conditions associated with intestinal ischemia would be a key therapeutic strategy. Several such strategies, including early enteral nutrition, have been identified and instituted into clinical practice (1,20). However, the development of successful new clinical therapies is based on a complete knowledge of the mechanisms of the injuries they are being developed to treat. Consequently, a considerable amount of investigative attention has been committed to elucidating the pathogenesis of stress-and trauma/ shock-induced gut injury and gut barrier failure. These studies have largely focused on the ...

BACKGROUND Hemorrhagic shock is known to disrupt the gut barrier leading to end-organ dysfunction. The vagus nerve can inhibit detrimental immune responses that contribute to organ damage in hemorrhagic shock. Therefore, we explored whether stimulation of the vagus nerve can protect the gut and recover lung permeability in trauma-hemorrhagic shock (THS). METHODS Male Sprague-Dawley rats were subjected to left cervical vagus nerve stimulation at 5 V for 10 minutes. The right internal jugular and femoral artery were cannulated for blood withdrawal and blood pressure monitoring, respectively. Animals were then subjected to hemorrhagic shock to a mean arterial pressure between 30 mm Hg and 35 mm Hg for 90 minutes then reperfused with their own whole blood. After observation for 3 hours, gut permeability was assessed with fluorescein dextran 4 in vivo injections in a ligated portion of distal ileum followed by Evans blue dye injection to assess lung permeability. Pulmonary myeloperoxidase levels were measured and compared. RESULTS Vagal nerve stimulation abrogated THS-induced lung injury (mean [SD], 8.46 [0.36] vs. 4.87 [0.78]; p < 0.05) and neutrophil sequestration (19.39 [1.01] vs. 12.83 [1.16]; p < 0.05). Likewise, THS gut permeability was reduced to sham levels. CONCLUSION Neuromodulation decreases injury in the THS model as evidenced by decreased gut permeability as well as decreased lung permeability and pulmonary neutrophil sequestration in a rat model.

A standard therapy used today for prostate cancer is androgen ablation by gonadotropin-releasing hormone analogs (GnRH-a). Although most patients respond to androgen ablation as an initial systemic therapy, nearly all cases will develop androgen resistance, the management of which is still a major challenge. Here, we report that GnRH-a can directly induce apoptosis of the androgen-independent prostate cancer-derived DU145 and PC3 cell lines. Using specific inhibitors, we found that the apoptotic effect of GnRH-a is mediated by c-Jun NH 2 -terminal kinase (JNK) and inhibited by the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB) pathway. Indeed, in DU145 cells, GnRH-a activates the JNK cascade in a c-Src-and MLK3-dependent manner but does not involve protein kinase C and epidermal growth factor receptor. Concomitantly, GnRH-a reduces the activity of the PI3K-PKB pathway, which results in the dephosphorylation of PKB mainly in the nucleus. The reduction of PKB activity releases PKB-induced inhibition of MLK3 and thus further stimulates JNK activity and accelerates the apoptotic effect of GnRH-a. Interestingly, extracellular signal-regulated kinase is also activated by GnRH-a, and this occurs via a pathway that involves matrix metalloproteinases and epidermal growth factor receptor, but its activation does not affect JNK activation and the GnRH-a-induced apoptosis. Our results support a potential use of GnRH-a for the treatment of advanced prostate cancer and suggest that the outcome of this treatment can be amplified by using PI3K-PKB inhibitors.

TAP blocks with a PCA is an alternative option for pain control in patients undergoing esophagectomy and may reduce hypotension and need for volume resuscitation with similar pulmonary complications.

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