Abstract
Severe burn injury induces gut barrier dysfunction and subsequently a profound systemic inflammatory response. In the present study, we examined the role of the small intestinal brush border enzyme, intestinal alkaline phosphatase (IAP), in preserving gut barrier function and preventing systemic inflammation after burn wound infection in mice. Mice were subjected to a 30% total body surface area dorsal burn with or without intradermal injection of Pseudomonas aeruginosa. Mice were gavaged with 2000 units of IAP or vehicle at 3 and 12 hours after the insult. We found that both endogenously produced and exogenously supplemented IAP significantly reduced gut barrier damage, decreased bacterial translocation to the systemic organs, attenuated systemic inflammation, and improved survival in this burn wound infection model. IAP attenuated liver inflammation and reduced the proinflammatory characteristics of portal serum. Furthermore, we found that intestinal luminal contents of burn wound–infected mice negatively impacted the intestinal epithelial integrity compared with luminal contents of control mice and that IAP supplementation preserved monolayer integrity. These results indicate that oral IAP therapy may represent an approach to preserving gut barrier function, blocking proinflammatory triggers from entering the portal system, preventing gut-induced systemic inflammation, and improving survival after severe burn injuries.
Highlights
Patients with severe cutaneous burn injury are at risk for developing systemic sepsis, in some cases leading to shock, multiorgan failure (MOF), and even death [1]
We found that intestinal alkaline phosphatase (IAP)-KO mice had significantly higher absorption of orally gavaged FITC-dextran in their blood compared with their WT counterparts, indicating an increased gut permeability after a burn site infection in KO mice (Figure 1A)
The higher gut permeability was associated with an increased bacterial translocation to the mesenteric lymph nodes (MLNs) in the KO compared with the WT mice (Figure 1B)
Summary
Patients with severe cutaneous burn injury are at risk for developing systemic sepsis, in some cases leading to shock, multiorgan failure (MOF), and even death [1]. Several mechanisms linking the effects of external burn injury to intestinal barrier dysfunction have been suggested. Burn-induced hypovolemia can cause systemic ischemia and hypoperfusion, which may lead to breakdown of the intestinal epithelial layer and tight junctions, impairing barrier integrity and allowing for translocation of bacteria and bacterial-derived mediators. A myriad of other elements, such as burn-induced hypoxia, enterocyte apoptosis, and gut microbiome dysbiosis, have been suggested to contribute to intestinal barrier dysfunction after burn injury. Under conditions of intestinal barrier injury and the associated local inflammatory response, bacterial and other pathogenic inflammatory mediators enter the portal venous and mesenteric lymphatic systems, reaching distant organs. Burn wound infection is a frequent complication of burn injury, compounding the initial insult and further affecting the gut barrier [2, 8,9,10,11]
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