Targeting the gut to prevent sepsis from a cutaneous burn
Fatemeh Adiliaghdam, Paul Cavallaro, Vidisha Mohad, Marianna Almpani, Florian Kühn, Mohammad Hadi Gharedaghi, Mehran Najibi, Laurence G. Rahme, Richard A. Hodin
Fatemeh Adiliaghdam, Paul Cavallaro, Vidisha Mohad, Marianna Almpani, Florian Kühn, Mohammad Hadi Gharedaghi, Mehran Najibi, Laurence G. Rahme, Richard A. Hodin
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Research Article Gastroenterology Microbiology

Targeting the gut to prevent sepsis from a cutaneous burn

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.

Authors

Fatemeh Adiliaghdam, Paul Cavallaro, Vidisha Mohad, Marianna Almpani, Florian Kühn, Mohammad Hadi Gharedaghi, Mehran Najibi, Laurence G. Rahme, Richard A. Hodin

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Figure 5

IAP reduces burn wound infection–induced intestinal inflammation and prevents the barrier damage secondary to luminal inflammatory mediators.

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IAP reduces burn wound infection–induced intestinal inflammation and pre...
(A) TNF-α and (B) IL-6 levels in the distal ileum tissue of sham, burn wound–infected mice with or without IAP supplementation measured by ELISA. (C) IL-6 levels from colonic explants measured by ELISA. (D) Fecal lipocalin-2 levels measured at the indicated time points and normalized by fecal weight. (E) Percentage of measured transepithelial electrical resistance (TEER) in Caco-2 Transwells at the indicated time points divided by measurements at the 0-hour time point. LPS (100 ng/mL) and equal amounts of PBS were used as a positive and negative control, respectively. The TEER readings were documented every 6 hours for 48 hours. (F) Area under the curve (AUC) values calculated for TEER readings. (G and H) Zonula Occludes1 (ZO1) and Claudin1 mRNA expression levels in Caco-2 monolayer at 48 hours after incubation with luminal contents from the indicated groups measured by qPCR. Data are expressed as mean ± SEM. One-way ANOVA with multiple post hoc comparisons using Tukey’s test was performed. Each group included 5 animals and data are representative of 3 biological replicates. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. IAP, intestinal alkaline phosphatase.