Early infection during burn-induced inflammatory response results in increased mortality and p38-mediated neutrophil dysfunction

Adediran, Samuel; Dauplaise, Derrick J.; Kasten, Kevin R.; Tschöp, Johannes; Dattilo, Jonathan R.; Goetzman, Holly S.; England, Lisa G.; Cave, Cindy M.; Robinson, Chad T.; Caldwell, Charles C.

doi:10.1152/ajpregu.00132.2010

Cited by 19 publications

(10 citation statements)

References 50 publications

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“…Mice were subjected to a full-thickness scald injury as previously described 21 . Briefly, mice were weighed and anesthetized with 4.5% isoflurane in oxygen prior to clipping hair from their dorsal surface.…”

Section: Methodsmentioning

confidence: 99%

Bronchoalveolar Lavage Microvesicles Protect Burn-Injured Mice from Pulmonary Infection

Rice

Pugh

Xia

et al. 2017

Journal of the American College of Surgeons

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Background Pseudomonas aeruginosa (PA) is a major cause of morbidity and mortality among burn patients, despite antibiotic therapy. There is a need to identify innate immune defenses that prevent PA infection in injured adults in an effort to find therapeutic alternatives to antibiotics. Here, we tested our hypothesis that Microvesicles (MVs) in bronchoalveolar (BAL) fluid have a role in the immunity of the lung in response to pathogens. Study Design MVs were isolated from murine BAL fluid, quantified using nanoparticle tracking analysis, and injected into burn injured mice prior to PA infection. Survival was assessed and BAL bacterial loads enumerated. Neutrophil number and IL-6 activity were determined. Lungs were harvested and sphingosine (SPH) content analyzed via immunohistochemistry. Antimicrobial effects of MV and SPH enriched MVs were assessed in an in vitro assay. Results Burn injured mice have reduced BAL MV number and SPH content as compared to sham. When BAL MVs from healthy mice are administered to injured mice, survival and bacterial clearance are robustly improved. We further observed that intranasal administration of MVs restores SPH levels after burn injury, MVs directly kill bacteria, and this bacterial killing is increased when the MVs supplemented with SPH. Conclusion Using a pre-clinical model, BAL MVs are reduced after scald injury and BAL MV restoration to injured mice improves survival and bacterial clearance. The antimicrobial mechanisms leading to improved survival includes the quantity and SPH content of BAL MVs.

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Section: Methodsmentioning

confidence: 99%

Bronchoalveolar Lavage Microvesicles Protect Burn-Injured Mice from Pulmonary Infection

Rice

Pugh

Xia

et al. 2017

Journal of the American College of Surgeons

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“…A “second hit” of endotoxemia or Pseudomonas aeruginosa infection seems to lead to increased systemic and organ-specific inflammation (current study and Refs. 22 and 23). In contrast, prior thermal injury appears to blunt the inflammatory response to a subsequent “second hit” consisting of cecal ligation and puncture.…”

Section: Discussionmentioning

confidence: 99%

Prior Thermal Injury Accelerates Endotoxin-Induced Inflammatory Cytokine Production and Intestinal Nuclear Factor-κB Activation in Mice

Huber

Bailey

Schuster

et al. 2012

Journal of Burn Care & Research

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The objective of this study was to increase the understanding of the “second-hit” response in thermal injury. The authors hypothesized that prior thermal injury increases the endotoxin-induced inflammatory response of intestinal mucosa. Mice underwent sham or 25% TBSA scald injury. Seven days after injury, mice were injected with lipopolysaccharide. Blood, jejunum, and colon specimens were obtained at intervals. Serum, jejunal, and colon inflammatory cytokine levels were measured by enzyme-linked immunosorbent assay. Jejunal and colon nuclear factor (NF)-κB activation was measured by electrophoretic mobility shift assay. After remote thermal injury, lipopolysaccharide exposure led to an acute increase in serum interleukin (IL)-6, IL-10, and chemokine keratinocyte-derived chemokine (KC) levels. This correlated with lipopolysaccharide-induced increased IL-6 in colon and chemokine KC in the jejunum and colon in burned mice when compared with sham-injured mice. Lipopolysaccharide-induced NF-κB activation occurred more rapidly in jejunum and colon from burned mice compared with sham-injured mice. Prior thermal injury accelerates lipopolysaccharide-induced inflammatory cytokine production systemically in jejunum and colon. The “second hit” of lipopolysaccharide led to earlier intestinal NF-κB activation in burned mice compared with sham-injured mice. These results indicate that there is a heightened inflammatory response by jejunum and colon in response to a “second hit” of lipopolysaccharide after burn injury.

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“…We target the burn wound, the actual source of inflammatory signaling in order to block the initiation of SIRS. In determining a key inflammatory pathway target, p38 MAPK was identified as central in the host response to burn injury (31–34). By applying a topical p38 MAPK inhibitor directly to the burn wound, we hypothesized that local inflammatory source control would lead to improved survival and organ function by blocking the initiation of SIRS.…”

Section: Discussionmentioning

confidence: 99%

Delayed Topical p38 MAPK Inhibition Attenuates Full-Thickness Burn Wound Inflammatory Signaling

Carter

Warsen

Mandell

et al. 2014

Journal of Burn Care & Research

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Objective Inflammatory signaling pathways, such as p38 MAPK play a central role in host responses to injury. In our previous studies, topical p38 MAPK inhibitors effectively attenuated inflammatory signaling in a partial-thickness scald burn model, when applied to the burn wound immediately after injury. However, clinically relevant full-thickness scald burn wounds may act as a barrier to topical immune modulators and delayed application of topical p38 MAPK inhibitors may not be effective. In this study, we evaluate the efficacy of topical p38 MAPK inhibition on full-thickness scald burns with immediate and delayed treatment. Methods C57/BL6 mice received `Sham' or 30% TBSA full-thickness scald burn injury. After injury, the burn wounds were treated with a topical p38 MAPK inhibitor or vehicle. The treatment group received topical p38 MAPK inhibitor either immediately after burn or 4 hours (delayed) after injury. All animals were sacrificed at 12 or 24 h. Burn wounds underwent histological analyses. Skin and plasma were analyzed by ELISA or RT-qPCR for cytokine expression. Results Full-thickness scald burns resulted from immersion in 62°C water for 25 s. Topical p38 MAPK inhibitor attenuated dermal IL-6, MIP-2, and IL-1β expression and plasma IL-6 and MIP-2 cytokine expression. In addition, delayed application of topical p38 MAPK inhibitors significantly reduced dermal and plasma cytokine expression compared to vehicle control. Conclusion Topical p38 MAPK inhibitors remain potent in reducing full-thickness burn wound inflammatory signaling, even when treatment is delayed by several hours post injury. Topical application of p38 MAPK inhibitor may be a clinically viable treatment after burn injury.

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Early infection during burn-induced inflammatory response results in increased mortality and p38-mediated neutrophil dysfunction

Cited by 19 publications

References 50 publications

Bronchoalveolar Lavage Microvesicles Protect Burn-Injured Mice from Pulmonary Infection

Bronchoalveolar Lavage Microvesicles Protect Burn-Injured Mice from Pulmonary Infection

Prior Thermal Injury Accelerates Endotoxin-Induced Inflammatory Cytokine Production and Intestinal Nuclear Factor-κB Activation in Mice

Delayed Topical p38 MAPK Inhibition Attenuates Full-Thickness Burn Wound Inflammatory Signaling

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