Selective decontamination of the digestive tract attenuated the myocardial inflammation and dysfunction that occur with burn injury

2004 ◽  
Vol 287 (5) ◽  
pp. H2241-H2251 ◽  
Author(s):  
Jureta W. Horton ◽  
Jing Tan ◽  
D. Jean White ◽  
David L. Maass ◽  
James A. Thomas
Keyword(s):  
Digestive Tract ◽  
P38 Mapk ◽  
Nuclear Translocation ◽  
Burn Injury ◽  
Inflammatory Responses ◽  
Total Body Surface Area ◽  
Selective Decontamination ◽  
Cytokine Secretion ◽  
Myocardial Inflammation ◽  
Sprague Dawley

This study examined the effects of oral antibiotics to selectively decontaminate the digestive tract (SDD) on postburn myocardial signaling, inflammation, and function. We hypothesized that antibiotic therapy to eliminate pathogens from the gastrointestinal (GI) tract would reduce myocardial inflammatory responses and improve postburn myocardial performance. Sprague-Dawley rats received polymyxin E (15 mg), tobramycin (6 mg), and 5-flucytosin (100 mg) by oral gavage twice daily for 3 days preburn and 24 h postburn. Experimental groups included 1) sham burn given vehicle (3 ml water), 2) sham plus SDD, 3) burn over 40% total body surface area (TBSA) plus SDD, and 4) burn over 40% TBSA given vehicle. All burns received lactated Ringer solution (4 mg·kg−1·%burn−1); myocardial signaling (PKCε/p38 MAPK/NF-κB) was studied 2, 4, and 24 h postburn; and cytokine secretion (systemic and myocyte secreted cytokines, ELISA) and cardiac function were examined 24 h postburn. Vehicle-treated burn injury increased myocardial PKCε/p38 MAPK expression, promoted NF-κB nuclear translocation, promoted TNF-α, IL-1β, IL-6, and IL-10 secretion, and impaired myocardial function. SDD attenuated burn-related proinflammatory myocardial signaling, cytokine secretion, and myocardial contractile defects. Our data suggest that burn-related loss of GI barrier function and translocation of microbial products serve as upstream mediators of postburn myocardial inflammatory signaling and dysfunction.

scholarly journals Reducing susceptibility to bacteremia after experimental burn injury: a role for selective decontamination of the digestive tract

2007 ◽  
Vol 102 (6) ◽  
pp. 2207-2216 ◽  
Author(s):  
Jureta W. Horton ◽  
David L. Maass ◽  
Jean White ◽  
Joseph P. Minei
Keyword(s):  
Digestive Tract ◽  
Cardiac Myocyte ◽  
Burn Injury ◽  
Inflammatory Responses ◽  
Left Ventricular ◽  
Selective Decontamination ◽  
Myocardial Inflammation ◽  
Oral Gavage ◽  
Experimental Burn ◽  
Tnf Α

We proposed that selective decontamination of the digestive tract (SDD) initiated after experimental burn injury would decrease myocardial inflammation and dysfunction after a second insult such as septic challenge. Rats were divided into eight experimental groups. Groups included sham burn plus sham sepsis, burn alone, sepsis alone, and burn plus sepsis given either water by oral gavage for 5 days after burn (or sham burn) or given oral antibiotics (polymyxin E, 15 mg; tobramycin, 6 mg; 5-flucytosin, 100 mg given by oral gavage, 2× daily for 5 days after burn or sham burn). Cardiac function and inflammation were studied 24 h after septic challenge. In the absence of SDD, burn alone, sepsis alone, or burn plus septic challenge promoted cardiac myocyte secretion of TNF-α (burn, 174 ± 11; sepsis, 269 ± 19; burn + sepsis, 453 ± 14 pg/ml), IL-1β (burn, 35 ± 2; sepsis, 29 ± 1; burn + sepsis, 48 ± 7 pg/ml), and IL-6 (burn, 143 ± 18; sepsis, 116 ± 3; burn + sepsis, 248 ± 12 pg/ml) compared with values measured in sham (TNF-α, 3 ± 1; IL-1β, 1 ± 0.4; IL-6, 6 ± 1.5 pg/ml) ( P < 0.05). Impaired ventricular contraction and relaxation responses were evident in the absence of SDD [burn + sepsis: left ventricular pressure (LVP), 65 ± 4 mmHg; rate of LVP rise (+dP/d t), 1,320 ± 131 mmHg/s compared with values measured in sham: LVP, 96 ± 4 mmHg; +dP/d t, 2,095 ± 99 mmHg/s, P < 0.05]. SDD treatment of experimental burn attenuated septic challenge-related inflammatory responses and improved myocardial contractile responses, producing cardiac TNF-α, IL-1β, and IL-6 levels, LVP, +dP/d t, and rate of LVP fall (−dP/d t) values that were significantly better ( P < 0.05) than values measured in burn plus sepsis in the absence of SDD. This work confirms that endogenous gut organisms contribute to sensitivity to subsequent infectious challenge.

scholarly journals Effects of burn injury on myocardial signaling and cytokine secretion: possible role of PKC

2007 ◽  
Vol 292 (2) ◽  
pp. R887-R896 ◽  
Author(s):  
Jing Tan ◽  
David L. Maass ◽  
D. Jean White ◽  
Jureta W. Horton
Keyword(s):  
Burn Injury ◽  
Total Body Surface Area ◽  
Cytokine Secretion ◽  
Sprague Dawley ◽  
Inhibitory Peptide ◽  
Adult Rat ◽  
Pkc Isoforms ◽  
Major Burn

This study examined the effects of major burn injury on the cellular distribution of several PKC isoforms in adult rat hearts and examined the hypothesis that PKC plays a regulatory role in cardiomyocyte cytokine secretion. Burn trauma was given over 40% total body surface area in Sprague-Dawley rats. An in vitro model of burn injury included addition of burn serum, 10% by volume, to primary cardiomyocyte cultures (collagen perfusion). In vivo burn injury produced redistribution of PKCδ, PKCε, and PKCα from the cytosol (soluble) to the membrane (particulate) component of the myocardium. This activation of the PKC isoforms was evident 2 h after burn injury and progressively increased over 24 h postburn. Addition of burn serum to isolated myocytes produced similar PKC isoform redistribution from the soluble to the particulate compartment, promoted myocyte Ca2+ and Na+ loading, and promoted robust myocyte secretion of inflammatory cytokines similar to that reported after in vivo burn injury. Pretreating cardiomyocytes with either calphostin or PKCε inhibitory peptide, a potent inhibitor of PKCε, prevented burn serum-related redistribution of the PKCε isoform and prevented burn serum-related cardiomyocyte secretion of TNF-α, IL-1β, IL-6, and IL-10. These data suggest that the PKCε isoform plays a pivotal role in myocardial inflammatory response to injury, altering cardiac function by modulating cardiomyocyte inflammatory cytokine response to injury.

scholarly journals Hypertonic saline dextran after burn injury decreases inflammatory cytokine responses to subsequent pneumonia-related sepsis

2006 ◽  
Vol 290 (4) ◽  
pp. H1642-H1650 ◽  
Author(s):  
Jureta W. Horton ◽  
David L. Maass ◽  
D. Jean White
Keyword(s):  
Hypertonic Saline ◽  
Burn Injury ◽  
Inflammatory Responses ◽  
Contractile Function ◽  
Total Body Surface Area ◽  
Isotonic Saline ◽  
Ringer Solution ◽  
Myocardial Inflammation ◽  
Adult Rats ◽  
Tnf Α

The present study examined the hypothesis that hypertonic saline dextran (HSD), given after an initial insult, attenuates exaggerated inflammation that occurs with a second insult. Adult rats ( n = 15 per group) were divided into groups 1 (sham burn), 2 [40% total body surface area burn + 4 ml/kg isotonic saline (IS) + 4 ml·kg−1·% burn−1 lactated Ringer solution (LR)], and 3 (burn + 4 ml/kg HSD + LR), all studied 24 h after burns. Groups 4 (sham burn), 5 (burn + IS + LR), and 6 (burns + HSD + LR) received intratracheal (IT) vehicle 7 days after burns; groups 7 (burn + IS + LR) and 8 (burn + HSD + LR) received IT Streptococcus pneumoniae (4 × 106 colony-forming units) 7 days after burn. Groups 4–8 were studied 8 days after burn and 24 h after IT septic challenge. When compared with sham burn, contractile defects occurred 24 h after burn in IS-treated but not HSD-treated burns. Cardiac inflammatory responses (pg/ml TNF-α) were evident with IS (170 ± 10) but not HSD (45 ± 5) treatment vs. sham treatment (80 ± 15). Pneumonia-related sepsis 8 days after IS-treated burns ( group 7) exacerbated TNF-α responses/contractile dysfunction vs. IS-treated burns in the absence of sepsis ( P < 0.05). Sepsis that occurred after HSD-treated burns ( group 8) had less myocyte TNF-α secretion/better contractile function than IS-treated burns given septic challenge ( group 7, P < 0.05). We conclude that an initial burn injury exacerbates myocardial inflammation/dysfunction occurring with a second insult; giving HSD after the initial insult attenuates myocardial inflammation/dysfunction associated with a second hit, suggesting that HSD reduces postinjury risk for infectious complications.

Gender-related differences in myocardial inflammatory and contractile responses to major burn trauma

2004 ◽  
Vol 286 (1) ◽  
pp. H202-H213 ◽  
Author(s):  
Jureta W. Horton ◽  
D. Jean White ◽  
David L. Maass
Keyword(s):  
Burn Injury ◽  
Inflammatory Responses ◽  
Total Body Surface Area ◽  
Left Ventricular Pressure ◽  
Experimental Models ◽  
Left Ventricular ◽  
Female Rats ◽  
Sprague Dawley ◽  
Burn Trauma ◽  
Major Burn

Gender-related differences in immune responses to hemorrhage and sepsis have been described. However, most trauma studies continue to limit experimental models to males to avoid the variable responses associated with hormonal fluctuation in proestrus/estrus females. In the present study, male and female (either diestrus or proestrus/estrus) Sprague-Dawley rats (250–325 g) were given a third-degree scald burn over 40% total body surface area and fluid resuscitated (4 ml/kg per %burn of lactated Ringer solution); sham burn males and diestrus as well as sham burn proestrus/estrus female rats were included to provide controls. Twenty-four hours postburn, hearts were either perfused to examine mechanical function (Langendorff, n = 8 to 9 hearts/group) or to prepare cardiomyocytes (collagenase digestion, n = 4 to 5 hearts/group). Left ventricular developed pressure and the positive and negative first derivative of left ventricular pressure responses to increases in preload were significantly lower in burned males compared with responses measured in either burned proestrus/estrus or burned diestrus females; burn trauma increased cardiomyocyte secretion of tumor necrosis factor-α, interleukin-1β, and nitric oxide to a lesser extent in proestrus/estrus females than levels secreted by either diestrus females or males. Similarly, myocytes from proestrus/estrus females accumulated significantly less sodium/calcium compared with values measured in males ( P < 0.05). Our data confirm gender-related differences in myocardial function and myocardial inflammatory responses to burn injury.

A Single Intravenous Infusion of Human Choriodecidual Mesenchymal Stem Cell Decreases Early Burn Mortality in a Rodent Model

2021 ◽  
Author(s):  
Eng-Kean Yeong ◽  
Thai-Yen Ling
Keyword(s):  
Intravenous Infusion ◽  
Culture Medium ◽  
Inflammatory Responses ◽  
Total Body Surface Area ◽  
Optimal Dosage ◽  
Sprague Dawley ◽  
Post Injury ◽  
Group B ◽  
Group D ◽  
Single Intravenous Infusion

Abstract Background:Systemic inflammatory responses (SIR) are the main cause of pulmonary dysfunction leading to mortality within hours of extensive burns. Based on previous studies showing that cell entrapment occurs in the lungs following the infusion of human choriodecidual mesenchymal stem cells (hcMSCs), we hypothesize that the intravenous infusion of hcMSCs, with an immunomodulatory potential, will decrease the risk of SIR induced pulmonary failure leading to mortality in burn patients. Methods:Forty adult male Sprague-Dawley rats were randomized into two groups. Group A (sham control, n = 10) received no injury or intervention; the remaining rats (n = 30) were subjected to burns covering 40 % of the total body surface area by immersion of the dorsum in 100 °C water for 15 s under general anesthesia. Injured rats were further randomized into different treatment groups: Group B (saline only control, n = 10), Group C (saline plus culture medium control, n = 10), and Group D (saline plus 2 × 106 hcMSCs, n = 10). Culture medium or hcMSCs were given in a single infusion via the tail vein immediately after burns. Mortality was evaluated on post-burn days 7 and 14. Results:The overall mortality among injured rats was 30 % (9/30). In the first week post-injury, four rats in Group C and three in Group B versus none in Group D died. In the second week, one rat in both Groups C and D died. Altogether, mortality among Group D rats was 10 %, significantly lower than that in groups B and C combined (40 %; p<0.001).Conclusions:We show that a single intravenous infusion of 2 × 106 hcMSCs decreased burn mortality in a severely burned animal model. However, clinical translation requires additional studies to exclude potential adverse effects and to determine the optimal dosage and timing of administration.

Caspase inhibition reduces cardiac myocyte dyshomeostasis and improves cardiac contractile function after major burn injury

2007 ◽  
Vol 103 (1) ◽  
pp. 323-330 ◽  
Author(s):  
Deborah L. Carlson ◽  
David L. Maass ◽  
Jean White ◽  
Patricia Sikes ◽  
Jureta W. Horton
Keyword(s):  
Cardiac Myocyte ◽  
Burn Injury ◽  
Contractile Function ◽  
Total Body Surface Area ◽  
Cysteine Proteases ◽  
Sodium Concentration ◽  
Sprague Dawley ◽  
Cardiac Contractile Function ◽  
Caspase 1 ◽  
Major Burn

In the heart, thermal injury activates a group of intracellular cysteine proteases known as caspases, which have been suggested to contribute to myocyte inflammation and dyshomeostasis. In this study, Sprague-Dawley rats were given either a third-degree burn over 40% total body surface area plus conventional fluid resuscitation or sham burn injury. Experimental groups included 1) sham burn given vehicle, 400 μl DMSO; 2) sham burn given Q-VD-OPh (6 mg/kg), a highly specific and stable caspase inhibitor, 24 and 1 h prior to sham burn; 3) burn given vehicle, DMSO as above; 4) burn given Q-VD-OPh (6 mg/kg) 24 and 1 h prior to burn. Twenty-four hours postburn, hearts were harvested and studied with regard to myocardial intracellular sodium concentration, intracellular pH, ATP, and phosphocreatine (23Na/31P nuclear magnetic resonance); myocardial caspase-1, -3,and -8 expression; myocyte Na+ (fluorescent indicator, sodium-binding benzofurzan isophthalate); myocyte secretion of TNF-α, IL-1β, IL-6, and IL-10; and myocardial performance (Langendorff). Burn injury treated with vehicle alone produced increased myocardial expression of caspase-1, -3, and -8, myocyte Na+ loading, cytokine secretion, and myocardial contractile depression; cellular pH, ATP, and phosphocreatine were stable. Q-VD-OPh treatment in burned rats attenuated myocardial caspase expression, prevented burn-related myocardial Na+ loading, attenuated myocyte cytokine responses, and improved myocardial contraction and relaxation. The present data suggest that signaling through myocardial caspases plays a pivotal role in burn-related myocyte sodium dyshomeostasis and myocyte inflammation, perhaps contributing to burn-related contractile dysfunction.

Estrogen-provided cardiac protection following burn trauma is mediated through a reduction in mitochondria-derived DAMPs

2014 ◽  
Vol 306 (6) ◽  
pp. H882-H894 ◽  
Author(s):  
Xiao Yao ◽  
Jane G. Wigginton ◽  
David L. Maass ◽  
Lisha Ma ◽  
Deborah Carlson ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Structural Integrity ◽  
Troponin I ◽  
Burn Injury ◽  
Total Body Surface Area ◽  
Sterile Inflammation ◽  
Effective Control ◽  
Cardiac Protection ◽  
Sprague Dawley ◽  
17Β Estradiol

Mitochondria-derived danger-associated molecular patterns (DAMPs) play important roles in sterile inflammation after acute injuries. This study was designed to test the hypothesis that 17β-estradiol protects the heart via suppressing myocardial mitochondrial DAMPs after burn injury using an animal model. Sprague-Dawley rats were given a third-degree scald burn comprising 40% total body surface area (TBSA). 17β-Estradiol, 0.5 mg/kg, or control vehicle was administered subcutaneously 15 min following burn. The heart was harvested 24 h postburn. Estradiol showed significant inhibition on the productivity of H2O2 and oxidation of lipid molecules in the mitochondria. Estradiol increased mitochondrial antioxidant defense via enhancing the activities and expression of superoxide dismutase (SOD) and glutathione peroxidase (GPx). Estradiol also protected mitochondrial respiratory function and structural integrity. In parallel, estradiol remarkably decreased burn-induced release of mitochondrial cytochrome c and mitochondrial DNA (mtDNA) into cytoplasm. Further, estradiol inhibited myocardial apoptosis, shown by its suppression on DNA laddering and downregulation of caspase 1 and caspase 3. Estradiol's anti-inflammatory effect was demonstrated by reduction in systemic and cardiac cytokines (TNF-α, IL-1β, and IL-6), decrease in NF-κB activation, and attenuation of the expression of inflammasome component ASC in the heart of burned rats. Estradiol-provided cardiac protection was shown by reduction in myocardial injury marker troponin-I, amendment of heart morphology, and improvement of cardiac contractility after burn injury. Together, these data suggest that postburn administration of 17β-estradiol protects the heart via an effective control over the generation of mitochondrial DAMPs (mtROS, cytochrome c, and mtDNA) that incite cardiac apoptosis and inflammation.

scholarly journals Burn injury induces intestinal inflammatory response mediated by Th17 in burn-primed endotoxemic mice

2020 ◽  
Author(s):  
Kazuhiko Sekine ◽  
Takayuki Shibusawa ◽  
Seitaro Fujishima ◽  
Naoki Aikawa ◽  
Junichi Sasaki
Keyword(s):  
Lamina Propria ◽  
Mononuclear Cells ◽  
Burn Injury ◽  
Inflammatory Responses ◽  
Total Body Surface Area ◽  
Vital Role ◽  
Mice Model ◽  
Th17 Response ◽  
Lamina Propria Mononuclear Cells ◽  
Tnf Α

Objective: This study aimed to elucidate the mechanism underlying the susceptibility to infection-related acute lung injury by focusing on the role of gut mucosal T-helper (Th) 17 cells that preferentially produce IL-17 with probiotics in a burn-primed endotoxemic mice model. Methods: Mice were subjected to a 15% total body surface area third-degree burn. Survival from lethal lipopolysaccharide (LPS) administration (3 mg/kg) on 11th day post burn was assessed in mice fed by chow with or without 1.2% Lactobacillus powder after burn injury. Lamina propria mononuclear cells were enzymatically isolated from the ileum removed on 11th day post burn and incubated along with 1 μg/mL LPS or 10 μg/mL anti-CD3 antibody for 24 h; subsequently, the following seven cytokines were analyzed in the supernatant: IFN-γ, TNF-α, IL-2, IL-4, IL-6, IL-10, and IL-17. Results: Lactobacillus treatment post-burn injury markedly improved survival after lethal endotoxemia in burn-primed mice (64.3% vs. 21.4%, p = 0.03). The production of proinflammatory cytokines such as TNF-α, IL-6, and IL-17 by lamina propria mononuclear T-lymphocytes and macrophages including Th17 response was augmented by burn injury but decreased with Lactobacillus treatment after burn injury. Conclusions: Th17- and Th17-mediated inflammatory responses in the gut mucosa may play a vital role, which could be attenuated by Lactobacillus treatment, in survival of lethal endotoxemia in burn-primed mice.

T cells from burn-injured mice demonstrate a loss of sensitivity to glucocorticoids

2010 ◽  
Vol 299 (2) ◽  
pp. E299-E307 ◽  
Author(s):  
Michele D'Elia ◽  
Julie Patenaude ◽  
Charles Dupras ◽  
Jacques Bernier
Keyword(s):  
T Cells ◽  
T Cell ◽  
P38 Mapk ◽  
Thermal Injury ◽  
Burn Injury ◽  
Total Body Surface Area ◽  
T Cell Response ◽  
Mitogen Activated Protein Kinase ◽  
Activated T Cells ◽  
Cell Functions

Glucocorticoids (GC) are steroid hormones that modulate T cell functions and restrain their hyperresponsiveness following stimulation. Naive T lymphocytes are sensitive to GC but become more resistant when they are activated. A balance between activation and inhibition signals is important for a targeted and effective T cell response. Thermal injury is characterized by an immune dysfunction and hyperactive T cells visible at day 10 postburn. In this study, our objective was to evaluate T cell sensitivity to GC following thermal injury and to identify mechanisms that could modulate their sensitivity. One mechanism that we hypothesized was increased p38 mitogen-activated protein kinase (MAPK) activity that could lead to GC resistance. Male C57BL/6 mice underwent a full-thickness 20% total body surface area. At 10 days postinjury, splenic T cells were isolated. Glucocorticoid receptor (GR) expression was higher in T cells from burn-injured mice. Interestingly, these cells were also less sensitive to GC-induced apoptosis prior to and poststimulation. Furthermore, anti-CD3-activated T cells from burn-injured mice showed increased proliferation and CD25 expression, which resisted corticosterone's (CORT) suppressive effect. Anti-CD3-activated CD4+CD44+ memory cells from burn-injured mice expressed the highest level of CD25 and were resistant to CORT. Increased phosphorylation of p38 MAPK was also noted in activated T cells from burn-injured mice. Pharmacological inhibition of p38 MAPK decreased cell proliferation and normalized interferon-γ (IFNγ) production. In conclusion, we demonstrate that a unique event like burn injury induces a loss of sensitivity to GC in splenic T cells and have identified p38 MAPK as a key modulator for this resistance.

scholarly journals Burn serum causes a CD14-dependent mitochondrial damage in primary cardiomyocytes

2010 ◽  
Vol 298 (6) ◽  
pp. H1951-H1958 ◽  
Author(s):  
Qun S. Zang ◽  
David L. Maass ◽  
Jane G. Wigginton ◽  
Robert C. Barber ◽  
Bobbie Martinez ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Burn Injury ◽  
Ex Vivo ◽  
Membrane Damage ◽  
Total Body Surface Area ◽  
Membrane Integrity ◽  
Mitochondrial Damage ◽  
Sprague Dawley ◽  
Ex Vivo Model ◽  
Sd Rats

Studies from animal models suggest that myocardial mitochondrial damage contributes to cardiac dysfunction after burn injury. In this report, we used an ex vivo model of primary cardiomyocyte culture to investigate the mechanisms of burn-induced mitochondrial impairment. Briefly, blood serum was collected from Sprague-Dawley (SD) rats subjected to 40% total body surface area burn and added (10% vol/vol) to primary cardiomyocytes prepared from SD rats. The effect of the burn serum on mitochondrial function and membrane integrity in the myocytes was analyzed. Exposure of myocytes to burn serum doubled the mitochondrial membrane damage measured by two independent assays. This treatment also significantly elevated mitochondrial oxidative stress, indicated by a more than 30% increase in lipid oxidation. Downregulation of mitochondrial antioxidant defense was also evident since the activities of the antioxidant enzymes superoxide dismutase and glutathione peroxidase were reduced by about 30% and 50%, respectively. Burn serum also induced deficiency of mitochondrial metabolism, indicated by a 30% decrease in the activity of cytochrome c oxidase. These mitochondrial dysfunctions appear to be generated by oxidative stress because burn serum induced a significant increase of mitochondrial oxygen species (mtROS) in cardiomyocytes, and pretreatment of cardiomyocytes with the antioxidant N-acetyl-cysteine prevented the mitochondrial damages induced by burn serum. Remarkably, the increase in mtROS was abolished by an antibody-mediated blockade of CD14. Furthermore, burn injury-induced mitochondrial damage in cardiomyocytes was prevented in CD14 knockout mice. Taken together, these data suggested that burn injury produces CD14-dependent mitochondrial damage via oxidative stress in myocardium.

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