Reversal of the Effect of Albumin on Gut Barrier Function in Burn by the Inhibition of Inducible Isoform of Nitric Oxide Synthase

Chen, Lee Wei; Wang, Jyh Seng; Hwang, Bonnie; Chen, Jin Shyr; Hsu, Che-Wei

doi:10.1001/archsurg.138.11.1219

Cited by 25 publications

(11 citation statements)

References 23 publications

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“…We chose this intermediate time point to compare our results with a previously published intestinal permeability assay performed after 30% TBSA burn. 10 Four hours after severe burn there was a significant increase in 4 kDa FITC-Dextran measured in the systemic circulation after intraluminal injection into a loop of distal ileum (228 μ g/mL ± 23 μ g/mL vs. 44 μ g/mL ± 15 μ g/mL, p < 0.01). Treatment with PTX immediately after burn prevented intestinal permeability (44 μ g/mL ± 18 μ g/mL, p < 0.01 vs. burn).…”

Section: Resultsmentioning

confidence: 91%

Pentoxifylline Modulates Intestinal Tight Junction Signaling After Burn Injury: Effects on Myosin Light Chain Kinase

Costantini

Loomis²,

Putnam³

et al. 2009

Journal of Trauma: Injury, Infection &Amp; Critical Care

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Background Burn injury can result in loss of intestinal barrier function, leading to systemic inflammatory response syndrome and multiorgan failure. Myosin light chain kinase (MLCK), a tight junction protein involved in the regulation of barrier function, increases intestinal epithelial permeability when activated. Prior studies have shown that tumor necrosis factor (TNF)-α activates MLCK, in part through a nuclear factor (NF)-κ B-dependent pathway. We have previously shown that pentoxifylline (PTX) decreases both TNF-α synthesis and NF-κB activation in models of shock. Therefore, we postulate that PTX will attenuate activation of the tight junction protein MLCK, which may decrease intestinal tight junction permeability after severe burn. Methods Male balb/c mice undergoing a severe burn were randomized to resuscitation with normal saline (NS) or NS + PTX (12.5 mg/kg). Intestinal TNF-α levels were evaluated using enzyme linked immunosorbent assay. Gut extracts were obtained to assess MLCK, phosphorylated IKK, IκB-α, and NF-κB p65 levels by immunoblotting. Results Burn injury increased intestinal MLCK protein levels threefold in animals resuscitated with NS, whereas those receiving PTX had MLCK levels similar to control (p < 0.01). Treatment with PTX attenuated burn-induced intestinal permeability. PTX decreased cytoplasmic IKK, IκB-α phosphorylation, and nuclear NF-κB p65 translocation to sham levels (p < 0.05 vs. NS). Conclusion Treatment with PTX attenuates activation of the tight junction protein MLCK, likely through its ability to decrease local TNF-α synthesis and NF-κB activation after burn. PTX may have therapeutic utility by decreasing intestinal barrier breakdown after burn.

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Section: Resultsmentioning

confidence: 91%

Pentoxifylline Modulates Intestinal Tight Junction Signaling After Burn Injury: Effects on Myosin Light Chain Kinase

Costantini

Loomis²,

Putnam³

et al. 2009

Journal of Trauma: Injury, Infection &Amp; Critical Care

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“…In this study, we show that antibiotic treatment for 6 days significantly reduced numbers of aerobic bacteria belonging to the Enterobacteriaceae and Enterococcus in the intestinal mucosa and lumen and numbers of the anaerobic bacteria Lactococcus and Bifidobacterium in the mucosa but did not change numbers of Bacteroides in the mucosa and lumen. It has been reported that antibiotic treatment disrupted the intestinal microflora, leading to increased infection susceptibility by enteric bacteria, such as Listeria monocytogenes (17), C. difficile, Salmonella enterica (18), E. coli, and Enterococcus faecalis (19). Our PCR results demonstrated that the total amount of enteric bacteria was decreased and the amount of major groups of intestinal bacteria, such as the aerobic bacteria of the Enterobacteriaceae and Enterococcus as well as the anaerobic genera Lactobacillus and Lactococcus were significantly decreased in mice receiving antibiotics for 6 days.…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor Stimulation Induces Nondefensin Protein Expression and Reverses Antibiotic-Induced Gut Defense Impairment

Hsu

Chen

et al. 2014

Infect Immun

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dPrior antibiotic exposure is associated with increased mortality in Gram-negative bacteria-induced sepsis. However, how antibiotic-mediated changes of commensal bacteria promote the spread of enteric pathogenic bacteria in patients remains unclear. In this study, the effects of systemic antibiotic treatment with or without Toll-like receptor (TLR) stimulation on bacterium-killing activity, antibacterial protein expression in the intestinal mucosa, and bacterial translocation were examined in mice receiving antibiotics with or without oral supplementation of dead Escherichia coli or Staphylococcus aureus. We developed a systemic ampicillin, vancomycin, and metronidazole treatment protocol to simulate the clinical use of antibiotics. Antibiotic treatment decreased the total number of bacteria, including aerobic bacteria belonging to the family Enterobacteriaceae and the genus Enterococcus as well as organisms of the anaerobic genera Lactococcus and Bifidobacterium in the intestinal mucosa and lumen. Antibiotic treatment significantly decreased the bacterium-killing activity of the intestinal mucosa and the expression of nondefensin-family proteins, such as RegIII␤, RegIII␥, C-reactive protein-ductin, and RELM␤, but not the defensin-family proteins, and increased Klebsiella pneumoniae translocation. TLR stimulation after antibiotic treatment increased NF-B DNA binding activity, nondefensin protein expression, and bacterium-killing activity in the intestinal mucosa and decreased K. pneumoniae translocation. Moreover, germfree mice showed a significant decrease in nondefensin proteins as well as intestinal defense against pathogen translocation. Since TLR stimulation induced NF-B DNA binding activity, TLR4 expression, and mucosal bacterium-killing activity in germfree mice, we conclude that the commensal microflora is critical in maintaining intestinal nondefensin protein expression and the intestinal barrier. In turn, we suggest that TLR stimulation induces nondefensin protein expression and reverses antibiotic-induced gut defense impairment.

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“…Since no conjugation of any of the amino acid residues has taken place, the charge of the rHSA dimer should be the same as the native HSA (monomer albumin). In addition, environmental factors such as the presence of nitric oxide have also been reported to influence the extravasation of albumin (37).…”

Section: Discussionmentioning

confidence: 99%

Recombinant Human Serum Albumin Dimer has High Blood Circulation Activity and Low Vascular Permeability in Comparison with Native Human Serum Albumin

et al. 2006

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Purpose. Human serum albumin (HSA) is used clinically as an important plasma expander. Albumin infusion is not recommended for critically ill patients with hypovolemia, burns, or hypoalbuminemia because of the increased leakage of albumin into the extravascular spaces, thereby worsening edema. In the present study, we attempted to overcome this problem by producing a recombinant HSA (rHSA) dimer with decreased vascular permeability and an increased half-life. Methods. Two molecules of rHSA were genetically fused to produce a recombinant albumin dimer molecule. The pharmacokinetics and biodistribution of the recombinant proteins were evaluated in normal rats and carrageenin-induced paw edema mouse model. Results. The conformational properties of this rHSA dimer were similar to those for the native HSA (the HSA monomer), as evidenced by the Western blot and spectroscopic studies. The biological halflife and area under the plasma concentrationYtime curve of the rHSA dimer were approximately 1.5 times greater than those of the monomer. Dimerization has also caused a significant decrease in the total body clearance and distribution volume at the steady state of the native HSA. rHSA dimer accumulated to a lesser extent in the liver, skin, muscle, and fat, as compared with the native HSA. Up to 96 h, the vascular permeability of the rHSA dimer was less than that of the native HSA in paw edema mouse models. A prolonged plasma half-life of the rHSA dimer was also observed in the edema model rats. Conclusions. rHSA dimer has a high retention rate in circulating blood and a lower vascular permeability than that of the native HSA.

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Reversal of the Effect of Albumin on Gut Barrier Function in Burn by the Inhibition of Inducible Isoform of Nitric Oxide Synthase

Cited by 25 publications

References 23 publications

Pentoxifylline Modulates Intestinal Tight Junction Signaling After Burn Injury: Effects on Myosin Light Chain Kinase

Pentoxifylline Modulates Intestinal Tight Junction Signaling After Burn Injury: Effects on Myosin Light Chain Kinase

Toll-Like Receptor Stimulation Induces Nondefensin Protein Expression and Reverses Antibiotic-Induced Gut Defense Impairment

Recombinant Human Serum Albumin Dimer has High Blood Circulation Activity and Low Vascular Permeability in Comparison with Native Human Serum Albumin

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