Hong-Tai Tang

Activation of p38 MAPK by Reactive Oxygen Species Is Essential in a Rat Model of Stress-Induced Gastric Mucosal Injury

Stress ulceration is a common complication in critically ill patients and can result in significant upper gastrointestinal bleeding associated with a high morbidity and mortality. At present, little is known of the molecular mechanisms underlying the incidence of this type of gastric damage. In the present study, we investigated the temporal activation of the redox-sensitive p38 signaling transduction cascade and its roles in a well-defined experimental model of cold immobilization stress-induced gastric ulceration. Exposure of Sprague-Dawley rats to 6 h of cold immobilization stress led to a rapid activation of p38 in the gastric mucosa at as early as 15 min after stress, and this activation was maximal after 1.5 h of stress and still persisted until the end of stress. Selectively blocking p38 by pretreatment with SB 239063, a potent and selective p38 inhibitor, suppressed the stress-promoted TNF-α, IL-1β, and CINC-1 production and then prevented the subsequent neutrophil infiltration, gastric mucosal epithelial necrosis and apoptosis, and the ulcerative lesions formation. Prior administration of the free radical scavengers, tempol and N-acetyl-l-cysteine, abolished the stress induction of p38 activation and the resulting mucosal inflammation and gastric injury. These results demonstrate that reactive oxygen species-mediated p38 activation plays an essential role in the pathogenesis of stress-induced gastric inflammatory damage in the rat model of cold immobilization stress. Our findings suggested that inhibition of p38 activation might be a potential strategy for the prophylaxis and treatment of stress ulceration.

Factors affecting survival in adult patients with massive burns

OBJECTIVE To identify treatment-related factors associated with mortality in massively burned adult patients. METHODS This retrospective cohort study examined survival outcomes at a burn unit of 54 beds and 10 burn ICU beds, totaling 900 admissions per year. The cases of 102 adult patients, admitted consecutively from January 1993 to October 2007, with massive burns (burn area>70% of the total body surface area, TBSA) were studied. Relevant variables were recorded from the initial injury and throughout the hospital course. Survival analysis, based on univariate and stepwise multivariate Cox proportional hazards regression, was performed to determine which variables predicted mortality. RESULTS The overall mortality rate was 30.4%. Burn size, severe inhalation injury, full-thickness burns, serum creatinine levels, inotropic support, platelet counts<20,000 per mm3, sepsis and ventilator dependency were significantly associated with mortality as determined by univariate analysis. Only sepsis, ventilator dependency and platelet counts were significant independent predictors of mortality as determined by multivariate analysis. CONCLUSIONS Sepsis, ventilator dependence (indicating severe respiratory complications), and low platelet counts (indicating thrombocytopenia) are associated with increased mortality risk in adult patients with massive burns. Methods should be sought to ameliorate these complications during treatment in burn-care units.

Notoginsenoside R1 attenuates renal ischemia-reperfusion injury in rats.

Ischemia-reperfusion (I/R) injury of the kidney is a complex pathophysiological process and a major cause of acute renal failure. It has been shown that I/R injury is related to inflammatory responses and activation of apoptotic pathways. Inhibition of certain elements of inflammatory responses and apoptotic pathway seemed to ameliorate renal I/R injury. As an effective element of Panax notoginseng, NR1 has antioxidant, anti-inflammatory, antiapoptotic, and immune-stimulatory activities. Therefore, we speculate that NR1 can attenuate renal I/R injury. Ischemia-reperfusion injury was induced by renal pedicle ligation followed by reperfusion along with a contralateral nephrectomy. Male Sprague-Dawley rats were randomized to four groups: sham group, I/R control group, NR1-1 group (rats treated with NR1, 20 mg·kg−1·d−1) and NR1-2 group (rats treated with NR1, 40 mg·kg−1·d−1). All animals were killed 72 h after I/R induction. Blood and renal tissues were collected. Renal dysfunction was observed by the level of serum creatinine and histological evaluation. Apoptosis and inflammatory response in the tissue of kidney were detected mainly with molecular biological methods. NR1 attenuated I/R-induced renal dysfunction as indicated by the level of serum creatinine and histological evaluation. It prevented the I/R-induced increases in the levels of proinflammatory cytokine TNF-&agr;, myeloperoxidase activity, phosphorylation of p38, and activation of nuclear factor &kgr;B with cell apoptosis in the kidney and enhanced expression of antiapoptosis cytokine bcl-2. Treatment with NR1 improves renal function after I/R associated with a significant reduction in cell apoptosis and inflammatory responses, which may be related to p38 and nuclear factor &kgr;B inhibition.

Sustained activation of nuclear factor-κB by reactive oxygen species is involved in the pathogenesis of stress-induced gastric damage in rats

Objective:Stress ulceration is a common complication in critically ill patients, but the mechanisms involved are poorly understood. In this study we investigated the temporal activation of the redox-sensitive transcription factor nuclear factor-&kgr;B and its roles in an experimental model of cold immobilization stress-induced gastric mucosal lesions. Design:Prospective, controlled, and randomized animal study. Setting:University research laboratory. Subjects:Male Sprague-Dawley rats. Interventions:The rats were subjected to cold immobilization stress for a total of 6 hrs. The temporal profiles of nuclear factor-&kgr;B activation and expression of tumor necrosis factor-&agr;, interleukin-1&bgr;, cytokine-induced neutrophil chemoattractant-1 (CINC-1), intercellular adhesion molecule-1 (ICAM-1), and inducible nitric oxide synthase (iNOS) were determined in the gastric corpus mucosa of stressed rats. To study the roles of nuclear factor-&kgr;B activation, rats received an intravenous bolus of a specific nuclear factor-&kgr;B inhibitor Bay 11-7082 (20 mg/kg) 1 hr before stress. For antioxidant administration, rats were treated with intravenous injection of a free radical scavenger pyrrolidine dithiocarbamate (50, 100, and 200 mg/kg) 1 hr before stress. Measurements and Main Results:Exposure of rats to 6 hrs of stress led to a rapid and persistent activation of nuclear factor-&kgr;B, which was associated with transient degradation of inhibitory protein I&kgr;B&agr; and slower but sustained degradation of I&kgr;B&bgr;. Nuclear factor-&kgr;B activation preceded the induction of tumor necrosis factor-&agr;, interleukin-1&bgr;, CINC-1, ICAM-1, and iNOS messenger RNAs, all of which were linearly increased with the duration of stress. Bay 11-7082 selectively blocked the stress-induced nuclear factor-&kgr;B activation and up-regulation of tumor necrosis factor-&agr;, interleukin-1&bgr;, CINC-1, ICAM-1, and iNOS messenger RNAs. Inhibition of expression of these proinflammatory genes prevented the increases in myeloperoxidase activity (an indicator of neutrophil infiltration) in gastric mucosa and the development of gastric damage. Pyrrolidine dithiocarbamate dose-dependently inhibited the stress-induced nuclear factor-&kgr;B pathway activation and consequential proinflammatory gene expression, neutrophil infiltration, and gastric damage, suggesting the involvement of reactive oxygen species in these processes. Conclusions:Sustained activation of nuclear factor-&kgr;B by reactive oxygen species is an important in vivo mechanism mediating stress-induced gastric inflammatory damage in rats.

Angiotensin II induces type I collagen gene expression in human dermal fibroblasts through an AP-1/TGF-β1-dependent pathway

Angiotensin II is critically involved in skin wound healing, but the underlying mechanism remains unclear. This study investigated the effect of angiotensin II on type I collagen gene activation in human dermal fibroblasts and the possible mechanism involved. Angiotensin II stimulated the mRNA and protein expression of type I collagen and TGF-beta1. Effects were abolished by the angiotensin AT1 receptor antagonist ZD7155 but not by the AT2 blocker PD123319. Blockade of TGF-beta1 markedly inhibited angiotensin II-induced type I collagen gene expression. Activator protein-1 (AP-1) decoy ODNs transfection suppressed angiotensin II-induced TGF-beta1 expression, and also, diminished type I collagen expression. These data indicated that angiotensin II induces collagen gene activation in human dermal fibroblasts through an AT1-mediated AP-1/TGF-beta1 signaling pathway.

Esophageal echo-Doppler monitoring in burn shock resuscitation: are hemodynamic variables the critical standard guiding fluid therapy?

BACKGROUND Ever since the introduction of invasive hemodynamic monitoring to major burn care, its utility remains controversial. Besides complications, invasive monitoring as a guideline for burn shock resuscitation is often associated with significant excessive fluid burden. This study was to summarize the clinical experiences of noninvasive esophageal echo-Doppler (ED) monitoring in burn shock resuscitation and discuss the significance of hemodynamic variables in assessment of fluid therapeutic goal. METHODS Twenty-one burn patients with an average total body surface area of 78.86% +/- 7.75% (62-92%) was enrolled in this retrospective study. Fluid therapy was guided according to Chinese general formula and adjusted with urinary output 1 mL/kg/hr as resuscitation goal. Hemodynamic parameters using ED was obtained, including cardiac output (CO), stroke volume (SV), myocardial contractility parameter--maximum acceleration at onset of systole (Acc), afterload parameter--total systemic vascular resistance (TSVR), preload parameter SV/Acc. RESULTS All patients were clinically diagnosed with a relatively stable condition during early shock stage. There existed inherent and dynamic tendency of hemodynamics during burn shock resuscitation with low CO, Acc, SV/Acc, and high TSVR at first followed by a continuous trend of increase in CO, Acc and SV/Acc and decrease in TSVR. Significant correlations could be seen between CO and Acc, CO and TSVR, CO and SV/Acc. The Standardized Regression Coefficients of Acc, TSVR, and SV/Acc with CO as dependent variable were 0.343, -0.670, and 0.053, respectively demonstrating that myocardial contractility and angiotasis played more important role than blood volume did in hemodynamic variation. CONCLUSIONS Hemodynamic variables cannot routinely substitute traditional variables as the burn shock resuscitation goal. Because of its noninvasiveness, ability to real-timely provide complete profile of hemodynamics, ED monitoring is a good adjunctive method for clinical judgment.

Role of inhibition of p38 mitogen-activated protein kinase in liver dysfunction after hemorrhagic shock and resuscitation

BACKGROUND The liver is one of the organs most frequently affected by trauma and hemorrhagic shock; the exact role of p38 mitogen-activated protein kinase (MAPK) activation in response to hepatic hemorrhagic shock/resuscitation (HS/R) remains unclear. MATERIALS AND METHODS C57Bl/6 mice were divided into four groups: sham-operated group, SB-only group, control group, and SB + HS/R group. Hepatocellular injury (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) and tumor necrosis factor (TNF-α) and interleukin (IL-1β) messenger ribonucleic acid (mRNA) expression in the liver were assessed 6 h after resuscitation, p38 MAPK activation in the liver was assessed at 30 min after resuscitation. RESULTS p38 MAPK activation was higher in the control group than other groups 30 min after resuscitation. p38 MAPK activation level in the SB + HS/R group did not change significantly compared with that of sham and SB-only groups, but was significantly lower than that in the control group. The TNF-α mRNA expression in the control group was significantly higher than that in the sham group. The TNF-α mRNA levels after HS/R in the SB + HS/R group were significantly lower than those in the control group and were roughly the same as those in the sham and SB-only groups. IL-1β mRNA expression showed similar changes in the four groups. Serum ALT and AST levels in the control group were significantly higher than those in the sham group. The increase in serum ALT and AST levels after HS/R in the SB + HS/R group was significantly less pronounced than that in the control group and markedly higher than that in the sham group. CONCLUSIONS p38 MAPK was phosphorylated during the HS/R process. Inhibiting the activation of p38 MAPK may attenuate HS/R injury to the liver.

An open, parallel, randomized, comparative, multicenter investigation evaluating the efficacy and tolerability of Mepilex Ag versus silver sulfadiazine in the treatment of deep partial-thickness burn injuries.

BACKGROUND Partial-thickness burns are among the most frequently encountered types of burns, and numerous dressing materials are available for their treatment. A multicenter, open, randomized, and parallel study was undertaken to determine the efficacy and tolerability of silver sulfadiazine (SSD) compared with an absorbent foam silver dressing, Mepilex Ag, on patients aged between 5 years and 65 years with deep partial-thickness thermal burn injuries (2.5–25% total body surface area). METHODS Patients were randomly assigned to either SSD (n = 82) applied daily or a Mepilex Ag dressing (n = 71) applied every 5 days to 7 days. The treatment period was up to 4 weeks. RESULTS There was no significant difference between the two treatment groups with respect to the primary end point of time to healing, which occurred in 56 (79%) of 71 patients after a median follow-up time of 15 days in the Mepilex Ag group compared with 65 (79%) of 82 patients after a median follow-up time of 16 days in the SSD group (p = 0.74). There was also no significant difference in the percentage of study burn healed. Patients in the Mepilex Ag group had 87.1% of their study burn healed (out of the total burn area) compared with 85.2% of patients in the SSD group. However, the mean total number of dressings used was significantly more in the SSD group (14.0) compared with the Mepilex Ag group (3.06, p < 0.0001). There was no significant difference in the time until skin graft was performed between the two study groups. CONCLUSION There was no difference in healing rates between Mepilex Ag and SSD, with both products well tolerated. The longer wear time of Mepilex Ag promotes undisturbed healing and makes it easier for patients to continue with their normal lives sooner. LEVEL OF EVIDENCE Therapeutic study, level III.

Pathogenic alteration in severe burn wounds

The present study aims to define the trend of time related changes with local bacterial alteration of bacterial resistance in severe burns in our burn center during a 12-year period. Retrospective analysis of microbiological results on severely burned wounds between 1998 and 2009 was carried out. A study of 3615 microbial isolates was performed. Staphylococcus aureus was the most commonly isolated pathogen (38.2%) followed by A. baumannii (16.2%), Streptococcus viridans (11.4%), Pseudomonas aeruginosa (10.4%), coagulase-negative staphylococci (CNS, 9.2%). The species ratios of S. aureus and A. baumannii increased significantly from 1st to 8th week of hospitalization, while those of Streptococcus viridans, P. aeruginosa and coagulase-negative staphylococci decreased during the same period. Bacterial resistance rates were compared between the periods 1998-2003 and 2004-2009. Vancomycin remained as the most sensitive antibiotic in S. aureus including methicillin-resistant S. aureus (MRSA). It was very likely that the majority of infections caused by Streptococcus viridans, P. aeruginosa and coagulase-negative staphylococci occurred in the early stage of burn course and the majority of infections caused by A. baumannii occurred 4 weeks after admission. The use of different antibiotics was probably the major contributor to these trends.

Burn injuries caused by ship fire: A 12-year study in Shanghai

UNLABELLED The 105 patients admitted to our Burn Institute from 1st January 1996 to 31st December 2007, with ship fire-related burns were studied retrospectively. The mean age was 30.2+/-12.6 years with a range of 1-58. One hundred and three patients (98.1%) were men and 2 (1.9%) women. The mean total burn surface area (TBSA) was 46.5%, mostly deep burns. The most common areas of burn were the head, neck and upper limb. Summer months July, August, June and September were times of highest incidence. Fifty-seven (54.3%) patients had inhalation injury, 42 received tracheotomy, and 38 received mechanical ventilation. The treatment was complex, difficult, long, and costly. The interval between burn and start of resuscitation ranged from 2.1 to 67 h with a mean of (5.9+/-4.4)h. Forty-two patients (40%) started intravenous fluid resuscitation 6h after burn. Twenty-four patients (23%) received insufficient fluid resuscitation developed hypotension and severe shock at admission. Ninety-two (87.6%) patients required operations including tracheotomy, debridement and grafting, per patient was 5.2. The mean length of hospital stay was 44.2 days. Pulmonary edema was the most common complication during the early post-burn period (within 7 days), and sepsis during the later period (>7 days). Nine patients died of MODS or sepsis, giving a mortality rate of 8.57%. CONCLUSION Caution and preventive measures are needed for persons in ships for fire-related burns.