thiourea and Burns

Suppressed adaptive immune function is one of the major concerns responsible for the development of opportunistic infections and subsequent sepsis with high mortality in severe burns. Endoplasmic reticulum stress (ERS) is the endogenous self-protective mechanism, and it plays an important role in almost every process of living by regulating the balance between homeostasis and apoptosis. The current study investigated the involvement of ERS in the pathogenesis of dysfunction of dendritic cells (DCs) in burn mice. Our results show a significant ERS response in splenic DC after burn injury. Treatment with salubrinal (Sal, reported to protect cells against ERS-induced apoptosis.) decrease the apoptotic rate of DC induced by burns, and promote maturation and activation of DC, as well as the ability to promote T cell proliferation and polarization towards Th1 immunity (all P<0.05). Gene silence of XBP-1 (key molecular in ERS response) results in the increased apoptosis and suppressed phenotypical maturation of splenic DC in burn mice. These results show that the excessive ERS is essential for immunosuppression during severe thermal injury. XBP-1 plays a pivotal role in DC functional immunomodulation in burn mice. Inhibition of apoptotic ERS response benefits mice from major burns.

Topics: Adaptive Immunity; Animals; Apoptosis; Burns; Cells, Cultured; Cinnamates; Coculture Techniques; Cytokines; Dendritic Cells; Disease Models, Animal; Endoplasmic Reticulum Stress; Lymphocyte Activation; Male; Mice, Inbred BALB C; Phenotype; RNA Interference; Severity of Illness Index; Spleen; Th1 Cells; Thiourea; Time Factors; X-Box Binding Protein 1

Burn injury has been shown to impair intestinal transit. p38 mitogen-activated protein kinase (MAPK) has been shown to be involved in the production of proinflammatory mediators such as interleukin (IL)-1beta, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). The aims of this study were to investigate the effects of SB203580, a specific p38 MAPK inhibitor, on intestinal transit and to elucidate its possible mechanism.. Burn rats and sham rats were divided into 4 groups: saline, S-methylisothiourea (a selective iNOS inhibitor), nimesulide (a selective COX-2 inhibitor), or SB203580. Intestinal transit was measured using phenol red and assessed using the geometric center. The protein or gene expression of NOS, COX-2, and IL-1beta were measured by real-time reverse-transcription polymerase chain reaction or Western blot analysis. p38 MAPK activity or myeloperoxidase (MPO) activity was determined by using the p38 MAPK assay kit or MPO assay kit.. Intestinal transit was delayed significantly with burn injury, improved significantly with S-methylisothiourea and nimesulide, but almost completely normalized with SB203580. p38 MAPK activity, MPO activity, iNOS, COX-2, and IL-1beta protein or gene expression increased markedly after burn injury. SB203580 inhibited p38 MAPK and MPO activity, and reduced iNOS, COX-2, and IL-1beta protein or gene expression.. Burn-induced delayed intestinal transit is associated with the p38 MAPK pathway. Inhibition of the p38 MAPK pathway ameliorates delayed intestinal transit, at least in part, by inhibiting iNOS, COX-2, and IL-1beta expression. Thus, p38 MAPK could represent a novel target for therapy of gut dysmotility after burn injury.

Topics: Animals; Burns; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Enzyme Inhibitors; Gastrointestinal Transit; Imidazoles; Intestinal Diseases; Male; p38 Mitogen-Activated Protein Kinases; Pyridines; Rats; Rats, Sprague-Dawley; Sulfonamides; Thiourea

Despite histamine being a potent endogenous vasoactive agent released in increasing amounts postburn, its role in postburn oedema formation has been controversial and its effect on burn circulation poorly investigated. The present study investigated the involvement of H(1), H(2) and H(3) receptors in postburn edema in rats exposed to skin and muscle burns and their influence on skin circulation postburn. We used the selective antagonists clemastine (H(1)), ranitidine (H(2)), thioperamide (H(3)) and the selective H(3) receptor agonist, imetit. Results showed that none of the antagonists or the H(3) agonist had significant effect on postburn edema measured by quantitative spectrophotometric analysis of extravasated Evans blue-albumin in the full-thickness burned skin or muscle. Clemastine and thioperamide failed to induce significant effect on blood flow in the partial- or full-thickness skin burn injury as measured by laser Doppler flowmetry, while ranitidine significantly (P<0.01) reduced blood flow in the full-thickness burn. In contrast, the H(3) receptor agonist, imetit, significantly increased blood flow, both in the partial-thickness burn injury (P<0.05) and in the full-thickness burn (P<0.01). Moreover, imetit significantly (P<0.01) increased mean arterial pressure while thioperamide significantly (P<0.01) reduced systemic pressure. In conclusion, H(1), H(2) and H(3) receptors are not important actors in the regulation of vascular patency permeability, whereas H(3) receptors play an important role by increasing skin circulation postburn, presumably by relaxation of vascular smooth muscle and/or by interacting with other inflammatory neurotransmitters. Data also suggest that H(2) receptor blockers may not be best choice for stress ulcer prophylaxis in burn patients.

Topics: Animals; Burns; Clemastine; Edema; Histamine Agonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Imidazoles; Male; Piperidines; Ranitidine; Rats; Rats, Sprague-Dawley; Receptors, Histamine; Receptors, Histamine H3; Regional Blood Flow; Skin; Statistics, Nonparametric; Thiourea

We found that rats subjected to thermal skin injury (burn) had increased serum hydrogen peroxide (H2O2) scavenging activity, serum catalase activity, erythrocyte (RBC) fragility, and edematous lung injury (lung leak) when compared to sham-treated rats. Serum H2O2 scavenging activity was inhibited by addition of sodium azide, a catalase inhibitor. Treatment of rats with the oxygen radical scavenger, dimethylthiourea (DMTU), decreased RBC fragility and lung leak but did not alter increased H2O2 scavenging or catalase activity of serum from rats subjected to skin burn. We conclude that increased serum catalase activity is a consequence of thermal skin injury and that increased serum catalase activity may be a mechanism that modulates H2O2-dependent processes following skin burn.

Topics: Animals; Burns; Catalase; Erythrocytes; Free Radical Scavengers; Hemolysis; Hydrogen Peroxide; Lung; Permeability; Rats; Skin; Thiourea

Inasmuch as xanthine oxidase (XO)-derived O2* metabolites may contribute to vascular endothelial injury and Factor VIII antigen (F8Ag) is a component of endothelial cells, we hypothesized that XO-derived O2* might damage and cause distant organ endothelial cells to release F8Ag in rats subjected to skin burn. We found that serum F8Ag (ELISA) increased in the blood of rats subjected to skin burn (70 degrees C water to shaved dorsal skin for 30 seconds) but not in sham control rats (30 degrees C water). Coincidentally, F8Ag levels also decreased in lung and kidney tissue sections (immunofluorescent staining) of burned rats but not sham rats. Increases in circulating F8Ag levels and decreases in tissue F8Ag levels appeared to result from XO-derived O2* metabolites: F8Ag levels did not increase in the blood and did not decrease in the tissues of rats pretreated with allopurinol (a specific XO inhibitor, 50 mg/kg) or dimethylthiourea (DMTU) (a permeable O2* metabolite scavenger, 250 mg/kg). Lung injury as assessed by permeability studies (I125-albumin leak) paralleled changes in blood F8Ag levels in sham, burn, allopurinol-, and DMTU-treated groups. We conclude that skin burn causes a systemic vascular injury that can be inhibited by allopurinol or DMTU and is reflected by increased circulating and tissue decreased Factor VIII antigen levels. Release of Factor VIII antigen may serve as a valuable marker of distant organ injury in patients with skin burn.

Topics: Allopurinol; Animals; Antigens; Burns; Capillary Permeability; Endothelium; Factor VII; Kidney; Lung; Male; Osmolar Concentration; Pulmonary Circulation; Rats; Skin; Thiourea; von Willebrand Factor

Previous studies from our laboratory have demonstrated that thermal injury to the skin of rats is associated with the production of oxygen radicals by complement-activated blood neutrophils, resulting in acute lung injury as demonstrated by increases in lung vascular permeability and morphological evidence of vascular endothelial cell damage, interstitial edema, and alveolar hemorrhage. In the present study, the analysis of sera from thermally injured rats reveals an isoenzyme profile for lactate dehydrogenase (LDH;EC 1.1.1.27) that is compatible with origin from lung. The appearance of LDH-4 isoenzyme in serum of thermally injured rats correlates linearly with indices of lung damage, supporting the results of previous studies suggesting that thermal trauma to the skin can cause oxygen radical production by complement-activated blood neutrophils with resultant acute microvascular injury in the lung interstitium. Furthermore, interventions that protect from oxidant-mediated lung injury (catalase, scavengers of hydroxyl radical, iron chelators or neutrophil depletion) result in significant reductions in serum levels of the LDH-4 isoenzyme following thermal injury to the skin. Thus, measurements of LDH isoenzyme patterns in serum appear to be useful in monitoring tissue damage such as oxygen radical-mediated acute lung injury.

Topics: Animals; Burns; Deferoxamine; Free Radicals; Isoenzymes; L-Lactate Dehydrogenase; Lung; Lung Diseases; Lung Injury; Neutrophils; Oxidants, Photochemical; Oxygen; Rats; Rats, Inbred Strains; Skin; Thiourea

Topics: Animals; Blood Substitutes; Burns; Dogs; Drug Combinations; Guanylthiourea; Homeostasis; Microcirculation; Oxygen Consumption; Polyvinyl Alcohol; Shock; Sodium Chloride; Thiourea

The effects of the H2-antagonists, metiamide and cimetidine, on the oedema following limb ischaemia or scald have been investigated in two strains of rat. No inhibition of oedema formation was found except when large doses of cimetidine were given before scalding. This effect was attributed to the fall in body temperature. Our results do not support the view that H2-receptors are concerned in the vascular response to injury.

Topics: Animals; Body Temperature; Burns; Cimetidine; Depression, Chemical; Edema; Guanidines; Male; Metiamide; Rats; Receptors, Histamine H2; Thiourea

Topics: Administration, Topical; Adolescent; Adult; Burns; Bursitis; Child; Child, Preschool; Contusions; Female; Humans; Inflammation; Insect Bites and Stings; Isothiuronium; Male; Middle Aged; Ointments; Sprains and Strains; Tenosynovitis; Thiourea; Wounds and Injuries

Our previous studies led to the development of a drug, 10-undecen-1- pseudothiourea iodide (AHR-1911), with the characteristics of a broad spectrum of antibacterial-antimycotic action and anti-inflammatory properties in experimental lesions induced by burns, dextran, albumin, carrageenin and kaolin. Using different vehicles for topical use, these two types of therapeutic property were separated, yielding two pharmaceutical preparations with different indications. One is a 0,25% AHR-1911 preparation in a polyoxyethyleneglycol base, which in in vivo experiments has the antimicrobial efficacy of gentamycin ointment; the other, containing 10% AHR-1911 in a vanishing cream base with triethanolamine stearate, possesses the anti-inflammatory efficacy of the newer topical steroid preparations. The clinical data for this latter preparation agree with the experimental findings. Its activity in clinical conditions was found first by Di Prisco in dermatological cases and confirmed in contact dermatitis patients by Riobueno. Its usefulness in burns and contusions with excoriations, without a single instance of secondary infection was reported by Rojas Mratínez; its effectiveness in bursitis and tenosynovitis may extend its field of application beyond that of dermatology. Particularly impressive were the good results obtained in insect bites, due possibly to the antihistaminic effect of the drug acting synergistically with the anti-inflammatory one. In the experience of all the clinicians the preparation was very well tolerated.

Topics: Bacterial Infections; Burns; Drug Evaluation; Humans; Inflammation; Isothiuronium; Ointments; Thiourea

Topics: Acetylcholine; Administration, Topical; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antifungal Agents; Arthritis; Arthrodermataceae; Bacteria; Blood Pressure; Burns; Candida; Candidiasis; Carrageenan; Depression, Chemical; Dextrans; Gastrointestinal Motility; Guinea Pigs; Hindlimb; Kaolin; Mice; Rabbits; Rats; Staphylococcal Infections; Thiourea