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Role of Oxidative and Nitrosative Stress in Pathophysiology of Toxic Epidermal Necrolysis and Stevens Johnson Syndrome—A Pilot Study

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      Abstract

      Background:

      Oxidative and nitrosative stress caused by drug metabolism may be a trigger for keratinocyte apoptosis in the epidermis seen in toxic epidermal necrolysis (TEN) and Stevens Johnson syndrome (SJS).

      Aims:

      To estimate oxidative damage in the serum and to examine the role of nitric oxide in mediating epidermal damage in patients with TEN and SJS.

      Materials and Methods:

      A prospective study was conducted among TEN and SJS patients and controls in a tertiary care center between January 2006 and February 2010. Patients with a maculopapular drug rash without detachment of skin constituted the control group 1 (drug exposed). Patients without a drug rash constituted the control group 2 (drug unexposed). The serum values of protein carbonyls, malondialdehyde, conjugated diene and nitrates were measured. Two-group comparison with the non-parametric Mann–Whitney U test was used. Significance of differences if any was established using Pearson's Chi-square test.

      Results:

      Ten patients in the SJS-TEN group (study group), 8 patients in control group 1 and 7 patients in control group 2 were included. More than one drug was implicated in 4/10 patients in group 1 and 3/8 patients in group 2. SCORTEN of 0, 1 and 3 at admission were seen in 2, 6 and 2 patients, respectively. The serum values of protein carbonyls, malondialdehyde, conjugated diene and nitrates were not significantly increased in the study group when compared to the controls.

      Conclusions:

      There was no elevation of oxidative stress markers in patients with TEN and SJS as compared to the control population.

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      Most cited references 20

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      Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin.

      Toxic epidermal necrolysis (TEN, Lyell's syndrome) is a severe adverse drug reaction in which keratinocytes die and large sections of epidermis separate from the dermis. Keratinocytes normally express the death receptor Fas (CD95); those from TEN patients were found to express lytically active Fas ligand (FasL). Antibodies present in pooled human intravenous immunoglobulins (IVIG) blocked Fas-mediated keratinocyte death in vitro. In a pilot study, 10 consecutive individuals with clinically and histologically confirmed TEN were treated with IVIG; disease progression was rapidly reversed and the outcome was favorable in all cases. Thus, Fas-FasL interactions are directly involved in the epidermal necrolysis of TEN, and IVIG may be an effective treatment.
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        Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis.

        Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening adverse drug reactions characterized by massive epidermal necrosis, in which the specific danger signals involved remain unclear. Here we show that blister cells from skin lesions of SJS-TEN primarily consist of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, and both blister fluids and cells were cytotoxic. Gene expression profiling identified granulysin as the most highly expressed cytotoxic molecule, confirmed by quantitative PCR and immunohistochemistry. Granulysin concentrations in the blister fluids were two to four orders of magnitude higher than perforin, granzyme B or soluble Fas ligand concentrations, and depleting granulysin reduced the cytotoxicity. Granulysin in the blister fluids was a 15-kDa secretory form, and injection of it into mouse skin resulted in features mimicking SJS-TEN. Our findings demonstrate that secretory granulysin is a key molecule responsible for the disseminated keratinocyte death in SJS-TEN and highlight a mechanism for CTL- or NK cell--mediated cytotoxicity that does not require direct cellular contact.
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          Nitric oxide and its role in apoptosis.

          Nitric oxide (NO.), a potentially toxic molecule, has been implicated in a wide range of diverse (patho)physiological processes. It is appreciated that the production of NO. from L-arginine is important for nonspecific host defense, helping to kill tumors and intracellular pathogens. Cytotoxicity as a result of a massive NO.-formation is now established to initiate apoptosis. Apoptotic cell death in RAW 264.7 macrophages and several other systems as a result of inducible NO-synthase activation comprises upregulation of the tumor suppressor p53, activation of caspases, chromatin condensation, and DNA fragmentation. The involvement of NO was established by blocking adverse effects by NO-synthase inhibition. Overexpression of the antiapoptotic protein Bcl-2 rescued cells from apoptosis by blocking signal propagation downstream of p53 and upstream of caspase activation. As the wide variety of NO.-effects is achieved through its interactions with targets via redox and additive chemistry, the biological milieu, as a result of internal and external stimuli, may modulate toxicity. Therefore, transducing pathways of NO. are not only adopted to cytotoxicity but also refer to cell protection. NO.-signaling during protection from apoptosis is in part understood by the requirement of gene transcription and protein synthesis. NO.-formation causes upregulation of protective proteins such as heat shock proteins, cyclooxygenase-2, or heme oxygenase-1 which in a cell specific way may attenuate apoptotic cell death. Alternatively, protection may result as a consequence of a diffusion controlled NO./O2- (superoxide) interaction. The NO./O2--interaction redirects the apoptotic initiating activity of either NO. or O2- towards protection as long as reduced glutathione compensates the resultant oxidative stress. Protective principles may further arise from cyclic GMP formation or thiol modification. NO shares with other toxic molecules such as tumor necrosis factor-alpha the unique ability to initiate and to block apoptosis, depending on multiple variables that are being elucidated. The crosstalk between cell destructive and protective signaling pathways, their activation or inhibition under the modulatory influence of NO. will determine the role of NO in apoptotic cell death.
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            Author and article information

            Affiliations
            From the Department of Dermatology, Venereology and Leprology, Division of Gastrointestinal Sciences, Christian Medical College, Vellore, Tamil Nadu, India
            [1 ] Wellcome Trust Research Laboratory, Division of Gastrointestinal Sciences, Christian Medical College, Vellore, Tamil Nadu, India
            Author notes
            Address for correspondence: Dr. Peter Dincy, Department of Dermatology, Venereology and Leprosy, Christian Medical College, Vellore - 632 004, Tamil Nadu, India. E-mail: dincypeter@ 123456gmail.com
            Journal
            Indian J Dermatol
            Indian J Dermatol
            IJD
            Indian Journal of Dermatology
            Medknow Publications & Media Pvt Ltd (India )
            0019-5154
            1998-3611
            Sep-Oct 2015
            : 60
            : 5
            : 427-431
            4601406 IJD-60-427 10.4103/0019-5154.159617
            Copyright: © Indian Journal of Dermatology

            This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

            Categories
            Basic Research

            Dermatology

            keratinocyte apoptosis, oxidative stress, toxic epidermal necrolysis

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