Nitric Oxide Synthase in Toxic Epidermal Necrolysis and Stevens–Johnson Syndrome

Lerner, Lisa H.; Qureshi, Abrar A.; Reddy, Bhaskar V.; Lerner, Ethan A.

doi:10.1046/j.1523-1747.2000.00816.x

Cited by 60 publications

(60 citation statements)

References 32 publications

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“…These effects might be mediated by an increase in Ca 2+ intracellular influx or mobilization from the intracellular pool, the formation of ROS including nitric oxide [38], and hyperactivity of the CD95 and TNF-α systems. Complex interaction probably links these cytotoxic effects.…”

Section: Ten Pathomechanismmentioning

confidence: 99%

Novel Treatments for Drug-Induced Toxic Epidermal Necrolysis (Lyell’s Syndrome)

Paquet

Pierard

Quatresooz³

2005

Int Arch Allergy Immunol

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Drug-induced toxic epidermal necrolysis (TEN) is a life-threatening disease characterized by extensive destruction of the epidermis. It apparently results from the formation of specific toxic drug metabolites by the keratinocytes. The mortality rate which averages 25–30% is mainly due to secondary septicemia, and to ionic and metabolic disturbances following loss of epidermal integrity. Apoptosis is the likely mechanism leading to massive keratinocyte death in TEN. Dysregulations in the tumor necrosis factor-α (TNF-α) pathway, CD95 system (Fas ligand, CD95L; Fas receptor, CD95R) and calcium homeostasis in the epidermis are involved in this apoptotic process. An active role has also been ascribed to T lymphocytes, macrophages and factor XIIIa-positive dermal dendrocytes. Despite progress, treatment of TEN remains controversial. In the past, systemic glucocorticoids were used in order to target the inflammatory reaction in TEN. However, there was no evidence for improvement of the healing process, while corticosteroids worsened the prognosis by increasing the risk of septicemia. Only a few cases have been treated with other drugs including cyclophosphamide, pentoxyfilline, thalidomide, anti-TNF-α antibodies and cyclosporin A. In the recent past, some TEN patients were treated with intravenous human immunoglobulins (IVIG). The rationale for such a treatment was to block the CD95 system on keratinocytes. The early promising clinical results of IVIG treatment in TEN were subsequently challenged. This review compares the effectiveness and drawbacks of the major drugs presently used in TEN treatment. Some future prospects in TEN management are also discussed.

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Section: Ten Pathomechanismmentioning

confidence: 99%

Novel Treatments for Drug-Induced Toxic Epidermal Necrolysis (Lyell’s Syndrome)

Paquet

Pierard

Quatresooz³

2005

Int Arch Allergy Immunol

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“…Treatment modalities that have been the object of case reports or small series include banana leaves [13], pentoxyfylline [14], antioxidants [15]and corticosteroids [16]. The use of corticosteroids is still controversial [17].…”

Section: Introductionmentioning

confidence: 99%

Effect of High-Dose Intravenous Immunoglobulin Therapy in Stevens-Johnson Syndrome: A Retrospective, Multicenter Study

et al. 2003

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Background:Stevens-Johnson syndrome (SJS) is a severe cutaneous drug reaction associated with considerable morbidity, possible transition to toxic epidermal necrolysis (TEN) and death in certain cases. Objective: To determine whether treatment with high-dose IVIG in SJS patients may improve outcome. Methods: Data from 12 patients (collected between January 1997 and November 2000 from7 university dermatology centers in Europe and North America) diagnosed with SJS according to a recent consensus definition was analyzed retrospectively. All patients had progressive ongoing epidermal detachment at the time of treatment initiation. Patients with overlap syndromes and TEN were excluded. Tolerance, survival at 45 days after onset and total healing time were assessed. Results: Twelve SJS patients (mean age 44 years) were treated with IVIG at a mean dose of 0.6g/kg/day for an average of 4 days. An objective response to IVIG infusion was observed in all patients within a mean of 2 days, and the overall survival rate was 100%. Total skin healing occurred, on average, within 8.3 days. Time to total healing was shorter in a group of patients with fewer severe underlying diseases who had received IVIG infusion rapidly after the onset of skin lesions. Conclusion: High-dose IVIG may be effective in blocking the progression of SJS and reducing the time to complete skin healing.

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“…TNF-· also stimulates inducible NO synthase (iNOS) leading to the production of a large amount of NO (35). Increased expression of iNOS has been demonstrated in TEN (36). Generation of ROS may also increase CD95R expression on keratinocytes (37).…”

Section: Tentative Physiopathological Pathway Of Ten Epidermal Destrumentioning

confidence: 98%

“…interferon, interleukin-1 and TNF-· (35). In TEN, iNOS is induced in keratinocytes, but the steps between exposure to a drug and the activation of iNOS remain unclear (36).…”

Section: Tentative Physiopathological Pathway Of Ten Epidermal Destrumentioning

confidence: 99%

Toxic epidermal necrolysis: Revisiting the tentative link between early apoptosis and late necrosis (Review)

Paquet

Pierard

2007

Int J Mol Med

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Abstract. Toxic epidermal necrolysis (TEN) is a dramatic drug-induced reaction that may lead to full destruction of the epidermis and epithelial mucosae. The keratinocytes themselves seem to play a major role in the pathogenic mechanism. Biochemical and morphological studies performed on early epidermal lesions demonstrated that keratinocytes undergo apoptosis, but histological and clinical data show evidence of necrosis of the epidermis later in the disease evolution. Based on the limited information currently available about TEN pathomechanism, we present a 'mitochondrial hypothesis' that may explain both early apoptosis and late necrosis in TEN epidermis. Strong electrophilic drug metabolites are generated in TEN-affected keratinocytes due to an impaired detoxication pathway. These compounds presumably disrupt the electron transfer chain in the mitochondriae resulting in a decline in ATP production, loss of electrochemical gradient across the inner membrane (Δψm), and partial reduction in O 2 with production of reactive oxygen species (ROS). The latter compounds directly damage cell membranes and act as intracellular chemical messengers stimulating proapoptotic systems such as CD95 and TNF-·, which in turn can activate nitric oxide (NO) metabolism. NO interacts with ROS to enhance their toxic effects. These proapoptotic events represent swift processes in the involved cells. The loss of Δψm and the opening of permeability transition pores in the mitochondrial membrane lead to osmotic swelling and rupture of these organelles with subsequent necrosis of the cell. The necrotic events follow apoptosis when both phenomena are present.

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Nitric Oxide Synthase in Toxic Epidermal Necrolysis and Stevens–Johnson Syndrome

Cited by 60 publications

References 32 publications

Novel Treatments for Drug-Induced Toxic Epidermal Necrolysis (Lyell’s Syndrome)

Novel Treatments for Drug-Induced Toxic Epidermal Necrolysis (Lyell’s Syndrome)

Effect of High-Dose Intravenous Immunoglobulin Therapy in Stevens-Johnson Syndrome: A Retrospective, Multicenter Study

Toxic epidermal necrolysis: Revisiting the tentative link between early apoptosis and late necrosis (Review)

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