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

Abstract

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.

Toxic epidermal necrolysis: Review of pathogenesis and management

“…43 The aforementioned events are proposed to cause apoptosis in the short term; however, the loss of mitochondrial integrity and permeability pores lead to cellular swelling and subsequent necrosis. 7 This correlates with the early apoptosis and late necrosis seen histologically in TEN. Current therapies may not target the initiating events in TEN but rather abrogate later events once a process of epidermal destruction has already begun.…”

Toxic Epidermal Necrolysis and Graft-versus-Host Reaction: Revisiting a Puzzling Similarity

“…The following phase of TEN is characterized by full-thickness epidermal necrosis. Hence, it is assumed that the TEN pathomechanism likely combines early apoptosis and late necrosis [13, 14]. …”

Facing up to toxic epidermal necrolysis

“…A two-step pathomechanism involving the initiation and amplification phases was recently suggested in TEN [2,8]. This hypothesis is not yet supported by full experimental data and demonstration.…”

“…Close interactions between inflammatory cells and keratinocytes lead to the massive epidermal destruction. At this stage, necrosis prevails over single-cell apoptosis [8].…”