Erythroderma and Epidermal Necrosis Induced by a Type of Proton Pump Inhibitor in Beagle Dogs

Abstract

Reddish skin covering the entire body (erythroderma) was observed in a preliminary one-week oral toxicity study of a type of proton pump inhibitor in Beagle dogs. Histologically, full-thickness epidermal necrosis accompanied by apoptosis, evidenced by an immunohistochemical positive reaction to cleaved caspase-3, and detachment of the epidermis were observed in the skin. In the epidermis and upper dermis, a slight infiltration of mononuclear cells was seen, which was predominantly positive for MAC387 (macrophages) and partly positive for CD3 (T lymphocytes). These findings have some similarities to drug-induced severe skin reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) and may represent incipient changes of such lesions. The skin lesions observed in these dogs are being considered as a potential animal model of cutaneous drug reactions. (J Toxicol Pathol 2007; 20: 257-261)

Apoptosis as a Mechanism for Keratinocyte Death in Canine Toxic Epidermal Necrolysis

“…10 In contrast, 2 later case reports of 1 dog each affected with drug-induced TEN showed numerous activated caspase-3 and TUNEL-positive apoptotic epidermal keratinocytes, thereby challenging the initial hypothesis of massive necrosis in favor of a possible role of apoptosis in canine TEN development. 8,9 The results of our study extend these recent observations and provide additional support for epidermal keratinocyte apoptosis to represent one of the initial steps in canine TEN pathogenesis, as proposed 20 years ago for human TEN. 12…”

“…The author of a recent review article, which compared the etiology, pathogenesis, and diagnostic and therapeutic aspects of EM and TEN, proposed that locally extensive to confluent waves of apoptosis with little lymphocyte-mediated cell attack represent the hallmark of epidermal TEN cell death in both humans and dogs. 17 Unfortunately, existing reports into the pathogenesis of keratinocyte cell death in canine TEN were not addressed, [8][9][10] leaving uncertainty about the pathogenesis of disease, the understanding of which is critical for mechanism-based therapy to provide an optimal outcome to canine patients affected with this often fatal disease. The first investigation of cell death in various animal skin diseases, which included 4 dogs with TEN, showed no TUNELpositive cells in the epidermis; the author concluded that massive necrosis rather than apoptosis was responsible for the epidermal cell death of animal TEN.…”