Possible involvement of gelatinase A (MMP2) and gelatinase B (MMP9) in toxic epidermal necrolysis or Stevens-Johnson syndrome

Abstract

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are considered to be drug-induced diseases, and are characterized by extensive mucocutaneous disorder and epidermal necrosis which result in the detachment of the epidermis. Inactive and active forms of metalloproteinases (MMP2 and MMP9) secreted by skin explants maintained in organ culture for 72 h and in blister fluid from two TEN and three SJS patients were investigated. Interestingly, lesional skin from both the TEN and the SJS patients cultured for 3 days in conditioned medium showed high levels of both 72 kDa progelatinase A and 66 kDa activated gelatinase A, and the 66 kDa activated form was not observed in cultures of skin from control individuals. Furthermore, indirect immunodetection showed the presence of MMP2 and MMP9 in TEN and SJS patients' skin. Increased gelatinase activity in the culture medium of TEN and SJS skin maintained in organ culture and in blister fluid indicates that these gelatinases may be responsible for the detachment of the epidermis in these drug-induced necrolyses.

Expression of matrix metalloproteinases 2, 9 and 11 in erythema multiforme: immunohistochemical comparison with Stevens–Johnson syndrome/toxic epidermal necrolysis

“…Also, both EM and SJS/TEN lesions were characterized by higher expression of gelatinases than LP and healthy skin specimens. Taken together, these findings are in contrast to previous studies, which did not highlight differences between SJS/TEN and LP, and healthy control specimens 3–5 . The expression of gelatinases by various cell types, such as keratinocytes, fibroblasts, T lymphocytes and macrophages, may be induced by various proinflammatory mediators, such as tumour necrosis factor (TNF)‐α 2 and free radicals.…”

“…Among the effectors of the tissue damage, matrix metalloproteinases (MMPs) 2 and 9 (gelatinases) have been demonstrated in the blister fluid and in the epidermis of SJS/TEN lesions 3,4 . The expression of several MMPs has also been demonstrated in normal skin and in other immune‐mediated cutaneous diseases, including those featuring interface dermatitis, such as lichen planus (LP) 5 .…”

Toxic epidermal necrolysis

“…Increased gelatinase A and B activity, expression of calprotectin (an antimicrobial protein not found in normal skin), and increased nitric oxide (which can induce apoptosis of keratinocytes) are all additional features. [124][125][126] Precisely what role, if any, these abnormalities play in pathogenesis remains to be elucidated.…”

Immunologic Mediators in Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis

“…Their role in the pathogenesis of SJS/ TEN is unclear. 19,50,61,62 Granulysin Granulysin was recently shown as critical to the widespread epidermal necrosis observed in SJS/TEN, and has been proposed as a primary mediator of apoptosis in the disorder. Gene expression profiling has identified granulysin as the most highly expressed cytotoxic molecule in SJS/TEN blister fluid, with concentrations of granulysin two to four orders of magnitude higher than that of perforin/ granzyme B or sFasL.…”