TNF-α‒Mediated Keratinocyte Expression and Release of Matrix Metalloproteinase 9: Putative Mechanism of Pathogenesis in Stevens‒Johnson Syndrome/Toxic Epidermal Necrolysis.

Stevens‒Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are severe cutaneous adverse drug reactions characterized by widespread keratinocyte cell death and epidermal detachment. At present, there is little understanding of how the detachment occurs or how it is abrogated by the TNF-α inhibitor etanercept, an effective SJS/TEN treatment. RNA sequencing was used to identify upregulated transcripts in formalin-fixed paraffin-embedded SJS/TEN skin biopsies. Epidermal matrix metalloproteinase 9 (MMP9) expression was assessed by immunohistochemistry in skin biopsies and cultured human skin explants exposed to serum from patients with cutaneous adverse drug reactions. TNF-α‒induced MMP9 expression and activity and its abrogation by etanercept were determined using the HaCaT immortalized keratinocyte cell line. Epidermal MMP9 expression was significantly higher in SJS/TEN skin (70.6%) than in healthy control skin (0%) (P = 0.0098) and nonbullous skin reactions (10.7%) (P = 0.0002). SJS/TEN serum induced significant MMP9 expression and collagenase activity in healthy skin explants, which was reduced by etanercept. Etanercept was also able to negate the TNF-α‒induced MMP9 expression in the HaCaT cell line. Data suggest that elevated epidermal MMP9 expression and collagenase activity are a putative pathogenic mechanism in SJS/TEN, which is limited by etanercept. Modulation of MMP9 expression and activity represents, to our knowledge, a previously unreported therapeutic target for the treatment of SJS/TEN.

Plasma cadmium and zinc and their interrelationship in adult Nigerians: potential health implications.

Zinc (an essential trace element) and cadmium (a ubiquitous environmental pollutant with acclaimed toxicity) have been found to occur together in nature, with reported antagonism between the two elements. The present study aimed at determination of plasma levels of zinc (Zn) and cadmium (Cd) and their interrelationship in adult Nigerians. The series comprised adults (n=443) aged ≥18 yrs (mean ± SD 38.4±13.7 yrs), consisting of 117 males, 184 non-pregnant and 140 pregnant females. Sociodemographic data were collected by questionnaire while anthropometrics were determined using standard methods. Plasma Cd and Zn were determined by using an atomic absorption spectrophotometer. The mean plasma zinc and cadmium were 94.7±18.1 µg/dl and 0.150±0.548 µg/dl, respectively. Age, sex, pregnancy, and parity had no effect on either plasma Zn or Cd. Although educational level had no effect on plasma Zn, it had a significant effect on Cd; subjects possessing either secondary or tertiary education had significantly lower plasma Cd than subjects without formal education. Moreover, there seemed to be an inverse relationship between Cd and Zn, but this was not statistically significant (r=-0.089; p=0.061). Although plasma Zn was not related to BMI (r=0.037; p=0.432), Cd was significantly negatively correlated with BMI (r=-0.124; p=0.009). It may be concluded that adult Nigerians in Ebonyi State have elevated plasma levels of Cd, with apparent impact on the levels of plasma Zn. This has important public health implications considering the essential roles of Zn in the protection of Cd mediated adverse health effects. While food diversification is recommended to improve plasma Zn, efforts should be made to reduce exposure to Cd to mitigate partially its possible adverse effects.