Evaluation of selective and non-selective cyclooxygenase inhibitors on sulfur mustard-induced pro-inflammatory cytokine formation in normal human epidermal keratinocytes. (15th September 2019)

• Record Type: Journal Article
• Authors: Wagner, Simon; Lang, Simon; Popp, Tanja; Schmidt, Annette; Thiermann, Horst; Steinritz, Dirk; Kehe, Kai
• Is Part Of: Toxicology letters. Volume 312(2019)
• Page Start: 109
• Page End: 117
• Publication Date: 2019-09-15
• Subjects: ASA acetylsalicylic acid -- AU artificial units -- CaCl2 calcium chloride -- COX cyclooxygenase -- DMSO dimethyl sulfoxide -- ELISA enzyme-linked immunosorbent assay -- EtOH ethanol -- IL-6 interleukin-6 -- IL-8 interleukin-8 -- JAK-STAT Janus kinase-signal transducers and activators of transcription -- KGM2 keratinocyte growth medium 2 -- NHEK normal human epidermal keratinocytes -- NF-kB nuclear factor kappa-light-chain-enhancer of activated b-cells -- NSAID non-steroidal-anti-inflammatory-drug -- PBS phosphate buffered saline -- PGE2 prostaglandin E2 -- SM sulfur mustard -- TNF-α tumor necrosis factor-alpha; COX -- NSAID -- NHEK -- Sulfur mustard -- PGE2 -- IL-6 -- IL-8 -- TNF-α; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2019.03.012
• Languages: English
• ISSNs: 0378-4274

Abstract

Abstract: Sulfur mustard (SM) is a highly toxic chemical warfare agent, which produces blisters after skin contact. Treatment of SM-induced adverse health effects, such as cutaneous blistering, ulceration, and inflammation remains a challenging task. Antidotes or specific therapeutic measures are lacking. Some drugs ( e.g. cyclooxygenase (COX) inhibitors) exhibited beneficial effects after SM poisoning in vivo . However, in vitro studies that evaluate and compare the potency of COX inhibitors are missing. In the presented study, non-specific (acetylsalicylic acid, ibuprofen, diclofenac, indomethacin, and piroxicam), COX-2-specific (celecoxib and parecoxib) inhibitors and COX-independent drugs (paracetamol and tofacitinib) were compared regarding anti-inflammatory and cytoprotective effects after SM exposure in post-exposure treatment settings. Normal human epidermal keratinocytes (NHEK) were used as a surrogate model. Prostaglandin E2 (PGE2 ) formation, a direct indicator for COX activity, was determined by ELISA. Changes in pro-inflammatory cytokine levels after SM exposures were assessed by quantitative determination of 27 inflammatory cytokines using a multiplex method. Cytotoxicity was determined using an XTT viability assay. The results demonstrated that SM highly increased PGE2 production and release of pro-inflammatory cytokines, predominantly IL-6, IL-8 and TNF-α. In general, all COX inhibitors and paracetamol were able to reduce the PGE2 formation, while tofacitinib, an inhibitor of Janus kinase, had no influence on PGE2 levels. In addition, IL-6, IL-8, and TNF-α formation were also inhibited, but sometimes independently of PGE2 . The COX-2 specific celecoxib was identified as the most potent drug to reduce IL-6, IL-8 and TNF-α formation after SM exposures in vitro . However, cell viability was not improved significantly by any of the investigated drugs in our experiments.