Cytokine, chemokine, and matrix metalloproteinase response after sulfur mustard injury to weanling pig skin

Abstract

Cutaneous exposure to sulfur mustard [bis(2-chloroethyl) sulfide; SM] produces a delayed inflammatory skin response and severe tissue injury. Pig skin has organ similarities to human skin that is characterized by the content and types of epidermal lipids, the density of hair follicles and presence of sweat glands, which together afford penetration of topically applied compounds, complex inflammatory responses, and subsequent wound healing. The goal of this study was to identify in vivo proinflammatory biomarkers of the SM porcine skin injury within 72 h after SM challenge, using the weanling pig model. Changes in gene expression of inflammatory mediators were examined at 3, 6, 24, 48, and 72 h, using subtraction library analyses and by quantitation of selected transcripts by reverse transcription-polymerase chain reaction (RT-PCR). Sequence analysis of subtraction libraries identified up-regulation of IL-8 at 24, 48, and 72 h. No other specific proinflammatory gene transcripts were isolated from the libraries. Specific transcript RT-PCR analysis showed increased production of interleukin-1beta (IL-1beta), interleukin-6 (IL-6), interleukin-8 (IL-8), and matrix metalloproteinase-9 (MMP-9, gelatinase B) mRNA levels in response to SM exposure. Tumor necrosis factor-alpha (TNF-alpha) expression was only slightly increased and no change in the levels of expression was observed for monocyte chemoattractant protein-1 and MMP-2. This study identifies the main proinflammatory mediators involved in SM-induced skin injury in a weanling pig model. The results suggest transcriptional activity in the inflammatory response proteins IL-8, IL-6, IL-1beta, and MMP-9 and modest changes in TNF-alpha that together produce inflammation and contribute to the pathogenesis of SM dermatotoxicity. Therefore, drugs preventing SM-induced inflammation should be prime candidates for medical intervention to lessen collateral inflammation associated with tissue destruction.

Sulphur Mustard Induced Toxicity, Mechanism of Action and Current Medical Management

“…A time and dose-dependent increase in the expression of IL-6 in early stages followed by a sharp decrease in later stages in IL-6 expression in the mouse skin 16 , mouse ear 77 , weanling pigskin 58 and hairless mouse skin 78 after SM exposure that are consistent findings. Several in vitro and in vivo studies have suggested the role of inducible nitric oxide synthase [iNOS] induced NO synthesis, which is mainly produced by neutrophils and leukocytes 44,79,80 .…”

“…Several pathways have been recognized to be concerned in the gene expression of proinflammatory mediators. There is an immediate release of IL-1, IL-6, IL-8, TNFα and GM-CSF after SM exposure 16,[56][57][58] . This cytokine pattern has strong chemotactic activity for neutrophils and macrophages.…”

Microarray Analysis of Mouse Ear Tissue Exposed to Bis-(2-chloroethyl) Sulfide: Gene Expression Profiles Correlate with Treatment Efficacy and An Established Clinical Endpoint

“…The systems studied include mouse ear (Sabourin et al, 2000(Sabourin et al, , 2004aRogers et al, 2004), pig skin (Sabourin et al, 2002), cultured human keratinocytes Fig. 6.…”

“…This results in large fluid-filled lesions that are long-lasting and slow to heal (Papirmeister et al, 1991;Petrali and Oglesby-Megee, 1997). The formation of blisters is accompanied by a potent inflammatory response, observed as increased production of inflammatory mediators and infiltration of the exposure area by activated immune cells (Rikimaru et al, 1991;Tsuruta et al, 1996;Sabourin et al, 2000Sabourin et al, , 2002.…”

Sulfur mustard and respiratory diseases: Revisit with special reference to the “Comments on ‘Sulfur Mustard and Respiratory Diseases’, Tang and Loke () and a prepared Integrated Mechanism for Chronic Pulmonary Disease from Exposure to Sulfur Mustard” by Saburi and Ghanei ()

“…However, results from Emad's group, and some of Ghanei's group (such as Aghanouri et al, 2004;Attaran et al 2010;Zarin et al, 2010) are more relevant to pulmonary diseases as they focused on localized tissue changes of cytokines and chemokines in bronchoalveolar lavage fluid or lung biopsies. To link changes of cytokines and chemokines at system level (in serum) to pulmonary diseases may be too speculative as it has been well known that mustard could also induce inflammatory (cytokine and chemokine) changes in other organs such as skin (Arroyo et al, 2000(Arroyo et al, , 2003(Arroyo et al, , 2004Blaha et al, 2000a,b;Cowan et al, 2002;Kehe et al, 2009;Ricketts et al, 2000;Sabourin et al, 2002;Tanaka et al, 1997;Tsuruta et al, 1996;Wormser et al, 2005), eye (Ghasemi et al, 2012), liver (Anand et al, 2009). …”