Sulfur mustard downregulates iNOS expression to inhibit wound healing in a human keratinocyte model

AbstractWound healing is a complex process, and disturbance of even a single mechanism can result in chronic ulcers developing after exposure to the alkylating agent sulfur mustard (SM). A possible contributor may be SM-induced chronic senescent mesenchymal stem cells (MSCs), unable to fulfil their regenerative role, by persisting over long time periods and creating a proinflammatory microenvironment. Here we show that senescence induction in human bone marrow derived MSCs was time- and concentration-dependent, and chronic senescence could be verified 3 weeks after exposure to between 10 and 40 µM SM. Morphological changes, reduced clonogenic and migration potential, longer scratch closure times, differences in senescence, motility and DNA damage response associated genes as well as increased levels of proinflammatory cytokines were revealed. Selective removal of these cells by senolytic drugs, in which ABT-263 showed initial potential in vitro, opens the possibility for an innovative treatment strategy for chronic wounds, but also tumors and age-related diseases.

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Suppression of Sulfur Mustard-Increased IL-8 in Human Keratinocyte Cell Cultures by Serine Protease Inhibitors

Alternative Toxicological Methods ◽

10.1201/9780203008799.ch28 ◽

2003 ◽

Author(s):

William Smith ◽

Clarence Broomfield ◽

Fred Cowan

Keyword(s):

Serine Protease ◽

Protease Inhibitors ◽

Cell Cultures ◽

Sulfur Mustard ◽

Serine Protease Inhibitors ◽

Human Keratinocyte ◽

Keratinocyte Cell

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Effects of amniotic fluid on human keratinocyte gene expression ‐ Implications for wound healing

Experimental Dermatology ◽

10.1111/exd.14515 ◽

2021 ◽

Author(s):

Erika Nyman ◽

Elvira Lindholm ◽

Jonathan Rakar ◽

Johan PE Junker ◽

Gunnar Kratz

Keyword(s):

Gene Expression ◽

Wound Healing ◽

Amniotic Fluid ◽

Human Keratinocyte

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Nitric Oxide Synthase Gene Transfer Overcomes the Inhibition of Wound Healing by Sulfur Mustard in a Human Keratinocyte In Vitro Model

ISRN Toxicology ◽

10.5402/2012/190429 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 7

Author(s):

Hiroshi Ishida ◽

Radharaman Ray ◽

Jack Amnuaysirikul ◽

Keiko Ishida ◽

Prabhati Ray

Keyword(s):

Nitric Oxide ◽

Wound Healing ◽

Nitric Oxide Synthase ◽

Gene Transfer ◽

Sulfur Mustard ◽

No Production ◽

Skin Injury ◽

Inos Gene ◽

Oxide Synthase

Sulfur mustard (SM) is a chemical warfare agent that causes extensive skin injury. Previously we reported that SM exposure resulted in suppression of inducible nitric oxide synthase (iNOS) expression to inhibit the healing of scratch wounds in a cultured normal human epidermal keratinocyte (NHEK) model. Based on this finding, the present study was to use adenovirus-mediated gene transfer of iNOS to restore the nitric oxide (NO) supply depleted by exposure to SM and to evaluate the effect of NO on wound healing inhibited by SM in NHEKs. The effect of the iNOS gene transfer on iNOS protein expression and NO generation were monitored by Western blot and flow cytometry, respectively. Wound healing with or without the iNOS gene transfer after SM exposure was assessed by light and confocal microscopy. The iNOS gene transfer via adenovirus resulted in overexpression of the iNOS and an increase in NO production regardless of SM exposure in the NHEK model. The gene transfer was also effective in overcoming the inhibition of wound healing due to SM exposure leading to the promotion of wound closure. The findings in this study suggest that the iNOS gene transfer is a promising therapeutic strategy for SM-induced skin injury.

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