Procedure for assessing myeloperoxidase and inflammatory mediator responses in hairless mouse skin†

Blank, James A.; Lane, Laura A.; Menton, R. G.; Casillas, Robert P.

doi:10.1002/1099-1263(200012)20:1+<::aid-jat667>3.0.co;2-d

Cited by 7 publications

(9 citation statements)

References 11 publications

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“…At the wound margins, epithelial cells began to migrate into the wound. This inflammatory response is consistent with previous reports in humans and animals showing that SM-induced injury is associated with leukocyte accumulation in the skin (Benson et al, 2011; Blank et al, 2000; Dachir et al, 2010; Ghabili et al, 2010; Mishra et al, 2010; Tewari-Singh et al, 2010; Vogt et al, 1984). Consistent with reports in hairless guinea pigs (Benson et al, 2011), the inflammatory response was transient and by 14 days post-exposure; there was evidence of tissue repair including neoepidermis migrating from the wound edge and marked epidermal hyperplasia, which was associated with the reappearance of an intact stratum corneum.…”

Section: Discussionsupporting

confidence: 93%

“…Towards this goal, percutaneous closed cup vapor systems have been used to analyze SM-induced skin injury in several animal species including hairless and neonatal mice, guinea pigs and pigs (Anderson et al, 2002; Benson et al, 2011; Dachir et al, 2010; Graham et al, 2008; McAdams, 1956; Mershon et al, 1990; Smith et al, 1997a; Yourick et al, 1995). These models have been shown to be highly sensitive to SM exhibiting histopathological and inflammatory responses generally similar to other vesicant injury models, and to humans (Blank et al, 2000; Dorandeu et al, 2010; Ricketts et al, 2000; Sabourin et al, 2003; Smith et al, 1997a). In the present studies, we used the vapor cup model in hairless mice to demonstrate that SM-induced DNA damage in the skin readily leads to expression of markers of inflammation and tissue repair.…”

Section: Introductionmentioning

confidence: 92%

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Structural changes in the skin of hairless mice following exposure to sulfur mustard correlate with inflammation and DNA damage

Joseph

Gerecke

Heck

et al. 2011

Experimental and Molecular Pathology

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Sulfur mustard (SM, bis(2-chloroethyl)sulfide) is a bifunctional alkylating agent that causes dermal inflammation, edema and blistering. To investigate the pathogenesis of SM-induced injury, we used a vapor cup model which provides an occlusive environment in which SM is in constant contact with the skin. The dorsal skin of SKH-1 hairless mice was exposed to saturated SM vapor or air control. Histopathological changes, inflammatory markers and DNA damage were analyzed 1–14 days later. After 1 day, SM caused epidermal thinning, stratum corneum shedding, basal cell karyolysis, hemorrhage and macrophage and neutrophil accumulation in the dermis. Cleaved caspase-3 and phosphorylated histone 2A.X (phospho-H2A.X), markers of apoptosis and DNA damage, respectively, were increased whereas proliferating cell nuclear antigen (PCNA) was down-regulated after SM exposure. By 3 days, epithelial cell hypertrophy, edema, parakeratosis and loss of epidermal structures were noted. Enzymes generating pro-inflammatory mediators including myeloperoxidase and cyclooxygenase-2 were upregulated. After 7 days, keratin-10, a differentiation marker, was evident in the stratum corneum. This was associated with an underlying eschar, as neoepidermis began to migrate at the wound edges. Trichrome staining revealed increased collagen deposition in the dermis. PCNA expression in the epidermis was correlated with hyperplasia, hyperkeratosis, and parakeratosis. By 14 days, there was epidermal regeneration with extensive hyperplasia, and reduced expression of cleaved caspase-3, cyclooxygenase-2 and phospho-H2A.X. These findings are consistent with the pathophysiology of SM-induced skin injury in humans suggesting that the hairless mouse can be used to investigate the dermatoxicity of vesicants and the potential efficacy of countermeasures.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 92%

Structural changes in the skin of hairless mice following exposure to sulfur mustard correlate with inflammation and DNA damage

Joseph

Gerecke

Heck

et al. 2011

Experimental and Molecular Pathology

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“…In the present study therefore, the role of MPO in these important events leading to NM-induced skin pathology was analyzed using MPO KO mice. Similar to earlier reports with SM and to our previous studies with CEES and NM, NM exposure in WT mice caused a robust NM-induced increase in neutrophil infiltration and MPO activity (Blank et al, 2000; Inturi et al, 2013; Jain et al, 2011b; Millard et al, 1997; Tewari-Singh et al, 2009; Vavra et al, 2004). However, this NM-induced increase in MPO activity was not observed in MPO KO mice confirming these mice were suitable for this study.…”

Section: Discussionsupporting

confidence: 92%

Myeloperoxidase deficiency attenuates nitrogen mustard-induced skin injuries

et al. 2014

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The pathologic mechanisms of skin injuries, following the acute inflammatory response induced by vesicating agents sulfur mustard (SM) and nitrogen mustard (NM) exposure, are poorly understood. Neutrophils which accumulate at the site of injury, abundantly express myeloperoxidase (MPO), a heme protein that is implicated in oxidant-related antimicrobial and cytotoxic responses. Our previous studies have shown that exposure to SM analog 2-chloroethyl ethyl sulfide (CEES) or NM results in an inflammatory response including increased neutrophilic infiltration and MPO activity. To further define the role of neutrophil-derived MPO in NMinduced skin injury, here we used a genetic approach and examined the effect of NM exposure (12 h and 24 h) on previously established injury endpoints in C57BL/6J wild type (WT) and B6.129X1-MPOtm1Lus/J mice (MPO KO), homozygous null for MPO gene. NM exposure caused a significant increase in skin bi-fold thickness, epidermal thickness, microvesication, DNA damage and apoptosis in WT mice compared to MPO KO mice. MPO KO mice showed relatively insignificant effect. Similarly, NM-induced increases in the expression of inflammatory and proteolytic mediators, including COX-2, iNOS and MMP-9 in WT mice, while having a significantly lower effect in MPO KO mice. Collectively, these results show that MPO, which generates microbicidal oxidants, plays an important role in NM-induced skin injuries. This suggests the development of mechanism-based treatments against NM-and SM-induced skin injuries that inhibit MPO activity and attenuate MPO-derived oxidants.

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“…It is known that the MPO is an enzyme present in the granules of leucocytes, mainly neutrophils and macrophages and responsible for secreting hypochlorite, being considered also an inflammatory process marker. [40] The CIA model shares some similar features to the RA disease, being joint cell infiltration one of them, which could explain the increase in the MPO activity, observed in the paw tissue. [4,27] Moreover, the NO molecule is also recognized as a mediator of the physiological responses by multiple mechanisms, including the intracellular cascades, protein nitration and formation of other intermediaries.…”

Section: Discussionmentioning

confidence: 95%

Bis(phenylimidazoselenazolyl) diselenide elicits antinociceptive effect by modulating myeloperoxidase activity, NOx and NFkB levels in the collagen-induced arthritis mouse model

Chagas

Fulco

Sari

et al. 2017

Journal of Pharmacy and Pharmacology

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Procedure for assessing myeloperoxidase and inflammatory mediator responses in hairless mouse skin†

Cited by 7 publications

References 11 publications

Structural changes in the skin of hairless mice following exposure to sulfur mustard correlate with inflammation and DNA damage

Structural changes in the skin of hairless mice following exposure to sulfur mustard correlate with inflammation and DNA damage

Myeloperoxidase deficiency attenuates nitrogen mustard-induced skin injuries

Bis(phenylimidazoselenazolyl) diselenide elicits antinociceptive effect by modulating myeloperoxidase activity, NOx and NFkB levels in the collagen-induced arthritis mouse model

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