Association of chemokines and prolactin with cherry angioma in a sulfur mustard exposed population — Sardasht-Iran cohort study

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Abstract

Exposure to SM leads to short and long term adverse effects on various organs including the skin. Cherry angioma is one of the late skin disorders in SM exposed individuals. The pathogenesis of abnormal angiogenesis in cherry angioma is not well known but the role of inflammatory mediators and certain hormones, including prolactin, in the regulation of angiogenesis in other diseases has been reported. Alterations in serum levels of prolactin and chemokines in SM-exposed victims and the impact on angiogenesis are indications of the role in SM-induced cherry angioma. As part of the SICS, this study seeks to evaluate the possible association of prolactin and chemokines in the emergence of SM-induced cherry angioma. The serum concentrations of prolactin, IL-8/CXCL8, RANTES/CCL5, MCP-1/CCL2, and fractalkine/CX3CL1 were titrated using sandwich ELISA technique. There was a significant difference in the level of prolactin between the exposed subgroups (with cherry angioma n = 72; mean: 10.13) and without cherry angioma (n = 268; mean: 13.13, p < 0.0096). Median of the serum levels of CCL2 in the exposed patients with cherry angioma was significantly higher than exposed patients without cherry angioma (median = 203.5 pg/ml and median = 187.10 pg/ml respectively, p = 0.035).

There was no significant difference in the serum levels of IL-8, RANTES and CX3L1 between the exposed subgroups with cherry angioma and without cherry angioma. This finding serves as a basis for further research on the molecular mechanisms and pathways involved in the pathogenesis of cherry angioma and other related disorders.

Highlights

► There was significant difference in the level of prolactin within the exposed subgroups with and without cherry angioma. ► Serum level of CCL2 in SM-exposed with cherry angioma was significantly lower than SM-exposed without cherry angioma. ► These findings serve as a basis for molecular mechanisms and pathways involved in the pathogenesis of cherry angioma.

Introduction

Sulfur mustard (SM) is an alkylating agent with cytotoxic, mutagenic, and vesicating properties with not yet fully understood mechanism(s) [1]. Exposure to SM leads to short- and long-term adverse effects on multiple organs especially the skin, the eyes, the respiratory tracts and the immune system [2]. There have been several studies on cutaneous complications of SM exposure in Iranian SM victims. The acute skin lesions are erythema, edema, blisters, pigmentation disorders, bulla, and ulceration, while the late skin lesions are pigmentation disorders, dry skin, eczema, cherry angioma, atrophy, uriticaria and vitiligo [2], [3], [4]. It was concluded that SM exposure causes significant delayed skin reactions. Cherry angioma is one of the late skin lesions in SM exposed individuals [3], [5]. Cherry angioma is also known to be associated with exposure to chemicals such as ethylene glycol monobutyl ether and bromides [6], [7].

A record of 19.9% for cherry angioma prevalence was reported by Moin et al. in Sardasht-Iran cohort study (SICS) [3]. However various records in different groups of Iranian SM exposed individuals were reported [8]. Little is known about the pathogenesis of abnormal angiogenesis in cherry angioma [9]. Angiogenesis, the growth of new blood vessels from pre-existing vessels is highly restricted in healthy tissues in part by the control of naturally occurring anti-angiogenic factors that prevent new vessel growth [10]. The role of inflammatory mediators [11] and certain hormones, including prolactin in the regulation of angiogenesis in other diseases, has been described [12].

It has been reported that the major form of prolactin (23 kDa) promotes the growth of new blood vessels, induces angiogenesis [12], and is proteolytically cleaved to form a 16 kDa prolactin which is a potent anti-angiogenic [13], [14], [15].

Furthermore, we have previously reported a reduction in most of the inflammatory mediators in an SM-exposed population [16], [17]. The role of inflammatory mediators in angiogenesis has been demonstrated [18]. Chemokines are small secreted proteins that have been shown to play a critical role in the regulation of angiogenesis during several pathophysiological processes [11], [19], [20].

Although no relationship has been discerned between cherry angioma and prolactin or chemokines, but according to the impact of these factors in angiogenesis and the alterations of chemokines in SM-exposed victims, it might be an indicative of possible role in SM-induced cherry angioma. As part of the SICS, the purpose of current study is to explore possible association between prolactin and chemokines in the development of SM-induced cherry angioma.

Section snippets

Study design and participants

Details of the study design and methodology of the SICS have been reported previously [1]. Briefly, 372 male volunteers from Sardasht with a history of SM exposed in June 1987 and 128 unexposed sex/age matched as control from the unexposed town of Rabat have been recruited. SICS was initiated in 2006 and the clinical evaluations and samples collection were done in June 2007. The experiments were completed during 6 months. In this study all SICS participants were included and divided into 4

Results

The number of patients with cherry angioma disorder was 72 (19.9%) in SM exposed group and 12 (9.4%) in the control group of SICS [3] which was significantly different (p = 0.007).

Discussion

Exposure to SM leads to many delayed skin complications including cherry angioma. The incidence of cherry angioma was reported to be 19.9% in SM-exposed group of Sardasht 20 years after SM exposure in SICS [3]. The pathogenesis of abnormal angiogenesis in cherry angioma is not clearly understood. It has been reported that prolactin and chemokines are associated with angiogenesis in different models [11], [14], [15], [18] and alterations in some factors involved in angiogenesis such as

Conclusion

SM exposure may create a certain disorganization which could lead to cherry angioma if prolactin is also elevated and CCL2 correlation is observed. This finding on the alterations of prolactin and CCL2 could serve as a basis for further research on the molecular mechanisms and pathways involved in the pathogenesis of cherry angioma and other related disorders.

The etiology of cherry angioma in SM-exposed patients might be different from the patients with no history of SM exposure and although

Declaration of interest

The authors report no conflict of interest in this study.

Acknowledgments

This study was carried out by the Immunoregulation Research Center of Shahed University and Janbazan Medical and Engineering Research Center (JMERC); the study was financially supported by the Iranian Foundation of Martyr and Veterans Affairs and the Ministry of Health and Medical Education. The authors would like to kindly thank all the participants in the study.

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