Particulate matter 2.5 induces the skin barrier dysfunction and cutaneous inflammation via AhR- and T helper 17 cell-related genes in human skin tissue as identified via transcriptome analysis.

Particulate matter (PM2.5) is an environmental pollutant causing skin inflammatory diseases via epidermal barrier damage. However, the mechanism and related gene expression induced by PM2.5 remains unclear. Our aim was to determine the effect of PM2.5 on human skin tissue ex vivo, and elucidate the mechanism of T helper 17 cell-related inflammatory cytokine and skin barrier function. We verified the expression levels of gene in PM2.5-treated human skin tissue using Quantseq (3' mRNA-Seq), and Gene Ontology (GO) terms and protein-protein interaction (PPI) networks were performed. The PM2.5 treatment significantly enhanced the expression of Th 1, 2, 17 and 22 cell-related genes (cut-off value: │1.2 │ > fold change and p < 0.05). Most of all, Th17 cell-related genes are upregulated and those genes are associated with skin epidermal barrier function and Aryl hydrocarbon receptor (AhR), a xenobiotic receptor, pathway. In human keratinocyte cell lines, AhR-regulated genes (e.g. AhRR, CYP1A1, IL6 and IL36G), Th17 cell-related genes (e.g. IL17C) and epidermal barrier-related genes (e.g. SPRR2A and KRT71) are significantly increased after PM2.5. In the protein level, the secretion of IL-6 and IL-36G was increased in human skin tissue following PM2.5 treatment, and the expression of SPRR2A and KRT71 was significantly increased. PM2.5 exposure could ruin the skin epidermal barrier function via AhR- and Th17 cell-related inflammatory pathway.

TRPV3 and Itch: The Role of TRPV3 in Chronic Pruritus according to Clinical and Experimental Evidence.

Itching is a sensory phenomenon characterized by an unpleasant sensation that makes you want to scratch the skin, and chronic itching diminishes the quality of life. In recent studies, multiple transient receptor potential (TRP) channels present in keratinocytes or nerve endings have been shown to engage in the propagation of itch signals in chronic dermatological or pruritic conditions, such as atopic dermatitis (AD) and psoriasis (PS). TRPV3, a member of the TRP family, is highly expressed in the epidermal keratinocytes. Normal TRPV3 signaling is essential for maintaining epidermal barrier homeostasis. In recent decades, many studies have suggested that TRPV3 contributes to detecting pruritus signals. Gain-of-function mutations in TRPV3 in mice and humans are characterized by severe itching, hyperkeratosis, and elevated total IgE levels. These studies suggest that TRPV3 is an important channel for skin itching. Preclinical studies have provided evidence to support the development of TRPV3 antagonists for treating inflammatory skin conditions, itchiness, and pain. This review explores the role of TRPV3 in chronic pruritus, collating clinical and experimental evidence. We also discuss underlying cellular and molecular mechanisms and explore the potential of TRPV3 antagonists as therapeutic agents.

Moisturizer in Patients with Inflammatory Skin Diseases.

As interest in skin increases, the cosmetic market is also growing. It is difficult to choose between the numerous types of basic cosmetics on the market. This article aims to provide advice and guidance on which products to recommend according to a patient's skin condition. Appropriate application of a moisturizer attempts not only to improve the dryness, but also improve the skin's natural barrier function to protect the skin from internal and external irritants to keep the skin healthy. Moisturizers consist of various ingredients, including occlusive agents, emollients, humectants, lipid mixture, emulsifiers, and preservatives. Pathophysiology of dry skin is also discussed to provide readers with the background they need to choose the right moisturizer for themselves. As moisturizers play an important role as adjuvant in the treatment of common skin diseases, such as atopic dermatitis, contact dermatitis, psoriasis, acne and rosacea, which type of moisturizer is appropriate for each disease was also dealt with. Basic cosmetics, especially moisturizers, should be recommended in consideration of the ingredients, effectiveness and safety of each product, and the skin condition of each patient.

Aryl Hydrocarbon Receptors: Evidence of Therapeutic Targets in Chronic Inflammatory Skin Diseases.

The aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, is important for xenobiotic metabolism and binds to various endogenous and exogenous ligands present in the skin. AhR is known to be associated with diseases in various organs; however, its functions in chronic inflammatory skin diseases, such as atopic dermatitis (AD) and psoriasis (PS), have recently been elucidated. Here, we discuss the molecular mechanisms of AhR related to chronic inflammatory skin diseases, such as AD and PS, and the mechanisms of action of AhR on the skin immune system. The importance of AhR molecular biological pathways, clinical features in animal models, and AhR ligands in skin diseases need to be investigated. In conclusion, the therapeutic effects of AhR ligands are demonstrated based on the relationship between AhR and skin diseases. Nevertheless, further studies are required to elucidate the detailed roles of AhR in chronic inflammatory skin diseases.

Aryl Hydrocarbon Receptor Repressor Is Hypomethylated in Psoriasis and Promotes Psoriasis-like Inflammation in HaCaT Cells.

It is known that DNA hypomethylation of aryl hydrocarbon receptor repressor (AhRR), one of the epigenetic markers of environmental pollutants, causes skin diseases. However, the function and mechanisms are still unknown. We aimed to determine whether AhRR is hypomethylated in PBMC of psoriasis patients, as well as to examine the expression of psoriasis-related inflammatory cytokines and antimicrobial peptides after 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treatment in HaCaT cells overexpressing or silencing AhRR. AhRR was determined by qPCR, Western blot, immunohistochemistry, and immunocytochemistry in skin tissue and HaCaT cells. DNA methylation of AhRR was performed by Infinium Human Methylation450 BeadChip in PBMC of psoriasis patients and methylation-specific PCR (MSP) in HaCaT cells. NF-κB pp50 translocation and activity were performed by immunocytochemistry and luciferase reporter assay, respectively. We verified AhRR gene expression in the epidermis from psoriasis patients and healthy controls. AhRR hypomethylation in PBMC of psoriasis patients and pAhRR-HaCaT cells was confirmed. The expression level of AhRR was increased in both TCDD-treated HaCaT cells and pAhRR-HaCaT cells. NF-κB pp50 translocation and activity increased with TCDD. Our results showed that AhRR was hypomethylated and overexpressed in the lesional skin of patients with psoriasis, thereby increasing AhRR gene expression and regulating pro-inflammatory cytokines through the NF-κB signaling pathway in TCDD-treated HaCaT cells.

Differential Diagnosis and Treatment of Itching in Children and Adolescents.

Itching is prevalent in children with skin disorders and associated with effects on their mood, quality of life, and social functioning. Surprisingly, there are no data on childhood prevalence of pruritus in the general population. The aim of this article is to explore the epidemiology, clinical manifestation, and treatment for itch (pruritus) in the pediatric population (from infancy to adolescence), and to be helpful to primary care physicians who assess and diagnose pediatric patients with itching. In this study, we searched for specific keywords using PubMed and MEDLINE (Ovid) and, then, refined the retrieved searches for each cause and treatment. As a result of reviewing the literature, atopic dermatitis was shown to be the most common cause of itching, especially during infancy and through preschool. Not only skin disorders but also systemic diseases, drugs, and postburn states can predispose an individual to itching in childhood. There are traditional and newly developed treatment modalities for itching in pediatric patients. However, because the pharmacokinetics and pharmacodynamics of childhood are different from those of adults, the medications for itching have to be applied carefully for these age groups. There are many areas to be elucidated regarding the prevalence and objective assessment of pruritus in pediatric patients. Moreover, the safety profiles of medications in the pediatric population need to be better understood. Further studies to investigate itching in childhood are warranted.

Pathophysiology and Treatment of Pruritus in Elderly.

Pruritus is a relatively common symptom that anyone can experience at any point in their life and is more common in the elderly. Pruritus in elderly can be defined as chronic pruritus in a person over 65 years old. The pathophysiology of pruritus in elderly is still unclear, and the quality of life is reduced. Generally, itch can be clinically classified into six types: Itch caused by systemic diseases, itch caused by skin diseases, neuropathic pruritus, psychogenic pruritus, pruritus with multiple factors, and from unknown causes. Senile pruritus can be defined as a chronic pruritus of unknown origin in elderly people. Various neuronal mediators, signaling mechanisms at neuronal terminals, central and peripheral neurotransmission pathways, and neuronal sensitizations are included in the processes causing itch. A variety of therapies are used and several novel drugs are being developed to relieve itch, including systemic and topical treatments.

Anaphylaxis: Five Years' Experience in the Emergency Rooms of Five University Hospitals in Korea.

BACKGROUND: Anaphylaxis is an allergic disease that requires special handling due to its potential fatality. Recent epidemiological data indicate that the incidence of anaphylaxis is rising. However, actual data on the prevalence or causes of anaphylaxis in Korea are limited. METHODS: The emergency room attendees diagnosed with anaphylaxis between 2011 and 2015 in five university hospitals were included. Medical records were reviewed retrospectively. RESULTS: During the 5 years, a total of 505 subjects were diagnosed with anaphylaxis. Respiratory presentations were more common in children than in adults, while adults presented more frequently with cardiovascular symptoms. Intraoral angioedema was more often observed in the countryside than in the city. Insect stings/bites were more common in the countryside than in the city. Drugs were much more common in adults than in children. In the countryside, the frequency of anaphylaxis was higher in summer and autumn than in spring and winter. The use of corticosteroids was less common in children than in adults, while children more frequently got treatment with inhaled beta 2 agonist. CONCLUSIONS: The principal causes of anaphylaxis in Korean patients were food, drugs, and stings/bites. The cause, clinical features and management of anaphylaxis were significantly different depending on age and region. These real-world data on anaphylaxis could be helpful to deepen that understanding of this condition for physicians and patients.

Oral Alitretinoin for Patients with Refractory Prurigo.

Background: prurigo is a chronic skin disorder associated with a history of chronic pruritus. The pathogenesis of prurigo is largely unknown and the treatment of prurigo is unsatisfactory and challenging. Conventional systemic treatments may be beneficial; however, their possible side effects and possible transient efficacy is still a problem. We aimed to present the clinical course and effect of treatment with alitretinoin on patients with prurigo nodularis initially treated with conventional treatments like oral antihistamine, cyclosporine, and phototherapy. Methods: all the patients had prurigo nodularis refractory to conventional treatment. Their medical records included demographic features, past medical history, duration of disease, and treatment modalities; and the clinical courses of the patients were reviewed for this retrospective study. We evaluated patient pruritus and skin lesions for the duration. Results: we present reports involving 10 patients with refractory prurigo. All the patients in our cases were treated with oral alitretinoin after previous treatments and reported the improvement of skin lesions and pruritus within 2 weeks to 3 months. Conclusions: we suggest that oral alitretinoin may be an effective and well tolerated treatment option for patients with intractable prurigo. Further clinical studies are warranted to confirm the long-lasting efficacy and safety of alitretinoin for treating patients with prurigo.

Transient receptor potential vanilloid-3 (TRPV3) channel induces dermal fibrosis via the TRPV3/TSLP/Smad2/3 pathways in dermal fibroblasts.

BACKGROUND: Excessive wound healing can lead to hypertrophic scars, which are not only a cosmetic issue but could also be itchy or painful. Previously, we reported that, in comparison with normal tissue, thymic stromal lymphopoietin (TSLP) expression was increased in skin burn scars when the activation of transient receptor potential vanilloid-3 (TRPV3) of keratinocytes was increased. However, the functional role of TRPV3 in dermal fibrosis remains unclear. OBJECTIVE: We aimed to determine whether TRPV3 affects the collagen production of human primary dermal fibroblasts (HPDFs) and to investigate the mechanism involved. METHOD: Human primary dermal fibroblasts were cultured and transformed into myofibroblasts using TSLP and carvacrol. Expression levels of α-SMA, fibronectin, and COL1A1 were determined using qPCR, western blotting, and immunofluorescence staining. Ca2+ influx was measured using a calcium-sensitive fluorescent dye, Fura3-AM. Nuclear factor of activated T-cells (NFAT) and phosphorylated-Smad2/3 were determined by western blotting. Silencing of TRPV3 with TRPV3-specific small interference RNA was evaluated using qPCR and western blotting. RESULTS: The expression levels of α-SMA, fibronectin, COL1A1, and TSLP were significantly increased in carvacrol-treated HPDFs. The expression levels of α-SMA, fibronectin, and COL1A1 were significantly increased by TSLP. The expression levels of TSLP and COL1A1 were significantly blocked by TRPV3 silencing in HPDFs. Regulation of Ca2+ influx and the expression levels of NFAT and p-Smad2/3 were significantly increased in carvacrol-treated HPDFs. ECM productions induced via the TRPV3/TSLP/Smad2/3 pathways. CONCLUSIONS: The activation of the TRPV3 channels regulates dermal fibrosis by reducing extracellular matrix production via the TRPV3/TSLP/Smad2/3 pathways in dermal fibroblasts.

Natural History of Chronic Urticaria in Korea.

BACKGROUND: Data on the natural history and prognostic variables of chronic urticaria (CU) are rare and information about spontaneous remission of CU is limited. OBJECTIVE: This study evaluated the natural history of CU and identified predictors for remission. METHODS: Total 329 Korean patients with CU, who had follow-ups more than 6 months after diagnosis during a 7-year period in the department of dermatology in three university hospitals were enrolled. Clinical data and laboratory findings obtained by medical records and telephone interviews were analyzed, retrospectively. RESULTS: The proportion recovered in 1, 3, and 5 years after the onset of CU was 10.8%, 18.8%, and 32.9%, respectively. The mean duration of CU was 6.3 years. There were no significant differences in median recovery time depending on sex, age group, severity of CU, and type of CU. The presence of angioedema was significantly related to CU severity. There were no differences in prognosis with respect to the presence of dermographism or angioedema. Patients with atopic dermatitis (AD) had a significantly worse prognosis than patients without a history of AD; but not in patients with the history of allergic rhinitis or asthma. Patients with abnormal laboratory findings did not differ significantly in prognosis. CONCLUSION: CU remission rate significantly differ according to the presence of AD. This study provides information about the natural course of CU of Korean patients.

2,3,7,8-Tetrachlorodibenzo-p-Dioxin Regulates the Expression of Aryl Hydrocarbon Receptor-Related Factors and Cytokines in Peripheral Blood Mononuclear Cells and CD4+ T cells from Patients with Atopic Dermatitis and Psoriasis.

BACKGROUND: Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, is important for xenobiotic metabolism and binds to various endogenous and exogenous ligands in the skin. However, the functional role of AhR in patients with psoriasis (PS) and atopic dermatitis (AD) remains unclear. OBJECTIVE: We aimed to determine whether AhR-regulated factors (AhR, CYP1A1, interleukin [IL]-17, IL-22) were affected by AhR ligands (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) in chronic inflammatory skin diseases such as PS and AD. METHODS: The expression levels of AhR-related factors were determined by quantitative PCR, western blotting, and immunocytochemistry. Specific siRNA targeting AhR was used to inhibit gene expression in human peripheral blood mononuclear cells (PBMC). Cytokine assays were performed to determine the protein production of CD4+ T cells. RESULTS: In comparison with healthy controls, TCDD-treated PBMCs and CD4+ T cells from patients with PS and AD showed an increase in AhR gene levels as well as significantly increased expression of AhR-related factors (such as AhR, CYP1A1, IL-17, and IL-22). In contrast, 6-formyl indolo [3,2-b] carbazole (FICZ) inversely affected the differentiation of CD4+ T cells and their cytokine expression levels as compared with TCDD. CD4+ T cells from patients with AD and PS showed higher expression levels of AhR, CYP1A1, IL-17, and IL-22. CONCLUSION: Our results suggest that TCDD-induced AhR-related factor upregulation in AD and PS patients may increase the expression of AhR-regulatory genes, thereby contributing to the development of AD and PS.

Effect of MeCP2 on TGF- ß1-induced Extracellular Matrix Production in Nasal Polyp-derived Fibroblasts.

Purpose Methyl-CpG-binding protein 2 (MeCP2), known as a transcriptional regulator, has been suggested to play an important role in myofibroblast differentiation in the lung. The purpose of this study was to investigate the role of MeCP2 in transforming growth factor (TGF)- ß1-induced myofibroblast differentiation and extracellular matrix (ECM) production in nasal polyp-derived fibroblasts (NPDFs). Methods To identify the expression of MeCP2 in nasal polyp tissues, immunohistochemistry staining and Western blot were performed. TGF- ß1-induced NPDFs were treated with 5-azacytidine, a DNA methylation inhibitor, and the expression levels of α-SMA and fibronectin were determined by semiquantitative reverse transcription polymerase chain reaction, immunofluorescent staining, and Western blotting. The total soluble collagen was analyzed by the Sircol collagen assay. MeCP2 silenced by MeCP2-specific small interference ( si) RNA was verified by Western blot. Results The expression levels of MeCP2 increased in nasal polyp tissues compared to normal inferior turbinate tissues. 5-Azacytidine significantly inhibited the expression of α-SMA and fibronectin mRNA in a dose-dependent manner. In addition, 5-azacytidine suppressed collagen production and the expression of MeCP2 in the same manner. The expression levels of a-SMA and collagen production were significantly blocked by MeCP2 silencing in TGF- ß1-induced NPDFs. Conclusions Our data suggest that MeCP2 plays an essential role in TGF- ß1-induced myofibroblast differentiation and ECM production in NPDFs.

Role of adenosine monophosphate-activated protein kinase on cell migration, matrix contraction, and matrix metalloproteinase-1 and matrix metalloproteinase-2 production in nasal polyp-derived fibroblasts.

PURPOSE: Activation of adenosine monophosphate-activated protein kinase (AMPK) by metformin, as a master regulator of metabolism, is involved in airway tissue remodeling. Here, we investigated the physical role of AMPK on cell migration, matrix contraction, and the production of matrix metalloproteinases (MMP) in nasal polyp-derived fibroblasts (NPDF). METHODS: Primary NPDFs from six patients with chronic rhinosinusitis and nasal polyps were isolated and cultured. To assess the effect of AMPK on fibroblast migration, we conducted scratch and migration assays in NPDF treated with metformin and/or compound C. A collagen gel contraction assay measured activity of contractile. MMP expression was measured with reverse transcription-polymerase chain reaction, Western blot, and zymography. To evaluate for specific AMPK action, we examined by AMPK small interfering RNA. RESULTS: Metformin, an activator of AMPK, significantly inhibited cell migration in NPDFs in a dose-dependent manner. Compound C, an inhibitor of AMPK, partially reversed the inhibitory effect of metformin. Metformin also significantly decreased contractile activity, with a concomitant reduction in the production of MMP-1 and MMP-2 but not of MMP-9. Specific silencing that targeted AMPK resulted in the enhancement of mobility and contractility and in the production of MMP-1 and MMP-2. CONCLUSION: AMPK played an important role in regulating cell migration, matrix contraction, and MMP production in NPDFs, which provided data that AMPK activator might be a therapeutic target for the prevention of tissue remodeling in nasal polyps.

Vitamin D attenuates myofibroblast differentiation and extracellular matrix accumulation in nasal polyp-derived fibroblasts through smad2/3 signaling pathway.

To investigate the potential role of vitamin D (1,25(OH)2D3) in preventing the development of nasal polyps, we examined the effect of vitamin D on myofibroblast differentiation and extracellular matrix (ECM) production in TGF-ß1-induced nasal polyp-derived fibroblasts (NPDFs) and elucidated the mechanisms underlying its inhibitory effect. 1,25(OH)2D3 significantly reduced expression levels of α-SMA, a myofibroblast marker, and fibronectin, a representative ECM component, in a dose-dependent manner in TGF-ß1-induced NPDFs. 1,25(OH)2D3 suppressed activated Smad2/3 in time-course. Up-regulation of α-SMA, fibronectin and phosphorylation of Smad2/3 by TGF-ß1 was unaffected by 1,25(OH)2D3 in NPDFs after vitamin D receptor-specific siRNA transfection. We confirmed that the Smad2/3-specific inhibitor SIS3 inactivated Smad2/3 and reduced α-SMA and fibronectin expression. Furthermore, acetylation of histone H3 was compromised by 1,25(OH)2D3, leading to inhibition of collagen 1A1, collagen 1A2 and α-SMA gene expression. Treatment with 1,25(OH)2D3 also significantly suppressed TGF-ß1-enhanced contractility and motility in a contraction assay and Transwell migration assay. Finally, 1,25(OH)2D3 had a similar effect in ex vivo organ cultures of nasal polyps. Taken together, our results suggest that 1,25(OH)2D3 might be an effective therapy for nasal polyps by reducing myofibroblast differentiation and ECM production mediated by Smad2/3-dependent TGF-ß1 signaling pathways in NPDFs.

Wogonin inhibits transforming growth factor ß1-induced extracellular matrix production via the p38/activator protein 1 signaling pathway in nasal polyp-derived fibroblasts.

BACKGROUND: Wogonin has been shown to have antifibrotic and anti-inflammatory effects in the lower airway. The purpose of this study was to evaluate the effects of wogonin on transforming growth factor (TGF) ß1-induced myofibroblast differentiation, extracellular matrix production, migration, and collagen contraction, and to determine the molecular mechanisms of wogonin in nasal polyp-derived fibroblasts (NPDF). METHODS: NPDFs were isolated from nasal polyps from eight patients. TGF-ß1-induced NPDFs were treated with wogonin. Cytotoxicity was evaluated by using a 3-(4,5- dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide assay. Fibroblast migration was evaluated with transwell and scratch migration assays. The expression levels of α-smooth muscle actin, fibronectin, phosphorylated-p38, and c-Fos were determined by Western blot and/or reverse transcription-polymerase chain reaction. The total collagen amount was analyzed with the Sircol collagen assay, and contractile activity was measured by a collagen gel contraction assay. RESULTS: Wogonin (0-60 µM) had no significant cytotoxic effects on TGF-ß1-induced NPDFs. Migration of NPDFs was significantly inhibited by wogonin treatment. The expression levels of α-smooth muscle actin and fibronectin were significantly reduced in wogonin-treated NPDFs. Collagen production and contraction were also significantly decreased by wogonin treatment. Wogonin markedly inhibited activation of the p38/activator protein 1 pathway in TGF-ß1-induced NPDFs. CONCLUSION: These results indicated that wogonin may inhibit TGF-ß1-induced myofibroblast differentiation, extracellular matrix production, migration, and collagen contraction through the p38/activator protein-1 pathway in NPDFs.

Rapamycin inhibits transforming growth factor beta 1 induced myofibroblast differentiation via the phosphorylated-phosphatidylinositol 3-kinase mammalian target of rapamycin signal pathways in nasal polyp-derived fibroblasts.

PURPOSE: Rapamycin has antiproliferative and antifibrogenic effects in vitro and in vivo. The purpose of this study was to evaluate the effects of rapamycin on transforming growth factor (TGF) beta 1 induced myofibroblast differentiation (alpha smooth-muscle actin [SMA]), extracellular matrix production, and collagen contraction in nasal polyp-derived fibroblasts (NPDF). The underlying molecular mechanisms of rapamycin were also determined in NPDFs. METHODS: NPDFs were grown in culture and transformed into myofibroblasts by using TGF beta 1 (5 ng/mL). For cytotoxicity evaluation, a 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide assay was used. Expression levels of alpha SMA, phosphorylated phosphatidylinositol 3-kinase (PI3K), and phosphorylated mammalian target of rapamycin (mTOR) were determined by using Western blot, reverse transcription-polymerase chain reaction, and immunofluorescence staining. The total amount of collagen was analyzed by using the Sircol collagen assay, and contractile activity was measured with a collagen gel contraction assay. Silencing mTOR with mTOR-specific small interference RNA was determined by using reverse transcription-polymerase chain reaction. RESULTS: Whereas rapamycin (range, 0-400 nM) had no significant cytotoxic effects on TGF beta 1 induced NPDFs, it significantly reduced the expression levels of alpha-SMA in TGF beta 1 induced NPDFs in a dose-dependent manner. TGF beta 1 induced collagen production and collagen contraction were significantly inhibited by rapamycin treatment. Rapamycin also attenuated the TGF beta 1 induced activation of PI3K and mTOR, and its inhibitory effects were similar to those of mTOR silencing and a specific PI3K inhibitor. CONCLUSIONS: Rapamycin inhibited TGF beta 1 induced myofibroblast differentiation, extracellular matrix production, and collagen contraction through the PI3K/mTOR signal pathways in NPDFs.

Antiallergic Effects of Trichostatin A in a Murine Model of Allergic Rhinitis.

OBJECTIVES: Trichostatin A (TSA), an inhibitor of histone deacetylase, has been shown to play an important role in attenuating asthmatic inflammation. However, the effect of TSA in allergic rhinitis is not known. The aims of this study were to investigate the effect of TSA on allergic nasal inflammation and on the induction of regulatory T cells in a murine model of allergic rhinitis. METHODS: BALB/c mice were sensitized intraperitoneally with ovalbumin (OVA) and then challenged intranasally with OVA. TSA (1 mg/kg) was given to the treatment group, and multiple parameters of allergic responses were evaluated to determine the effects of TSA on allergic rhinitis. Allergic nasal symptom scores, including frequency of rubbing and sneezing, were checked. Eosinophil infiltrations were stained with Chromotrope 2R, and the expression levels of OVA-specific IgE, T-helper 1 (Th1) cytokine (interferon-gamma [IFN-γ]), Th2 cytokines (interleukin [IL] 4 and IL-5) and Treg (Foxp3, IL-10, and transforming growth factor-beta [TGF-ß]) were measured by quantitative reverse transcription-polymerase chain reaction or enzyme-linked immunosorbent assay. RESULTS: TSA reduced the scores of allergic nasal symptoms and the amount of eosinophil infiltration into the nasal mucosa. TSA suppressed OVA-specific IgE levels and reduced expression of the IL-4 and IL-5. However, the expression of IFN-γ was unchanged in the treatment group. The levels of Foxp3, IL-10, and TGF-ß were increased in pretreatment with TSA as compared to control group. CONCLUSION: This study shows that TSA induced antiallergic effects by decreasing eosinophilic infiltration and Th2 cytokines in a murine model of allergic rhinitis via regulation of Tregs. Thus, TSA may be considered a potentially therapeutic agent in treating allergic rhinitis.

Stimulatory effects of histamine on migration of nasal fibroblasts.

BACKGROUND: Fibroblast migration is crucial for normal wound repair after sinonasal surgery. Histamine is known to be involved in wound healing by its effects on cell proliferation and migration. This study aimed to determine whether histamine affects the migration of nasal fibroblasts and to investigate the mechanism of action of histamine on nasal fibroblasts. METHODS: Primary cultures of nasal fibroblasts were established from inferior turbinate samples. Fibroblast migration was evaluated with scratch assays. Cells were treated with histamine and/or histamine receptor-selective antagonists. U-73122 and pertussis toxin, which are selective inhibitors of the lower signaling pathway of H1R and H4R, were used to confirm the modulation of nasal fibroblast migration by histamine. Fibroblast cytoskeletal structures were visualized with immunocytochemistry. RESULTS: Histamine significantly stimulated the migration of nasal fibroblasts. Antagonists selective for HR1 and HR4 significantly reduced nasal fibroblast migration. In immunocytochemical staining, histamine treatment increased membrane ruffling and pyrilamine, diphenhydramine, fexofenadine, and JNJ7777120 decreased histamine-induced membrane ruffling. U-73122 and pertussis toxin also decreased histamine-induced migration of fibroblasts. Histamine maintains its stimulatory effects on fibroblast migration in the presence of mitomycin C, which blocks proliferation of cells. CONCLUSION: We showed that histamine stimulates fibroblast migration in nasal fibroblasts. This effect appeared to be mediated by HR1 and HR4. However, because fibroblast migration also can be involved in scaring and fibrosis, more research is necessary to determine the effects of antihistamine on wound healing after sinus surgery.