Mast cells and atopic dermatitis. Stereological quantification of mast cells in atopic dermatitis and normal human skin

Stereological quantification of mast cell numbers was applied to sections of punch biopsies from lesional and nonlesional skin of atopic dermatitis patients and skin of healthy volunteers. We also investigated whether the method of staining and/or the fixative influenced the results of the determination of the mast cell profile numbers. The punch biopsies were taken from the same four locations in both atopic dermatitis patients and normal individuals. The locations were the scalp, neck and flexure of the elbow (lesional skin), and nates (nonlesional skin). Clinical scoring was carried out at the site of each biopsy. After fixation and plastic embedding, the biopsies were cut into 2 μm serial sections. Ten sections, 30 μm apart, from each biopsy were examined and stained alternately with either toluidine blue or Giemsa stain and mast cell profile numbers were determined. The study yielded the following results: (1) in atopic dermatitis lesional skin an increased number of mast cell profiles was found as compared with nonlesional skin, (2) comparing atopic dermatitis skin with normal skin, a significantly increased number of mast cell profiles per millimetre squared was found in specimens from the neck, (3) staining with toluidine blue yielded a lower number of mast cell profiles than Giemsa staining, (4) the use of Carnoy’s fixative resulted in a lower mast cell profile count than the use of formaldehyde, and (5) there was no statistically significant correlation between the clinical score and the number of mast cell profiles per millimetre squared. Using stereological techniques, this study indicated that mast cells might participate in the inflammatory process in skin leading to atopic dermatitis. Received: 17 April 1996     

Extracellular superoxide dismutase ameliorates house dust mite‐induced atopic dermatitis‐like skin inflammation and inhibits mast cell activation in mice

Extracellular superoxide dismutase (EC‐SOD) is an enzyme that catalyses the dismutation of superoxide anions. It has multiple functions, such as reactive oxygen species scavenging, anti‐angiogenic, anti‐inflammatory, antichemotatic and antitumor activities. Recently, we demonstrated that EC‐SOD inhibits ovalbumin‐induced allergic airway inflammation in mice. However, the anti‐allergic effect of EC‐SOD on skin tissue and the role of EC‐SOD in mast cells, which are important for allergic responses, have not been well studied. In this study, we investigated whether EC‐SOD can alleviate atopic dermatitis in mice and inhibit mast cell activation. Treatment with human recombinant EC‐SOD ameliorated house dust mite‐induced atopic dermatitis in mice. Furthermore, the levels of pro‐allergic cytokine gene expression and histamine release increased in EC‐SOD KO mast cells and decreased in EC‐SOD overexpressing mast cells, suggesting that EC‐SOD inhibits mast cell activation. Consistently, a passive cutaneous anaphylaxis experiment showed more blood leakage from EC‐SOD KO mouse ear skin, implying that the lack of EC‐SOD increases allergic responses. These results suggest that EC‐SOD inhibits mast cell activation and atopic dermatitis and that the loss of EC‐SOD causes more severe allergic responses, implying that EC‐SOD might be a good drug candidate for treatment of allergic disorders, such as atopic dermatitis.     

Mast cell mediators other than histamine induce pruritus in atopic dermatitis patients: a dermal microdialysis study

While histamine is the crucial mediator of pruritus in type 1 allergic reactions, its role in atopic dermatitis (AD) is unclear. In this study, the role of mast cell mediators in protein extravasation and pruritus was evaluated using intradermal microdialysis. The microdialysis capillaries were used to apply the mast cell degranulating substance compound 48/80 (C48/80; 0.05%) or histamine (0.01%) and also to deliver H1-blockers (cetirizine, 200 microg mL-1) in nine AD patients and nine controls. Large pore size membranes (3000 kDa) enabled simultaneous analysis of protein extravasation. Itch sensation was measured psychophysically and weal and flare reaction were evaluated planimetrically. Protein extravasation induced by histamine and C48/80 was significantly reduced in AD patients. Blockade of H1-receptors by cetirizine significantly reduced C48/80-induced protein extravasation in AD patients and controls to an identical level. C48/80-induced pruritus was abolished by cetirizine in controls, whereas pruritus in AD patients was unchanged after H1 blockade. We conclude that mast cell mediators others than histamine are involved in C48/80-induced pruritus in AD patients. Whether the reduced capacity of AD patients to induce protein extravasation is of pathophysiological relevance for pruritus remains to be established.     

Disordered cyclic nucleotide metabolism--a basic defect in atopic dermatitis

Dysfunction in a wide variety of cellular immune mechanisms occurs in atopic dermatitis and contributes to the clinical presentation of the condition. The increased incidence of cutaneous viral and fungal infections, observed clinically in atopic dermatitis, suggests altered T-lymphocyte function and elevated serum IgE levels suggest deregulation of B-lymphocyte function. The clinical features of pruritus and erythema raise the possibility of increased release of inflammatory mediators into the circulation. In vitro studies have confirmed abnormalities in T-lymphocyte subset numbers and function as well as increased releasability of histamine from blood basophils in atopic dermatitis. Recent studies have revealed abnormalities in the metabolism of cyclic AMP, an important mediator in cellular regulatory mechanisms, in atopic dermatitis. Leucocyte cyclic AMP responses to a variety of agonists are blunted in atopic dermatitis and are due, at least in part, to increased cyclic AMP phosphodiesterase activity. It is unclear at present whether this enzyme abnormality is genetically determined or whether it is induced by increased circulating levels of inflammatory mediators. A number of the in vitro abnormalities in atopic dermatitis appear to correlate with the increase in phosphodiesterase activity. Further research aimed at finding ways to inhibit phosphodiesterase activity in atopic dermatitis and consequently reversing other abnormalities in cellular function, will hopefully open up new avenues of therapy for this common and disabling condition.     

Psychoneuroimmunology of psychological stress and atopic dermatitis: pathophysiologic and therapeutic updates

Atopic dermatitis is a chronic inflammatory skin disease characterized by impaired epidermal barrier function, inflammatory infiltration, extensive pruritus and a clinical course defined by symptomatic flares and remissions. The mechanisms of disease exacerbation are still poorly understood. Clinical occurrence of atopic dermatitis is often associated with psychological stress. In response to stress, upregulation of neuropeptide mediators in the brain, endocrine organs, and peripheral nervous system directly affect immune and resident cells in the skin. Lesional and non-lesional skin of patients with atopic dermatitis demonstrates increased mast cells and mast cell-nerve fiber contacts. In the setting of stress, sensory nerves release neuromediators that regulate inflammatory and immune responses, as well as barrier function. Progress towards elucidating these neuroimmune connections will refine our understanding of how emotional stress influences atopic dermatitis. Moreover, psychopharmacologic agents that modulate neuronal receptors or the amplification circuits of inflammation are attractive options for the treatment of not only atopic dermatitis, but also other stress-mediated inflammatory skin diseases.     

Human inflammatory dendritic epidermal cells express a functional histamine H4 receptor

Expression of histamine H(4) receptor (H(4)R) on leukocytes suggests an immunomodulatory role of this receptor. Here we investigated the expression and function of H(4)R on human inflammatory dendritic epidermal cells (IDECs). H(4)R is expressed by IDEC of the skin. On monocyte-derived IDECs (Mo-IDECs), H(4)R is also expressed and upregulated by IFN-gamma. Functionally, histamine and H(4)R agonists clobenpropit and 4-methylhistamine downregulated the production of the Th2-linked chemokine CCL2 and the Th1 cytokine IL-12 on Mo-IDEC, whereas agonists for the other histamine receptors did not. An H(4)R-selective antagonist (JNJ7777120) blocked the effect of H(4)R agonists. Downregulation of CCL2 also led to a decreased migration of monocytes. Thus, IDEC express a functionally active H(4)R, which upon stimulation leads to downregulation of CCL2 and IL-12. This might have implications for the treatment of atopic dermatitis, since H(4)R agonists may have beneficial effects in downregulating inflammation.     

Lack of preventing effect of systemically and topically administered histamine H(1) or H(4) receptor antagonists in a dog model of acute atopic dermatitis

As there is evidence for an anti‐inflammatory efficacy of histamine H₄ receptor (H4R) selective antagonists, we aimed at testing the efficacy of the H4R antagonists JNJ7777120 and JNJ28307474 in comparison with histamine H₁ receptor (H1R) antagonists hydroxyzine and cetirizine for skin lesion prevention in a canine model of acute atopic dermatitis. Six atopic Maltese‐beagle dogs experimentally sensitized to Dermatophagoides farinae (Df) house dust mites were selected for this study. Twenty‐four hours after challenge by epicutaneous application of Df, erythematous skin lesions were scored. In this blinded, placebo and active controlled study, topical JNJ7777120 or JNJ28307474 was applied as a 1% solution before allergen challenge. The latter was also given orally at 15 mg/kg before and after allergen challenge. A 0.015% triamcinolone acetonide solution was used as a positive control. The H1R antagonists hydroxyzine and cetirizine were administered orally before challenge in a second experiment. Twenty‐four hours after challenge, placebo‐treated animals had a median lesional score of 2. Treatment with topical and oral JNJ28307474 resulted in a median score of 2.5. After topical administration of JNJ7777120, the median lesional score was 2. Hydroxyzine and cetirizine did also not reduce the median score of the placebo treatment. Triamcinolone acetonide prevented all dogs from having any lesions. Determination of histamine in lesions revealed that only during the initiation increased concentrations of histamine were detected. In conclusion, the preventive administration of H1R or H4R antagonists has no impact on the development of acute skin lesions in this experimental canine atopic dermatitis model.     

Mechanisms in allergic skin disorders

Background Allergic skin disorders are initiated and maintained through the action and interaction between resident tissue cells, infiltrating leucocytes and mediators. Review The major cellular components of the skin immune system are keratinocytes, dendritic cells such as epidermal Langerhans cells (LCs) and dermal dendritic cells, mast cells and fibroblasts. Following an allergenic stimulus, inflammatory and immunocompetent cells accumulate in the epidermis and dermis, giving rise to specific clinical and histological manifestations. Leucocytes which accumulate in the inflammatory focus attract more leucocytes and stimulate the resident cell population. Primary mediators, released by resident cells upon stimulation, play a vital role in initiating and controlling inflammation. The mediators induce vascular endothelial cells to express adhesion molecules, which mediate migration of leucocytes into the dermis, where chemotactic factors attract them to the inflammatory focus. Activation of trapped T-lymphocytes by antigen-presenting cells (APCs) is followed by the release of inflammatory cytokines. Allergic contact dermatitis (ACD) depends on the activation of specifically sensitised T-cells, and epidermal LCs are the primary APCs. Most contact allergens are small, chemically reactive moleculed and CD4⁺ Th1 type T-cells are the target cells. Atopic dermatitis is a chronic eczematous condition, involving antibody IgE, LCs and dermal dendritic cells as the APCs, with Th2 T-lymphocytes as the target cells. Urticaria comprises a heterogeneous group of conditions, characterised by a wheal and flare reaction. Mast cells are the principal source of mediators involved and histamine is the most important of these.     

Radiation-induced mast cell mediators differentially modulate chemokine release from dermal fibroblasts

Background

Ionizing radiation has been demonstrated to result in degranulation of dermal mast cells. Chemokines are thought to play a crucial role in the early phase of the cutaneous radiation reaction. In human skin, mast cells are located in close proximity to dermal fibroblasts, which thus are a potential target for the action of mast cell mediators.

Objective

In this study, we evaluated the effects of mast cell-derived histamine, serotonin, tumour necrosis factor (TNF)-α and tryptase on chemokine release from dermal fibroblasts.

Methods

Human mast cells (HMC-1) were investigated for histamine release and cytokine production after ionizing radiation using enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Receptor expression on human fetal foreskin fibroblasts (HFFF2) and human adult skin fibroblasts (HDFa) was examined by flow cytometry. Chemokine mRNA and protein expression were analyzed by gene array and ELISA, respectively.

Results

Ionizing radiation significantly increased histamine release and cytokine expression by HMC-1 cells. Receptors for histamine, serotonin, TNF-α and tryptase were detected both in HFFF2 and in HDFa cells. Dermal fibroblasts constitutively expressed distinct sets of chemokine mRNA. Mast cell mediators differentially affected the release of chemokines CCL8, CCL13, CXCL4 and CXCL6 by fibroblasts.

Conclusions

Our data suggest that radiation-induced mast cell mediators have a tremendous impact on inflammatory cell recruitment into irradiated skin. We postulate the activation of mast cells to be an initial key event in the cutaneous radiation reaction, which might offer promising targets for treatment of both normal tissue side effects in radiation therapy and radiation injuries.     

Topical adelmidrol 2% emulsion, a novel aliamide, in the treatment of mild atopic dermatitis in pediatric subjects: a pilot study

Recent studies have shown a correlation between an increased number of mast cells in patients with atopic dermatitis (AD) resulting in raised plasma levels of nerve growth factor (NGF), pointing to a possible key role of their interaction in the pathogenesis of AD. It is well known that mast cells synthesize, store and release NGF. Mast cells and NGF both appear to be involved in tissue inflammation and neuroimmune interactions, with NGF acting as a general "alert" molecule capable of recruiting and priming both local tissue and systemic defense processes following stressful events. Also, NGF has been demonstrated to increase mast cell histamine content and intracellular tryptase activity in a dose- and time-dependent fashion. Endogenous aliamides are capable of down-regulating mastocyte reactivity by their action through the vanilloid (VR1) receptors, and keratinocytes, and through the CB1 and CB2 cannabinoid receptors linked to G-protein, also expressed by sensitive nerve endings, macrophages, and epithelial cells. Therefore, aliamide action should be regarded as a multifaceted mechanism interfering with the inflammatory process occurring in AD further beyond the known and controversial anti-histamine pharmacologic effect. In this regard, the reduction of mast cell degranulation by adelmidrol, as demonstrated by in vitro and in vivo investigations in animals, would interfere with the release of other inflammatory mediators, including NGF. Based on these considerations, a pilot study aimed to assess the efficacy and safety of twice daily application of a topical emulsion containing adelmidrol 2%, a novel aliamide, in a series of 20 patients (11 male and 9 female, mean age 8 (range 3-16) years) affected by mild AD was performed. Complete resolution with no side effects was observed in 16 (80%) patients after 4 weeks of treatment, with no relapses at 8-week follow up. Six patches in six subjects with multiple lesions that had not been treated and served as controls showed no improvement. Controlled clinical studies in larger series are warranted to confirm the efficacy of aliamide in the management of AD.     

Cannabinoid 1 receptors in keratinocytes attenuate fluorescein isothiocyanate‐induced mouse atopic‐like dermatitis

Atopic dermatitis is a chronic inflammatory disease characterized by an impaired epidermal barrier function combined with a chronic Th2‐type inflammatory response and an intense pruritus. Here, we used an experimental mouse model for Th2‐type contact hypersensitivity (CHS) to fluorescein isothiocyanate (FITC) to investigate the potential role of cannabinoid 1 receptors (CB1) in the pathophysiology of mouse atopic‐like dermatitis. Mice lacking CB1 receptors globally (Cnr1^?/?) or specifically in keratinocytes (KC‐Cnr1^?/?) as well as wild‐type (WT) control mice were sensitized and challenged with FITC. We examined ear swelling responses, transepidermal water loss, Th2‐type skin inflammatory responses and serum IgE levels. Both Cnr1^?/? and KC‐Cnr1^?/? showed enhanced CHS responses to FITC and a delayed epidermal barrier repair when compared with WT mice. mRNA levels for IL‐4, thymic stromal lymphopoietin (TSLP) and CCL8, as well as eosinophil activity, were significantly increased in inflamed ear tissue of FITC‐challenged Cnr1^?/? and KC‐Cnr1^?/? mice. Importantly, CB1 receptor‐deficient keratinocytes secreted increased levels of TSLP, a proinflammatory mediator that drives Th2‐type skin inflammation in atopic dermatitis, under basal and Th2‐type inflammatory conditions. Taken together, our results demonstrate that CB1 receptors in keratinocytes help to maintain epidermal barrier homoeostasis and attenuate Th2‐type allergic inflammatory responses. Based on our work, we propose that enhanced epidermal allergen penetrance cooperates with increased production of TSLP and CCL8 by epidermal keratinocytes for the induction of type 2 CD4+ T helper cells. Our results place keratinocytes at the cross‐roads of outside‐in and inside‐out pathophysiologic mechanisms of atopic dermatitis.     

丹皮酚对RBL-2H3肥大细胞活化脱颗粒的影响

目的通过建立体外抑制肥大细胞脱颗粒的药效学模型,探讨丹皮酚抗Ⅰ型变态反应作用机制。方法用MTT比色法检测不同浓度的丹皮酚对RBL-2H3肥大细胞增殖的影响。通过ELISA法,明确体外RBL-2H3细胞活化分泌组胺及TNF-α动力学特征。检测不同浓度药物对RBL-2H3肥大细胞分泌组胺及TNF-α的影响。结果丹皮酚对RBL-2H3细胞增殖有抑制作用,IC50值为0.22 mg/mL。RBL-2H3细胞活化脱颗粒,分泌组胺的释放率在前30 m in上升较快,30 m in后上升进入平台期;TNF-α分泌的量在1h达高峰。丹皮酚抑制RBL-2H3细胞释放组胺和TNF-α作用不弱于色甘酸钠0.1,0.5 mg/mL。丹皮酚浓度的对数与其对RBL-2H3细胞释放组胺和TNF-α的抑制率呈线性相关(P=0.000<0.01)。结论丹皮酚呈剂量依赖性抑制RBL-2H3细胞分泌组胺和TNF-α。     

Histamine: The Quintessential Mediator

Histamine is unique in being the only substance described to date which fulfils all of the criteria established by Dale for an inflammatory mediator. Thus, histamine is known to cause the “Triple Response” of Lewis and to act via H₁ and H₂ receptors to produce vasodilation and increased vascular permeability; elevated levels of histamine are found in inflamed tissue; histamine is produced and stored in mast cells and mere are established mechanisms for histamine release via mast cell surface receptors; and antihistamines alleviate the clinical manifestations of histamine release. There have been several recent advances in our understanding of histamine pharmacology and of the pathomechanisms of chronic idiopathic urticaria (CIU), a disease in which histamine plays an important role. Two new histamine receptors have been identified, the inhibitory (H₃) receptor and the intracellular (H_ic) receptor involved in cell proliferation. There is now evidence that mast cell derived histamine release in patients with CIU is due to an autoimmune disease, mediated by autoantibodies to the α-subunit of the high affinity IgE receptor on mast cells and basophils. Removal of these autoantibodies by plasmapheresis, or treatment with intravenous immunoglobulins may cause clinical remission. Cyclosporin A has also been found to be of benefit to some patients with CIU probably due to a mast cell “stabilising” effect, leading to reduced release of histamine and other mediators. This article reviews our current knowledge on histamine, its role, receptors and mechanisms for release.     

Cannabinoids inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism and have a potential therapeutic value in the treatment of psoriasis

BACKGROUND: Cannabinoids from cannabis (Cannabis sativa) are anti-inflammatory and have inhibitory effects on the proliferation of a number of tumorigenic cell lines, some of which are mediated via cannabinoid receptors. Cannabinoid (CB) receptors are present in human skin and anandamide, an endogenous CB receptor ligand, inhibits epidermal keratinocyte differentiation. Psoriasis is an inflammatory disease also characterised in part by epidermal keratinocyte hyper-proliferation. OBJECTIVE: We investigated the plant cannabinoids Delta-9 tetrahydrocannabinol, cannabidiol, cannabinol and cannabigerol for their ability to inhibit the proliferation of a hyper-proliferating human keratinocyte cell line and for any involvement of cannabinoid receptors. METHODS: A keratinocyte proliferation assay was used to assess the effect of treatment with cannabinoids. Cell integrity and metabolic competence confirmed using lactate-dehydrogenase and adenosine tri-phosphate assays. To determine the involvement of the receptors, specific agonist and antagonist were used in conjunction with some phytocannabinoids. Western blot and RT-PCR analysis confirmed presence of CB1 and CB2 receptors. RESULTS: The cannabinoids tested all inhibited keratinocyte proliferation in a concentration-dependent manner. The selective CB2 receptor agonists JWH015 and BML190 elicited only partial inhibition, the non-selective CB agonist HU210 produced a concentration-dependent response, the activity of theses agonists were not blocked by either CB1/CB2 antagonists. CONCLUSION: The results indicate that while CB receptors may have a circumstantial role in keratinocyte proliferation, they do not contribute significantly to this process. Our results show that cannabinoids inhibit keratinocyte proliferation, and therefore support a potential role for cannabinoids in the treatment of psoriasis.     

Itch in atopic dermatitis - pathophysiology and treatment

Pruritus is an essential feature of atopic dermatitis with a high impact on the quality of life. Although the pathophysiology of atopic dermatitis itch is not fully understood, recent studies have demonstrated that a variety of mechanisms contribute to the induction and maintenance of the symptom. For example, an increased number of cutaneous nerve fibers and neuropeptides were identified in atopic dermatitis skin. Histamine and histamine 4 receptor as well as interleukin 31 are novel key players identified in itch induction, in addition to inflammatory cells such as mast cells, eosinophils and lymphocytes. The new findings suggest that target-specific therapies are most likely to control atopic dermatitis itch. To date, only few therapies are available and controlled studies are pending.     

Pimecrolimus (Elidel, SDZ ASM 981)—Preclinical pharmacologic profile and skin selectivity

The ascomycin macrolactam derivative pimecrolimus (Elidel, SDZ ASM 981; Novartis Pharma AG, Basel Switzerland) is a cell-selective inhibitor of inflammatory cytokines specifically developed for the treatment of inflammatory skin diseases, such as atopic dermatitis, allergic contact dermatitis, irritant contact dermatitis, and plaque-type psoriasis. It inhibits the production of inflammatory cytokines in T cells and mast cells and prevents the release of preformed inflammatory mediators from mast cells. Topically administered pimecrolimus is as effective as the high-potency corticosteroid clobetasol-17-propionate in a pig model of allergic contact dermatitis (ACD). Unlike clobetasol, however, it does not cause skin atrophy. Given orally, pimecrolimus is as potent or superior to tacrolimus (FK 506) in treating ACD in mice and rats. Pimecrolimus also effectively reduces skin inflammation and pruritus in hypomagnesemic hairless rats, a model that mimics acute signs of atopic dermatitis. Pimecrolimus shows only a low potential to impair systemic immune responses when compared with tacrolimus as shown in rats in (1) the localized graft-versus-host reaction, (2) the antibody formation to sheep red blood cells, and (3) kidney transplantation. Pimecrolimus permeates through pig skin in vitro at a 10-times lower rate than tacrolimus, indicating a lower potential for percutaneous absorption in vivo. The data suggest that pimecrolimus combines high anti-inflammatory activity in the skin with a low potential to impair systemic immune reactions.     

Mast cells of psoriatic and atopic dermatitis skin are positive for TNF-α and their degranulation is associated with expression of ICAM-1 in the epidermis

Abstract The release of cytokines from cutaneous cells may be of major importance in the initiation and development of many inflammatory skin disorders. For example, tumor necrosis factor-alpha (TNF-α), which in healthy skin is found preformed only in mast cells, is able to induce the expression of several adhesion molecules including intercellular adhesion molecule-1 (ICAM-1). Increased expression of ICAM-1 occurs in keratinocytes in lesional skin of psoriasis and atopic dermatitis (AD) and it is considered to be an important initiator of leucocyte/keratinocyte interactions in skin inflammation. We counted the mast cells showing TNF-α immunoreactivity using a double-staining method in nonlesional and lesional skin sections from 12 patients with AD and 12 patients with psoriasis. The percentage of TNF-α⁺ mast cells in lesional and nonlesional AD skin was 36 ± 22% and 21 ± 15% (P < 0.018, paired t-test), respectively, and in psoriatic skin was 16 ± 25% and 15 ± 15%, respectively (P < 0.89, paired t-test). We also cultured whole skin biopsies taken from the healthy-looking skin of psoriatic and AD patients in the presence of mast cell degranulator compound 48/80, which resulted in focal expression of ICAM-1 in the epidermis. In cultured keratinocytes, both histamine and an extract of a human mast-cell line (HMC-1) induced ICAM-1 immunostaining only in occasional cells, but the combination of histamine and the HMC-1 extract resulted in intense ICAM-1 staining in numerous cells. This enhancement of ICAM-1 staining was abolished by preincubation of the HMC-1 extract with anti-TNF-α antibody. These results suggest that the degranulation of mast cells induces the expression of ICAM-1 in keratinocytes probably via TNF-α and histamine. Received: 8 August 1997     

Ablation of human skin mast cells in situ by lysosomotropic agents

Mast cells are known to have a detrimental impact on numerous types of inflammatory skin diseases such as contact dermatitis, atopic eczema and cutaneous mastocytosis. Regimens that dampen skin mast cell‐mediated activities can thus offer an attractive therapeutic option under such circumstances. As mast cells are known to secrete a large array of potentially pathogenic compounds, both from preformed stores in secretory lysosomes (granules) and after de novo synthesis, mere inhibition of degranulation or interference with individual mast cell mediators may not be sufficient to provide an effective blockade of harmful mast cell activities. An alternative strategy may therefore be to locally reduce skin mast cell numbers. Here, we explored the possibility of using lysosomotropic agents for this purpose, appreciating the fact that mast cell granules contain bioactive compounds prone to trigger apoptosis if released into the cytosolic compartment. Based on this principle, we show that incubation of human skin punch biopsies with the lysosomotropic agents siramesine or Leu‐Leu methyl ester preferably ablated the mast cell population, without causing any gross adverse effects on the skin morphology. Subsequent analysis revealed that mast cells treated with lysosomotropic agents predominantly underwent apoptotic rather than necrotic cell death. In summary, this study raises the possibility of using lysosomotropic agents as a novel approach to targeting deleterious mast cell populations in cutaneous mastocytosis and other skin disorders negatively influenced by mast cells.