Mast Cell Growth Factor Research Articles

Seralutinib in adults with pulmonary arterial hypertension (TORREY): a randomised, double-blind, placebo-controlled phase 2 trial

Morbidity and mortality in pulmonary arterial hypertension (PAH) remain high. Activation of platelet-derived growth factor receptor, colony stimulating factor 1 receptor, and mast or stem cell growth factor receptor kinases stimulates inflammatory, proliferative, and fibrotic pathways driving pulmonary vascular remodelling in PAH. Seralutinib, an inhaled kinase inhibitor, targets these pathways. We aimed to evaluate the efficacy and safety of seralutinib in patients with PAH receiving standard background therapy. The TORREY trial was a phase 2, randomised, multicentre, multinational, double-blind, placebo-controlled study. Patients with PAH from 40 hospital and community sites were randomly assigned 1:1 via interactive response technologies to receive seralutinib (60 mg twice daily for 2 weeks, then increased to 90 mg twice daily as tolerated) or placebo by dry powder inhaler twice daily for 24 weeks. Randomisation was stratified by baseline pulmonary vascular resistance (PVR; <800 dyne·s/cm5 and ≥800 dyne·s/cm5). Patients were eligible if classified as WHO Group 1 PH (PAH), WHO Functional Class II or III, with a PVR of 400 dyne·s/cm5 or more, and a 6 min walk distance of between 150 m and 550 m. The primary endpoint was change in PVR from baseline to 24 weeks. Analyses for efficacy endpoints were conducted in randomly assigned patients (intention-to-treat population). Safety analyses included all patients who received the study drug. TORREY was registered with ClinicalTrials.gov (NCT04456998) and EudraCT (2019-002669-37) and is completed. From Nov 12, 2020, to April 20, 2022, 151 patients were screened for eligibility, and following exclusions, 86 adults receiving PAH background therapy were randomly assigned to seralutinib (n=44; four male, 40 female) or placebo (n=42; four male, 38 female), and comprised the intention-to-treat population. At baseline, treatment groups were balanced except for a higher representation of WHO Functional Class II patients in the seralutinib group. The least squares mean change from baseline to week 24 in PVR was 21·2 dyne·s/cm5 (95% CI -37·4 to 79·8) for the placebo group and -74·9 dyne·s/cm5 (-139·7 to -10·2) for the seralutinib group. The least squares mean difference between the seralutinib and placebo groups for change in PVR was -96·1 dyne·s/cm5 (95% CI -183·5 to -8·8; p=0·03). The most common treatment-emergent adverse event in both treatment groups was cough: 16 (38%) of 42 patients in the placebo group; 19 (43%) of 44 patients in the seralutinib group. Treatment with inhaled seralutinib significantly decreased PVR, meeting the primary endpoint of the study among patients receiving background therapy for PAH. Gossamer Bio.

PGR-KITLG signaling drives a tumor-mast cell regulatory feedback to modulate apoptosis of breast cancer cells

The immune microenvironment constructed by tumor-infiltrating immune cells and the molecular phenotype defined by hormone receptors (HRs) have been implicated as decisive factors in the regulation of breast cancer (BC) progression. Here, we found that the infiltration of mast cells (MCs) informed impaired prognoses in HR(+) BC but predicted improved prognoses in HR(−) BC. However, molecular features of MCs in different BC remain unclear. We next discovered that HR(−) BC cells were prone to apoptosis under the stimulation of MCs, whereas HR(+) BC cells exerted anti-apoptotic effects. Mechanistically, in HR(+) BC, the KIT ligand (KITLG), a major mast cell growth factor in recruiting and activating MCs, could be transcriptionally upregulated by the progesterone receptor (PGR), and elevate the production of MC-derived granulin (GRN). GRN attenuates TNFα-induced apoptosis in BC cells by competitively binding to TNFR1. Furthermore, disruption of PGR-KITLG signaling by knocking down PGR or using the specific KITLG-cKIT inhibitor iSCK03 potently enhanced the sensitivity of HR(+) BC cells to MC-induced apoptosis and exerted anti-tumor activity. Collectively, these results demonstrate that PGR-KITLG signaling in BC cells preferentially induces GRN expression in MCs to exert anti-apoptotic effects, with potential value in developing precision medicine approaches for diagnosis and treatment.

Unusual presentation of telangiectasia macularis eruptiva perstans at the site of healed herpes zoster; Wolf's isotopic response.

There are several reported cases of Wolf's isotopic response, including infections, cancers, inflammatory and immune-related disorders. It is interesting that the majority of these occurred after herpes zoster (HZ) had healed. In this article, we describe an unusual case of adult mastocytosis/telangiectasia macularis eruptiva perstans (TMEP) at the location of recovered HZ. Given that adult mastocytosis is thought to be caused by dysregulation of the mast cell growth factor receptor, the c-Kit proto-oncogene (CD117), and the fact that the varicella zoster virus-infected cutaneous lesions contain CD117-positive mast cells (CD117+MCs), we hypothesize that CD117+ MCs may be in charge of the local immunological response and cytokine release those results in TMEP after HZ.

M-MDSC in vitro generation from mouse bone marrow with IL-3 reveals high expression and functional activity of arginase 1.

Myeloid-derived suppressor cells (MDSC) represent major regulators of immune responses, which can control T cells via their inducible nitric oxide synthase (iNOS)- and arginase 1 (Arg1)-mediated effector functions. While GM-CSF is well documented to promote MDSC development, little is known about this potential of IL-3, an established growth factor for mast cells. Here, we show that IL-3, similar to GM-CSF, generates monocytic MDSC (M-MDSC) from murine bone marrow (BM) cells after 3 days of in vitro culture. At this time point, predominantly CD11b+ CD49a+ monocytic and CD11b+ CD49a- FcεR I- neutrophilic cells were detectable, while CD11blow/neg FcεR I+ mast cells accumulated only after extended culture periods. Both growth factors were equivalent in generating M-MDSC with respect to phenotype, cell yield and typical surface markers. However, IL-3 generated M-MDSC produced less TNF, IL-1β and IL-10 after activation with LPS + IFN-γ but showed higher Arg1 expression compared to GM-CSF generated M-MDSC. Arg1 was further induced together with iNOS after MDSC activation. Accordingly, an increased Arg1-dependent suppressor activity by the IL-3 generated M-MDSC was observed using respective iNOS and Arg1 inhibitors. Together, these data indicate that M-MDSC can be generated in vitro by IL-3, similar to GM-CSF, but with increased Arg1 expression and Arg1-mediated suppression capacity. This protocol now allows further in vitro studies on the role of IL-3 for MDSC biology.

Slow integrin-dependent migration organizes networks of tissue-resident mast cells

Immune cell locomotion is associated with amoeboid migration, a flexible mode of movement, which depends on rapid cycles of actin polymerization and actomyosin contraction1. Many immune cells do not necessarily require integrins, the major family of adhesion receptors in mammals, to move productively through three-dimensional tissue spaces2,3. Instead, they can use alternative strategies to transmit their actin-driven forces to the substrate, explaining their migratory adaptation to changing external environments4–6. However, whether these generalized concepts apply to all immune cells is unclear. Here, we show that the movement of mast cells (immune cells with important roles during allergy and anaphylaxis) differs fundamentally from the widely applied paradigm of interstitial immune cell migration. We identify a crucial role for integrin-dependent adhesion in controlling mast cell movement and localization to anatomical niches rich in KIT ligand, the major mast cell growth and survival factor. Our findings show that substrate-dependent haptokinesis is an important mechanism for the tissue organization of resident immune cells.

The protective effect of total glucosides of white paeony capsules on experimental autoimmune encephalomyelitis

AimsTo learn about the effect and mechanism of total glucosides of white peony capsule (TGP), on experimental autoimmune encephalomyelitis (EAE), an acknowledged animal model of multiple sclerosis (MS). MethodsThe rat model of EAE was induced by subcutaneous injection with guinea pig spinal cord homogenate. The severity of the disease model was assessed by clinical score, hematoxylin and eosin (H&E) and luxol fast blue (LFB). Immunohistochemical assay was used to observe the types of inflammatory cells and adhesive molecule expression. Enzyme-linked immunosorbent assay (ELISA) was applied to detect content of the stem cell growth factor / mast cell growth factor (scf/MGF), interleukin-6 (IL-6) and IL-2. Immunofluorescence assay was applied to observe the expression of connexin43 (Cx43), glial fibrillary acidic protein (GFAP), connexin47 (Cx47) and the monoclonal antibody anti-adenomatous polyposis coli (APC) clone CC1. ResultsCompare with the animals in EAE model group, TGP treated rats (particularly those treated with high doses) showed a significant decrease in morbidity, clinical scores, CNS infiltration of inflammatory cells (including mononuclear macrophages, CD4+ and CD8+ T cells) and demyelination. The key adhesion molecule ICAM-1, cytokines IL-2、IL-6 and scf/MGF were significantly decreased with TGP treatment. Oppositely, PD-1, connexin47 in oligodendrocytes and connexin43 in astrocytes were elevated with TGP treatment. ConclusionTo sum up, TGP exhibited a significantly prevention and treatment effect on EAE rat model, and this improvement was achieved through a combination way composed of glial and inflammatory cells, junction proteins, various factors including adhesion factors, interleukins and scf/MGF.

RANKL down-regulates the mast cell proliferation through inducing senescence.

An increase in the number of mast cells could contribute to inflammatory diseases and pathologic conditions. A receptor activator of NF-κB ligand (RANKL)/RANK system is one of the key signaling pathways accelerating mast cell-mediated allergic inflammatory reactions. However, the biological functions of RANKL in mast cell proliferation remains to be clarified. The aim of the present study is to clarify the role of RANKL in mast cell proliferation. Surprisingly, RANKL remarkably reduced the proliferation of human mast cell line, HMC-1 cells through the inhibition of murine double minute 2 (MDM2) and Ki-67 mRNA expressions in a dose-dependent manner. RANKL significantly reduced cell viability, whereas it increased cellular senescence via increasing levels of p53, phosphorylated(p)-p53, p21, and p16 and decreasing levels of retinoblastoma protein (pRb) and p-pRb in HMC-1 cells. Even in rat peritoneal mast cells, RANKL induced cellular senescence by increasing filamentous-actin polymerization. In addition, RANKL remarkably reduced thymic stromal lymphopoietin (TSLP)-induced mast cell proliferation via the downregulation of MDM2 and Ki-67. RANKL decreased levels of p-signal transducer and activator of transcription 6 in TSLP-stimulated HMC-1 cells. The mast cell growth factor, interleukin-13 was remarkably down-regulated by treatment with RANKL in TSLP-stimulated HMC-1 cells. Furthermore, RANKL increased the number of senescence-associated β-galactosidase-stained cells and protein levels of p53, p-p53, and p21 in TSLP-stimulated HMC-1 cells. These data suggest that RANKL down-regulates mast cell proliferation by inducing senescence.

Protein Kinase C α and β compensate for each other to promote stem cell factor-mediated KIT phosphorylation, mast cell viability and proliferation.

Mast cells (MCs) develop from hematopoietic progenitors and differentiate into mature MCs that reside within connective or mucosal tissues. Though the number of MCs in tissues usually remains constant, inflammation and asthma disturb this homeostasis, leading to proliferation of MCs. Understanding the signaling events behind this proliferative response could lead to the development of novel strategies for better management of allergic diseases. MC survival, proliferation, differentiation, and migration are all maintained by a MC growth factor, stem cell factor (SCF) via its receptor, KIT. Here, we explored how protein kinase C (PKC) redundancy influences MC proliferation in bone marrow‐derived MC (BMMC). We found that SCF activates PKCα and PKCβ isoforms, which in turn modulates KIT phosphorylation and internalization. Further, PKCα and PKCβ activate p38 mitogen activated protein kinase (MAPK), and this axis subsequently regulates SCF‐induced MC cell proliferation. To ascertain the individual roles of PKCα and PKCβ, we knocked down either PKCα or PKCβ or both via short hairpin RNA (shRNA) and analyzed KIT phosphorylation, p38 MAPK phosphorylation, and MC viability and proliferation. To our surprise, downregulation of neither PKCα nor PKCβ affected MC viability and proliferation. In contrast, blocking both PKCα and PKCβ significantly attenuated SCF‐induced cell viability and proliferation, suggesting that PKCα and PKCβ compensate for each other downstream of SCF signaling to enhance MC viability and proliferation. Our results not only suggest that PKC classical isoforms are novel therapeutic targets for SCF/MC‐mediated inflammatory and allergic diseases, but they also emphasize the importance of inhibiting both PKCα and β isoforms simultaneously to prevent MC proliferation.

Fluvastatin enhances IL-33-mediated mast cell IL-6 and TNF production

Statins are HMG-CoA reductase inhibitors prescribed for lowering cholesterol. They can also inhibit inflammatory responses by suppressing isoprenylation of small G proteins. Consistent with this, we previously found that fluvastatin suppresses IgE-mediated mast cell function. However, some studies have found that statins induced pro-inflammatory cytokines in macrophages and NK cells. In contrast to IgE signaling, we show that fluvastatin augments IL-33-induced TNF and IL-6 production by mast cells. This effect required the key mast cell growth factor, stem cell factor (SCF). Treatment of IL-33-activated mast cells with mevalonic acid or isoprenoids reduced fluvastatin effects, suggesting fluvastatin acts at least partly by reducing isoprenoid production. Fluvastatin also enhanced IL-33-induced NF-κB transcriptional activity and promoted neutrophilic peritonitis in vivo, a response requiring mast cell activation. Other statins tested did not enhance IL-33 responsiveness. Therefore, this work supports observations of unexpected pro-inflammatory effects of some statins and suggests mechanisms by which this may occur. Because statins are candidates for repurposing in inflammatory disorders, our work emphasizes the importance of understanding the pleiotropic and possible unexpected effects of these drugs.

Stem Cell Factor Neutralization Protects From Severe Anaphylaxis in a Murine Model of Food Allergy.

Food allergy is a growing public health problem with ~15 million people affected in the United States. In allergic food disease, IgE on mast cells bind to ingested antigens leading to the activation and degranulation of mast cells. Stem cell factor (SCF) is mast cell growth and activation factor that is required for peripheral tissue mast cells. We targeted a specific isoform of SCF, the larger 248 amino acid form, that drives peripheral tissue mast cell differentiation using a specific monoclonal antibody in a model of food allergy. Ovalbumin sensitized and intragastrically challenged mice were monitored for symptoms of anaphylaxis including respiratory distress, diarrhea, and a reduction in body temperature. During the second week of challenges, allergic mice were injected with an antibody to block SCF248 or given IgG control. Mice treated with α-SCF248 had a decreased incidence of diarrhea and no reduction in body temperature suggesting a reduction in anaphylaxis compared to IgG control treated animals. Re-stimulated mesenteric lymph nodes indicated that α-SCF248 treated mice had decreased OVA-specific Th2 cytokine production compared to IgG control treated allergic animals. The reduction of food induced anaphylaxis was accompanied by a significant reduction in gut leak. The mesenteric lymph node cells were analyzed by flow cytometry and showed a decrease in the number of type 2 innate lymphoid cells in mice injected with α-SCF248. Morphometric enumeration of esterase+ mast cells demonstrated a significant reduction throughout the small intestine. Using a more chronic model of persistent food-induced anaphylaxis, short term therapeutic treatment with α-SCF248 during established disease effectively blocked food induced anaphylaxis. Together, these data suggest that therapeutically blocking SCF248 in food allergic animals can reduce the severity of food allergy by reducing mast cell mediated disease activation.

IL-3 is essential for ICOS-L stabilization on mast cells, and sustains the IL-33-induced RORγt+ Treg generation via enhanced IL-6 induction.

SummaryIL‐33 is a member of the IL‐1 family. By binding to its receptor ST2 (IL‐33R) on mast cells, IL‐33 induces the MyD88‐dependent activation of the TAK1‐IKK2 signalling module resulting in activation of the MAP kinases p38, JNK1/2 and ERK1/2, and of NFκB. Depending on the kinases activated in these pathways, the IL‐33‐induced signalling is essential for production of IL‐6 or IL‐2. This was shown to control the dichotomy between RORγt+ and Helios+ Tregs, respectively. SCF, the ligand of c‐Kit (CD117), can enhance these effects. Here, we show that IL‐3, another growth factor for mast cells, is essential for the expression of ICOS‐L on BMMCs, and costimulation with IL‐3 potentiated the IL‐33‐induced IL‐6 production similar to SCF. In contrast to the enhanced IL‐2 production by SCF‐induced modulation of the IL‐33 signalling, IL‐3 blocked the production of IL‐2. Consequently, IL‐3 shifted the IL‐33‐induced Treg dichotomy towards RORγt+ Tregs at the expense of RORγt− Helios+ Tregs. However, ICOS‐L expression was downregulated by IL‐33. In line with that, ICOS‐L did not play any important role in the Treg modulation by IL‐3/IL‐33‐activated mast cells. These findings demonstrate that different from the mast cell growth factor SCF, IL‐3 can alter the IL‐33‐induced and mast cell‐dependent regulation of Treg subpopulations by modulating mast cell‐derived cytokine profiles.

Detection of the germline KIT S476I mutation in a kindred with familial mastocytosis associated with gastrointestinal stromal tumors

Mastocytosis represents a rare disease characterized by clonal proliferation of mast cells (MCs).1 It mostly occurs sporadically as cutaneous or systemic mastocytosis due to somatic activating KIT mutations encoding the MC growth factor receptor KIT. A positive family history is rare and partly attributed to activating germline KIT mutations. Patients with familial mastocytosis (FM) may suffer in addition from gastrointestinal stromal tumors (GISTs), cutaneous hyperpigmentation, and/or dysphagia.

The Mast Cell-SCF-CB1 Interaction Is a Key Player in Seborrheic Keratosis.

Mast cell (MC) is an important player in the development of skin diseases, including atopic dermatitis, psoriasis, and urticaria. It is reported that MC infiltration and activation are observed around various types of tumors and speculated that MCs play key roles in their pathogenesis. As MCs in human seborrheic keratosis (SK) have not been well investigated, here we focused on the MCs in SK. The number of c-Kit and tryptase-positive MCs was significantly increased around the SK compared with the marginal lesion. Degranulated MCs were also increased around the tumors. Furthermore, MC growth factor, stem cell factor (SCF), expression within the SK was significantly upregulated compared with the marginal lesion. Interestingly, one of the cognitive regulators of SCF expression, cannabinoid receptor type 1 (CB1) immunoreactivity was downregulated within the SK. Our results suggest that MCs play important roles in the pathogenesis of SK and that SCF can be also deeply involved in the development of SKs. Our current results highlight the CB1-SCF-MC interaction as a novel mechanism of SK development and this also will be utilized for developing a novel treatment.

The role of IL-9 secreting CD4+ T helper cells in promoting mast cell expansion in pulmonary models of inflammation

Abstract Mast cells are tissue resident cells with granules that contain histamine and other proinflammatory mediators. Mast cells are important effectors in immediate type I hypersensitivity reactions. In severe allergic reactions, immunoglobulin E (IgE)-mediated mast cell degranulation triggers localized and systemic anaphylaxis. In allergic asthma, mast cells and T cells interact in the generation of long-lasting inflammation. The molecular mechanisms responsible for mast cell expansion has not been fully elucidated. Because T cells are an important source of the mast cell growth factor IL-9, we are interested in understanding the role of IL-9, and IL-9-producing T cells in mast cell expansion and recruitment. We have identified a role of T helper 9 (Th9) cells in influencing mast cell number and function in pulmonary models of inflammation. Using adoptive transfer models, we have defined a contribution of Th9 cells in immediate hypersensitivity. We have demonstrated that IL-9 expands mast cell progenitor numbers in bone marrow and lung, suggesting that there are systemic effects of local IL-9 production. We hypothesize that increased mature mast cells in the pulmonary system are from recruitment and expansion of progenitor cells rather than expansion of mature cells in situ. Ongoing studies will directly examine the relative contribution and function of the two populations during models of allergic airway inflammation.

Epigenetic regulation of C-Kitlo FcɛR1a+ mast cells by cannabidiol during staphylococcal enterotoxin B-induced liver injury

Abstract Although recent studies have established cannabidiol (CBD) as a potent anti-inflammatory agent, the mechanisms governing these processes remain unclear. Our previous research demonstrated that CBD treatment induced expansion of CD11b+Gr-1+MDSC in the peritoneum, which suppressed T cell functions leading to attenuation of staphylococcal enterotoxin B (SEB)-mediated liver inflammation in mice. Using the same model, we characterize the effects of CBD administration in the liver. Briefly, mice were injected intraperitoneally (I.P.) with 50mg/kg of CBD for 4 days (d), followed by SEB challenge on d 3. Flow cytometry analysis revealed a significant reduction in Vβ8+ CD8+ T cells. In agreement with our earlier findings, mice treated with CBD displayed robust expansion of Gr-1+ MDSC in the liver, which was primarily comprised of Ly6CHI MHCIILO leukocytes. As mast cells have been found to play a role in CBD-mediated induction of MDSC via increased peroxisome proliferator-activated receptor gamma (PPARγ) signaling, we examined changes to liver mast cell populations. We discovered two distinct subsets of mast cells, C-KithiFcɛR1a+ and C-Kitlo FcɛR1a+present in the liver. CBD treatment promoted expansion of the C-Kitlo FcɛR1a+ subset. Analysis by miRNA microarray displayed enrichment of miRNAs targeting mast cell growth factor, KIT ligand (KITLG), and significant downregulation of miR-217-5p, which is conserved for the co-activator of PPARγ (PPARγC1A). Increased gene expression of PPARγ was confirmed by single-cell RNA sequencing (sc-RNAseq). Taken together, our results identify CBD induced epigenetic reduction of C-Kit expression and KITLG signaling in mast cells to favor PPARγ signaling as a novel anti-inflammatory mechanism.

Dermoscopy of Urticaria Pigmentosa.

Dermoscopy of Urticaria Pigmentosa.

Evaluation Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic patients

Background: Mast cells play an essential role in pathology of bronchial asthma. Stem cell factor (SCF) is a major mast cell growth factor, which could be involved in the local increase of mast cell number in the asthmatic airways when bind to its receptor (C-kit). Existing study aimed to evaluate role of gene expression of SCF and their receptor C-kit in development of bronchial asthma in Iraqi population. Methods: present study included 100 patients diagnostic with bronchial asthma (59 females and 41 males) their ages range from 2 to 61 years and 30 healthy individuals (14 females and 16 males) with the same age range as control group DNA extracted from whole blood samples and then subjected to real time PCR for detection of gene expression. Results: current data showed a significant correlation (p0.05) . The optimum cut-off values for gene expression of SCF and C-kit are ≥ 0.55, ≥2.328 respectively since there are associated with a perfect test for predicting asthma. In conclusion: high gene expression of SCF and C-kit associated with increase severity stage of bronchial asthma without treatment and can be reduced by treatment. How to Cite this Article Pubmed Style MUBARK NN, AL-MAAMORI JA, GHALI KH. Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic SRP. 2020; 11(1): 51-57. doi:10.5530/srp.2020.1.08 Web Style MUBARK NN, AL-MAAMORI JA, GHALI KH. Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic http://www.sysrevpharm.org/?mno=302645230 [Access: March 29, 2021]. doi:10.5530/srp.2020.1.08 AMA (American Medical Association) Style MUBARK NN, AL-MAAMORI JA, GHALI KH. Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic SRP. 2020; 11(1): 51-57. doi:10.5530/srp.2020.1.08 Vancouver/ICMJE Style MUBARK NN, AL-MAAMORI JA, GHALI KH. Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic SRP. (2020), [cited March 29, 2021]; 11(1): 51-57. doi:10.5530/srp.2020.1.08 Harvard Style MUBARK, N. N., AL-MAAMORI, . J. A. & GHALI, . K. H. (2020) Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic SRP, 11 (1), 51-57. doi:10.5530/srp.2020.1.08 Turabian Style MUBARK, NAWRAS NAJAH, JAFAR A. AL-MAAMORI, and KAREEM HAMED GHALI. 2020. Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic Systematic Reviews in Pharmacy, 11 (1), 51-57. doi:10.5530/srp.2020.1.08 Chicago Style MUBARK, NAWRAS NAJAH, JAFAR A. AL-MAAMORI, and KAREEM HAMED GHALI. Evaluation Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic patients. Systematic Reviews in Pharmacy 11 (2020), 51-57. doi:10.5530/srp.2020.1.08 MLA (The Modern Language Association) Style MUBARK, NAWRAS NAJAH, JAFAR A. AL-MAAMORI, and KAREEM HAMED GHALI. Evaluation Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic patients. Systematic Reviews in Pharmacy 11.1 (2020), 51-57. Print. doi:10.5530/srp.2020.1.08 APA (American Psychological Association) Style MUBARK, N. N., AL-MAAMORI, . J. A. & GHALI, . K. H. (2020) Gene Expression of Stem Cell Factor and C-kit among Bronchial Asthmatic Systematic Reviews in Pharmacy, 11 (1), 51-57. doi:10.5530/srp.2020.1.08

Mast cell disorders: From infancy to maturity.

Mast cells are typically linked to immediate hypersensitivity and anaphylaxis. This review looks beyond this narrow role, focusing on how these cells have evolved and diversified via natural selection promoting serine protease gene duplication, augmenting their innate host defense function against helminths and snake envenomation. Plasticity of mast cell genes has come at a price. Somatic activating mutations in the mast cell growth factor KIT gene cause cutaneous mastocytosis in young children and systemic mastocytosis with a more guarded prognosis in adults who may also harbor other gene mutations with oncogenic potential as they age. Allelic TPSAB1 gene duplication associated with higher basal mast cell tryptase is possibly one of the commonest autosomal dominantly inherited multi-system diseases affecting the skin, gastrointestinal tract, circulation and musculoskeletal system. Mast cells are also establishing a new-found importance in severe asthma, and in remodeling of blood vessels in cancer and atherosclerotic vascular disease. Furthermore, recent evidence suggests that mast cells sense changes in oxygen tension, particularly in neonates, and that subsequent degranulation may contribute to common lung, eye, and brain diseases of prematurity classically associated with hypoxic insults. One hundred and forty years since Paul Ehrlich's initial description of "mastzellen," this review collates and highlights the complex and diverse roles that mast cells play in health and disease.

Expression of c-kit in common benign and malignant breast lesions.

c-kit (CD117) is a transmembrane tyrosine kinase that acts as a type III receptor for mast cell growth factor. In recent years, the role of c-kit in the development of preinvasive and invasive breast carcinomas has been investigated. The aim of our study was to detect c-kit expression in the entire spectrum of common benign and malignant breast lesions in correlation with a well-studied myoepithelial or stem-cell like marker (p63). We evaluated 270 cases of benign and malignant breast lesions including fibrocystic disease, fibroadenoma, sclerosing adenosis, atypical ductal hyperplasia, ductal/lobular carcinoma in situ, and ductal/lobular/mixed type carcinoma. C-kit staining was evaluated in the cytoplasm/cell membrane in epithelial and myoepithelial cells and p63 in the nuclei of myoepithelial cells. c-kit was highly expressed (85.3%) in benign lesions (fibrocystic disease, sclerosing adenosis, fibroadenoma), and p63 expression was 95.5% in the aforementioned lesions. c-kit distribution in preinvasive and invasive lesions was as follows: ductal/lobular carcinoma in-situ, 43%/35%; ductal/lobular carcinoma, 36%/39%; and mixed type carcinoma, 20%. c-kit was highly expressed in myofibroblast/fibroblast cells only in grade III ductal/lobular carcinomas. c-kit was totally absent in stromal cells in benign lesions and in situ carcinomas whereas expression was weak in grade I and II carcinomas. Combined overexpression of c-kit and p63 is indicative of benign breast lesions. In contrast, there is reduced expression of c-kit in in situ and invasive breast carcinomas, with simultaneous overexpression in the stromal cells. This suggests that c-kit may play a role in breast cancer progression.

388 Sorafenib enhances mast cells maturation and degranulation in human skin

Sorafenib is a multi-kinase inhibitor for the treatment of advanced hepatocellular carcinomas. It inhibits tumor cell proliferation and tumor angiogenesis by targeting vascular endothelial growth factor receptors, platelet-derived growth factor receptor, c-Kit and Raf-1. Although sorafenib is reported as effective treatment for them, it has also been known to cause diverse cutaneous adverse reactions including hand-foot reaction, facial and scalp eruptions, alopecia and pruritus. However, the mechanism of these adverse effects has not been well-investigated. Mast cells (MC)s are reported to be associated with drug eruptions and pruritus. Here we focused on skin type MC biology by using human skin organ culture system treated with sorafenib and skin samples from patients with drug eruption by sorafenib. As a result, sorafenib significantly activated MC degranulation and increased both c-Kit and tryptase positive MC number in situ. However, sorafenib did not affect MC proliferation and apoptosis. This suggests that sorafenib stimulated MC maturation from resident precursor cells. Furthermore, sorafenib significantly increased the expression of Akt but not Erk within c-Kit positive MCs. Importantly, a PI3K inhibitor, wortmannin abrogated the increased number of MCs by sorafenib. This suggests that the compensatory upregulation of PI3K-signaling was induced by the inhibition of MAP kinase signaling by sorafenib. Sorafenib also significantly upregulated the expression of stem cell factor (SCF), a well-known MC growth factor within the epidermis of organ cultured skin samples. In addition, co-administration of SCF neutralizing antibody diminished the increase in MC number by sorafenib. When we investigated MCs biology within the skin samples from the patients with sorafenib induced drug eruptions, both the number of degranulated and total MCs was significantly increased. Our results indicate that sorafenib is a new activator for human skin type MCs degranulation and maturation, and MCs could be a new target for treating adverse effects by sorafenib.