Increased Numbers Of Mast Cells Research Articles

The effect of myeloablative radiation on urinary bladder mast cells

Radiation-induced cystitis is an inflammatory condition affecting the urinary bladder, which can develop as a side effect of abdominopelvic radiotherapy, specifically external-beam radiation therapy or myeloablative radiotherapy. A possible involvement of mast cells in the pathophysiology of radiation-induced cystitis has been indicated in cases of external-beam radiation therapy; however, there is no evidence that these findings apply to the myeloablative aetiology. As such, this study investigated potential changes to urinary bladder mast cell prevalence when exposed to myeloablative radiation. Lethally irradiated C57BL/6J mice that received donor rescue bone marrow cells exhibited an increased mast cell frequency amongst host leukocytes 1 week following irradiation. By 4 weeks, no significant difference in either frequency or cell density was observed. However mast cell diameter was smaller, and a significant increase in mast cell number in the adventitia was observed. This study highlights that mast cells constitute a significant portion of the remaining host leukocyte population following radiation exposure, with changes to mast cell distribution and decreased cell diameter four weeks following radiation-induced injury.

Investigating intestinal mast cell dynamics during acute heat stress in growing pigs.

Objectives were to examine the temporal pattern of intestinal mast cell dynamics and the effects of a mast cell stabilizer (ketotifen [Ket]) during acute heat stress (HS) in growing pigs. Crossbred barrows (n = 42; 32.3 ± 1.9kg body weight [BW]) were randomly assigned to 1 of 7 environmental-therapeutic treatments: (1) thermoneutral (TN) control (TNCon; n = 6), (2) 2h HS control (2h HSCon; n = 6), (3) 2h HS + Ket (2h HSKet; n = 6); (4) 6h HSCon (n = 6), (5) 6h HSKet (n = 6), (6) 12h HSCon (n = 6), or (7) 12h HSKet (n = 6). Following 5d of acclimation to individual pens, pigs were enrolled in two experimental periods (P). During P1 (3d), pigs were housed in TN conditions (21.5 ± 0.8°C) for the collection of baseline measurements. During P2, TNCon pigs remained in TN conditions for 12h, while HS pigs were exposed to constant HS (38.1 ± 0.2°C) for either 2, 6, or 12h. Pigs were euthanized at the end of P2, and blood and tissue samples were collected. Regardless of time or therapeutic treatment, pigs exposed to HS had increased rectal temperature, skin temperature, and respiration rate compared to their TNCon counterparts (1.9°C, 6.9°C, and 119 breaths/min; P < 0.01). As expected, feed intake and BW gain markedly decreased in HS pigs relative to their TNCon counterparts (P < 0.01). Irrespective of therapeutic treatment, circulating corticotropin-releasing factor decreased from 2 to 12h of HS relative to TNCon pigs (P < 0.01). Blood cortisol increased at 2h of HS (2-fold; P = 0.04) and returned to baseline by 6h. Plasma histamine (a proxy of mast cell activation) remained similar across thermal treatments and was not affected by Ket administration (P > 0.54). Independent of Ket or time, HS increased mast cell numbers in the jejunum (94%; P < 0.01); however, no effects of HS on mast cell numbers were detected in the ileum or colon. Jejunum and ileum myeloperoxidase area remained similar among treatments (P > 0.58) but it tended to increase (12%; P = 0.08) in the colon in HSCon relative to TNCon pigs. Circulating lymphocytes and basophils decreased in HSKet relative to TN and HSCon pigs (P ≤ 0.06). Blood monocytes and eosinophils were reduced in HS pigs relative to their TNCon counterparts (P < 0.01). In summary, HS increased jejunum mast cell numbers and altered leukocyte dynamics and proinflammatory biomarkers. However, Ket administration had no effects on mast cell dynamics measured herein.

Evaluation of Calretinin and enumeration of mast cells in rectum tissue biopsies of Hirschsprung and non-Hirschsprung disease in neonate and infant

The Hirschsprung disease (HD) is a complex genetic congenital condition characterized by the absence of ganglion cells in the myenteric and submucosal plexuses of the colon and rectum, leading to functional intestinal obstruction. A study was conducted from July 2022 to December 2022. The Toluidine blue stain and calretinin immunohistochemistry were applied to 36 cases of neonates and infants who clinically presented with symptoms suspicious of having HD, And the hematological study of cell blood counts test and compared the result of the HD group with the non-HD group and control group. The study showed an increase in mast cell numbers in the rectal biopsy tissue of HD patients compared with non-HD patients using Toluidine blue stain. The Immunohistochemistry for calretinin result displayed 27 (75%) cases as HD, while the remaining 9 (25%) cases were confirmed as non-HD and showed hypertrophied nerve fiber in HD cases. at the same time, the complete blood count result was unrelated to HD. Some worrying maternal risk factors were highlighted during pregnancy were the age of the mother at conception, maternal illness, intake of drugs, type of Childbirth, and number of previous maternal abortions; all of them show a non-significant difference between the HD group and non-HD group, also consanguineous marriage was detected and shows a significant difference between the HD group and non-HD group. Keywords: Hirschsprung, Calretinin, Toluidine blue, CBC count

Altered Esophageal Smooth Muscle Phenotype in Achalasia.

Achalasia is a disorder characterized by impairment in lower esophageal sphincter relaxation and esophageal aperistalsis, caused primarily by loss of inhibitory innervation. However, little is known about associated changes in esophageal smooth muscle. We examined the contractile phenotype and innervation of the circular smooth muscle, as well as inflammatory status, and correlated these with patient-specific parameters. Circular smooth muscle biopsies were obtained in consecutive patients with achalasia undergoing peroral endoscopic myotomy. Axonal innervation and neurotransmitter subtypes were determined with immunocytochemistry, and this was used with quantitative Polymerase Chain Reaction (qPCR) to characterize smooth muscle proliferation and cellular phenotype, as well as collagen expression. These were compared to control tissue obtained at esophagectomy and correlated with patient demographic factors including age, onset of symptoms, and Eckhardt score. Biopsies of smooth muscle were obtained from 25 patients with achalasia. Overall, there was increased mast cell number and collagen deposition but increased smooth muscle cell proliferation vs control. There was a striking drop in axon density over controls, with no differences among subtypes of achalasia. Immunocytochemical analysis showed increased expression of the contractile marker α-smooth muscle actin, principally in Type 1 achalasia, that increased with disease duration, while qPCR identified increased mRNA for smoothelin with decreased myosin heavy chain and collagen 3a1, but not collagen 1a1. The thickened circular smooth muscle layer in achalasia is largely denervated, with an altered contractile phenotype and fibrosis. Biopsies obtained during peroral endoscopic myotomy provide a means to further study the pathophysiology of achalasia.

Histochemical changes in the tooth and jaw germs of laboratory rats under the influence of ecotoxicants and during perinatal prevention

Relevance. Unreasonably high pollutant emissions into the environment, the ill-considered use of natural resources and the raw material orientation of exports have led to an environmental crisis in many areas.Purpose. To study the effect of ecotoxicants on the histochemical structure of tooth and jaw germs in laboratory rats and ways to reduce this effect during perinatal prevention.Materials and methods. The experiment included 50 white outbred rats weighing 180-250 grams. All animals formed five groups: 1 control and four experimental. All animals of the experimental groups were subject to gasoline and formaldehyde vapours inhalation exposure; Group 1 (control) was subject to only poisoning with ecotoxicants, Group 2 had peptinsorbent associated with ecotoxicant poisoning, Group 3 – a membrane protector – magnolia vine, Group 4 – beet, Group 5 – peptinsorbent, membrane protector and beet.Results. The histochemical study of tissues around the tooth germs in pup rats born from the control group rats after poisoning with ecotoxicants revealed an increased mast cell number in the tissues compared to intact rats. The samples of Group 2 rats showed that the mast cell number and characteristics practically did not differ from the control group after ecotoxicant poisoning. In the rats of Group 3, the number of mast cells was slightly lower than in the control group. In Group 4, the number of mast cells was not significantly lower than in the control group. In the rats of Group 5, the number of mast cells significantly decreased compared to the control and other experimental groups.Conclusion. Thus, during subchronic poisoning of pregnant female rats with ecotoxicants, the number of mast cells in the gingiva of rat pups increases against the background of microcirculation disorders. The number of mast cells in gingiva significantly decreases and approaches the normal values in rat pups after feeding pregnant rats with the combined mixture (peptinsorbent+membrane protector Schisandra+beetroot).

Stem cells therapeutic effect in a reserpine-induced fibromyalgia rat model: A possible NLRP3 inflammasome modulation with neurogenesis promotion in the cerebral cortex

Fibromyalgia is a chronic pain syndrome with a multifactorial pathophysiology affecting 2–8 % of the population. AimsTo investigate the therapeutic effects of bone marrow mesenchymal stem cells (BMSCs) against fibromyalgia-related cerebral cortex damage and the possible underlying mechanisms of action. Materials and methodsRats were randomly allocated into three groups; control, fibromyalgia and fibromyalgia treated with BMSCs groups. Physical and behavioural assessments were performed. Cerebral cortices were collected for biochemical and histological assessment. Key findingsFibromyalgia group showed behavioural changes indicating presence of pain, fatigue, depression, and sleep disturbances. Moreover, biochemical biomarkers alterations were demonstrated by a significant decrease in brain monoamines and GSH levels, but MDA, NO, TNF-alpha, HMGB-1, NLRP3, and caspase-1 levels significantly increased. Furthermore, histological assessment revealed structural and ultrastructural alterations indicating neuronal and neuroglial degeneration with microglia activation, an increase in mast cell number and IL-1β immune-expression. Additionally, a significant decrease in Beclin-1 immune-expression, and blood brain barrier disruption were noticed. Interestingly, BMSCs administration significantly improved behavioural alterations, restored the reduced brain monoamines and oxidative stress markers, and reduced TNF-alpha, HMGB-1, NLRP3, and caspase-1 levels. Profoundly, cerebral cortices demonstrated improved histological structure, significant decrease in mast cell number and IL-1β immune-expression, besides a significant increase in Beclin-1 and DCX immune-expression. SignificanceFor the best of our knowledge, this is the first study showing ameliorative effects for BMSCs treatment in fibromyalgia-related cerebral cortical damage. The neurotherapeutic effects of BMSCs could be attributed to NLRP3 inflammasome signaling pathway inhibition, mast cell deactivation, and stimulation of neurogenesis and autophagy.

Interleukin-9 promotes mast cell progenitor proliferation and CCR2-dependent mast cell migration in allergic airway inflammation

Allergic asthma is a chronic lung disease characterized by airway hyperresponsiveness and cellular infiltration that is exacerbated by immunoglobulin E-dependent mast cell (MC) activation. Interleukin-9 (IL-9) promotes MC expansion during allergic inflammation but precisely how IL-9 expands tissue MCs and promotes MC function is unclear. In this report, using multiple models of allergic airway inflammation, we show that both mature MCs (mMCs) and MC progenitors (MCp) express IL-9R and respond to IL-9 during allergic inflammation. IL-9 acts on MCp in the bone marrow and lungs to enhance proliferative capacity. Furthermore, IL-9 in the lung stimulates the mobilization of CCR2+ mMC from the bone marrow and recruitment to the allergic lung. Mixed bone marrow chimeras demonstrate that these are intrinsic effects in the MCp and mMC populations. IL-9-producing T cells are both necessary and sufficient to increase MC numbers in the lung in the context of allergic inflammation. Importantly, T cell IL-9-mediated MC expansion is required for the development of antigen-induced and MC-dependent airway hyperreactivity. Collectively, these data demonstrate that T cell IL-9 induces lung MC expansion and migration by direct effects on the proliferation of MCp and the migration of mMC to mediate airway hyperreactivity.

Chronic exposure to a mixture of phthalates shifts the white and brown adipose tissue phenotypes in female mice.

Phthalates are endocrine-disrupting chemicals used in consumer products. Although phthalates are obesogens and affect metabolic function, it is unknown if chronic exposure for 6 months to a phthalate mixture alters adipose tissue phenotype in female mice. After vehicle or mixture exposure, white adipose tissue and brown adipose tissue (WAT and BAT) were analyzed for expression of adipogenesis, proliferation, angiogenesis, apoptosis, oxidative stress, inflammation, and collagen deposition markers. The mixture altered WAT morphology, leading to an increase in hyperplasia, blood vessel number, and expression of BAT markers (Adipoq and Fgf2) in WAT. The mixture increased the expression of the inflammatory markers, Il1β, Ccl2, and Ccl5, in WAT. The mixture also increased expression of the proapoptotic (Bax and Bcl2) and antiapoptotic (Bcl2l10) factors in WAT. The mixture increased expression of the antioxidant Gpx1 in WAT. The mixture changed BAT morphology by increasing adipocyte diameter, whitening area, and blood vessel number and decreased expression of the thermogenic markers Ucp1, Pgargc1a, and Adrb3. Furthermore, the mixture increased the expression of adipogenic markers Plin1 and Cebpa, increased mast cell number, and increased Il1β expression in BAT. The mixture also increased expression of the antioxidant markers Gpx and Nrf2 and the apoptotic marker Casp2 in BAT. Collectively, these data indicate that chronic exposure to a phthalate mixture alters WAT and BAT lipid metabolism phenotypes in female mice, leading to an apparent shift in their normal morphology. Following long-term exposure to a phthalate mixture, WAT presented BAT-like features and BAT presented WAT-like features.

Relationships of pain-causing substances with dry skin and effects of zaltoprofen on alleviation of symptoms in arthritis model mice

Purpose: Skin dryness is a symptom of rheumatoid arthritis (RA). However, the mechanisms through which dry skin is induced in RA are unclear. Accordingly, in this study, we characterized substances related to pruritus and pain and then evaluated whether oral administration of zaltoprofen (ZLT) alleviated the symptom of dry skin induced by RA in model mice. Material and Methods: DBA/1JJmsSlc collagen-induced arthritis model mice were treated with ZLT, and transepidermal water loss (TEWL), capacitance, and inflammation-, pruritus-, and pain-related markers were assessed. Results: Our findings demonstrated that arthritis model mice treated with ZLT exhibited suppression of increases in TEWL and decreases in capacitance. Furthermore, ZLT also blocked the increase in mast cell numbers, substance P expression, and cyclo-oxygenase-2 expression in the skin and prevented enhancement of plasma levels of thymic stromal lymphopoietin, tumour necrosis factor-α, interleukin-6, histamine, and bradykinin. No changes in plasma levels of corticosterone or reactive oxygen species or skin levels of glucocorticoid receptor were observed in ZLT-treated arthritis model mice. Conclusions: Overall, these findings suggested that patients with RA may benefit from biopharmacy to alleviate joint symptoms and nonsteroidal anti-inflammatory drugs for pain relief and alleviation of skin symptoms.

Estrogen mediates inflammatory role of mast cells in endometriosis pathophysiology.

Endometriosis is an estrogen dependent, chronic inflammatory disease characterized by the growth of endometrial lining outside of the uterus. Mast cells have emerged as key players in regulating not only allergic responses but also other mechanisms such as angiogenesis, fibrosis, and pain. The influence of estrogen on mast cell function has also been recognized as a potential factor driving disease pathophysiology in number of allergic and chronic inflammatory conditions. However, precise information is lacking on the cross talk between endocrine and immune factors within the endometriotic lesions and whether that contributes to the involvement of mast cells with disease pathophysiology. In this study, we observed a significant increase in mast cell numbers within endometriotic lesions compared to matched eutopic endometrium from the same patients. Compared to eutopic endometrium, endometriotic lesions had significantly higher levels of stem cell factor (SCF), a potent growth factor critical for mast cell expansion, differentiation, and survival for tissue resident mast cells. Targeted mRNA Q-PCR array revealed that the endometriotic lesions harbour microenvironment (upregulation of CPA3, VCAM1, CCL2, CMA1, CCR1, and KITLG) that is conducive to mast cells recruitment and subsequent differentiation. To examine cross-talk of mast cells within the endometriotic lesion microenvironment, endometriotic epithelial cells (12Z) and endometrial stromal cells (hESC) incubated with mast cell-conditioned media showed significantly increased production of pro-inflammatory and chemokinetic cytokines. To further understand the impact of estrogen on mast cells in endometriosis, we induced endometriosis in C57BL/6 mice. Mature mast cells were significantly higher in peritoneal fluid of estrogen-treated mice compared to untreated mice within the sham operated groups. Mouse endometriotic lesion tissue revealed several genes (qRT-PCR) relevant in mast cell biology significantly upregulated in the estrogen treated, endometriosis-induced group compared to control endometrium. The endometriotic lesions from estrogen treated mice also had significantly higher density of Alcian blue stained mast cells compared to untreated lesions or control endometrium. Collectively, these findings suggest that endometriotic lesions provide a microenvironment necessary for recruitment and differentiation of mast cells. In turn, mast cells potentially release pro-inflammatory mediators that contribute to chronic pelvic pain and endometriosis disease progression.

Influence of electroacupuncture of"Zusanli"(ST36)on mast cells/TRPV1 signaling pathway in visceral hypersensitivity rats with functional dyspepsia

To explore the interventional mechanism of electroacupuncture (EA) of "Zusanli"(ST36)based on the involvement of mast cells/ transient receptor potential vanilloid type1 (TRPV1) signaling pathway in relieving visceral hypersensitivity in functional dyspepsia (FD) rats. Sixty SD rats (half male and half female, 10 days in age) were randomly divided into normal control, model, medication (ketotifen) and EA groups, with 15 rats in each group. The FD model was established by gavage of iodoacetamide combined with tail clamping (stress stimulation). Rats of the medication group received intraperitoneal injection of ketotifen (1 mg·kg-1·d-1) for 14 d, and those of the EA group received EA of ST36 for 20 min, once a day for 14 d. An air-balloon was inserted into the rat's stomach for recording changes of the intragastric pressure (mL/mm Hg) via a pressure transducer. The visceral hypersensitivity was assessed using abdominal withdrawal reflex (AWR) score and the number and degranulation of mast cells of gastric mucosa were observed using toluidine blue staining. The expression levels of TRPV1 and proteinase activated receptor 2 (PAR2) in the stomach were observed using immunofluorescence histochemistry and Western blot, separately, and the contents of SP and CGRP in the stomach detected using ELISA. When the intragastric pressure was at 50, 60 and 70 mm Hg, the gastric compliance was significantly decreased (P<0.01), and the levels of visceral sensitivity increased in the model group （P<0.01）。 TRPV1 immunofluorescence tensity, expression of PAR2 and TRPV1 proteins, and contents of SP and CGRP in the stomach were considerably up-regulated in the model group compared with the normal control group (P<0.01). In comparison with the model group, under intragastric pressure of 50，60 and 70 mm Hg, the gastric compliance was obviously increased, and the visceral hypersensitivity decreased in the EA group （P<0.01,P<0.05）. TRPV1 immunofluorescence intensity, expression levels of PAR2 and TRPV1 proteins, and the contents of SP and CGRP in the stomach were considerably down-regulated in both medication and EA groups compared with the model group (P<0.01, P<0.05). The therapeutic effect of EA was significantly superior to that of medication in up-regulating the gastric compliance （at 70 mm Hg）, and down-regulating the contents of SP and CGRP (P<0.05). No significant differences were found between the EA and medication groups in up-regulating gastric compliance at intragastric pressure of 50 and 60 mm Hg, and in down-regulating the visceral sensitivity, TRPV1 fluorescence intensity, and expression of PAR2 and TRPV1 proteins (P>0.05). Toluidine blue staining showed an apparent increase of mast cell number with obvious degranulation in the gastric mucosa of rats in the model group, which was milder in the EA and medication groups. EA of ST36 can suppress visceral hypersensitivity and increase the gastric compliance in FD rats, which may be related with its effects in inhibiting the activation of gastric mast cells, and down-regulating the expression of gastric PAR2 and TRPV1 proteins and SP and CGRP contents.

Mast cells selectively target large cholangiocytes during biliary injury via H2HR-mediated cAMP/pERK1/2 signaling.

Bile ducts are heterogenous in structure and function, and primary sclerosing cholangitis (PSC) damages specific bile ducts leading to ductular reaction (DR), mast cell (MC) infiltration, increased histamine release, inflammation, and fibrosis. Bile duct ligation (BDL) induces large duct damage via cyclic adenosine monophosphate (cAMP)/extracellular signal‐related protein kinase (ERK) signaling, and large cholangiocytes express H2 histamine receptor (H2HR). We evaluated how MCs interact with large cholangiocytes during cholestasis. Male wild‐type (WT) and MC‐deficient (Kit W‐sh ) mice 10–12 weeks of age were subjected to BDL for 7 days. Select Kit W‐sh mice were injected with MCs pretreated with control or H2HR antagonist (ranitidine, 25 μm, 48 h) via tail vein injection. In vitro, MC migration toward small mouse cholangiocytes (SMCCs) and large mouse cholangiocytes (LMCCs) treated with lipopolysaccharide or histamine (±ranitidine) was measured. LMCCs were stimulated with MC supernatants pretreated with control, α‐methyl‐dl‐histidine (to block histamine release), or ranitidine. Liver damage, large duct DR/senescence, inflammation, fibrosis, and cAMP/ERK immunoreactivity increased in BDL WT and Kit W‐sh +MC mice but decreased in BDL Kit W‐sh and Kit W‐sh +MC‐H2HR mice. In vitro, MCs migrate toward damaged LMCCs (but not SMCCs) blocked by inhibition of H2HR. Loss of MC histamine or MC‐H2HR decreases LMCC proliferation, senescence, H2HR, and cAMP/ERK levels. Human PSC livers have increased MC number found near DR, senescent ducts, and H2HR‐positive ducts. Conclusion: Infiltrating MCs preferentially interact with large ducts via H2HR signaling promoting biliary and liver damage. Mediation of MCs may be a therapeutic strategy for PSC.

Preliminary study of the ameliorative effects of melatonin on cadmium-induced morphological and biochemical alterations in the rat Harderian gland.

Herein is reported, for the first time in the rat Harderian gland (HG), the counteractive action of melatonin (Mlt), a well-known antioxidant radical scavenger, on the increased oxidative stress damages induced by a pro-oxidant substance, cadmium (Cd), an environmental pollutant also considered as endocrine disruptor. HG, an infraorbital gland present in almost all terrestrial vertebrates, produces a lipid secretion to lubricate the eyeball, as well as porphyrin/Mlt as light transducers. Moreover, HG is an extra-gonadal source of steroid sex hormones. Via ex vivo experiments lasting for 24 h, we verified the increased lipid peroxidation in Cd-treated glands, producing morphological alteration of the glandular epithelium, as well as an increased porphyrins accumulation. Moreover, Cd also induced a decreased protein level of the steroidogenic enzymes steroidogenic acute regulatory (StAR) and 3βHSD, and an increased mast cell number. Results obtained with Mlt cotreatment demonstrated that it decreased the levels of Cd-induced oxidative damage, with reversal of all the observed modification. Furthermore, the TUNEL assay showed that the increased number of apoptotic cells in Cd-treated HG was counteracted by the contemporaneous Mlt administration. Results confirmed that Mlt treatment restored the levels of two autophagy markers, LC3 and p62, counteracting the autophagy Cd-induced. Interestingly, the positive effects of Mlt alone were highlighted by the decreased rate of lipid peroxidation as compared with the control, confirming its antioxidant action. Combined data further confirmed the antioxidant action of Mlt in counteracting the degeneration provoked by reactive oxygen species (ROS) in the rat HG, a tissue extremely susceptible to oxidative stress condition.

Diagnostic and prognostic implications of mast cell microenvironment in smooth muscle tumors of the uterine corpus

Mast cells can be found almost everywhere throughout the human body, even in some benign soft tissue tumors (e.g. neurofibroma) and their presence within gynecological tumors has been well known for several decades. However, the prognostic role of their presence in various tumors is not yet understood as several scientific studies reveal contradictory information with both positive and negative correlation between the number of mast cells and tumor aggressiveness. In recent years, some authors reported that increased numbers of mast cell in the background of cervical and endometrial carcinomas are usually correlated with a worse prognosis when compared to similar histopathologic lesions with no mast cell microenvironment. On the other hand, similar studies regarding ovarian and breast carcinoma demonstrated strong positive correlation between increased mast cell numbers and favorable outcome. Therefore, we now have increasing evidence showing that mast cells tend to gather within and around neoplastic proliferations and could either promote or inhibit tumoral growth, based on regional stromal environment. In this article we aim to evaluate the mast cell microenvironment in smooth muscle tumors of the uterine corpus and attempt to establish their diagnostic implications and prognostic value.

Research progress of mast cell activation syndrome

Mast cells are the main effector cells in allergic diseases. Allergic diseases are mostly a direct result of mast cell mediator release effects, while allergen activation is only one of many triggers for mast cell mediator secretion. Increased mast cell number, high mast cell reactivity, or both can lead to abnormal mast cell activation. Mast cell activated syndrome (MCAS) refers to a group or a"spectrum"of mediator-related, symptomatically similar diseases in which mast cells are stimulated by multiple factors. The symptoms and signs of mast cell disease overlap with allergic diseases, but the etiology is different, which requires clinical attention. This article summarizes the research progress on mast cell activation syndrome in recent years thus increase awareness of the differential diagnosis.

Mesenchymal Stem Cell-Derived Exosomes Attenuate TLR7-Mediated Mast Cell Activation.

Mast cells are immune sentinels in the skin that respond to a wide range of pathological and environmental stimuli; they owe their function to the expression of Toll-like receptors (TLRs). We previously found that tonsil-derived mesenchymal stem cells (T-MSCs) were able to effectively attenuate TLR7-mediated skin inflammation in mice, which was accompanied by an increase in mast cell number. The present study investigated whether T-MSC extracellular vesicles, such as exosomes, are able to regulate mast cell activation in response to TLR7 stimulation. The HMC-1 human mast cell line was treated with a TLR7 agonist in the presence or absence of T-MSC exosomes, and the levels of expressed inflammatory cytokines were assessed. Additionally, mice were repeatedly injected with a TLR7 agonist with or without interval treatments with T-MSC exosomes and assessed dermal distribution of mast cells and related immune cells. We showed that T-MSC exosomes containing microRNAs that target inflammatory cytokines significantly reduced the expression of inflammatory cytokines in TLR7 agonist-treated HMC-1 cells. In addition, T-MSC exosomes inhibited the increase in the number of both dermal mast cells and CD14-positive cells in TLR7 agonist-treated mice. Our data suggest that T-MSC exosomes have regulatory effects on mast cell activation under inflammatory conditions, including TLR7 stimulation.

Quantification of mast cells in nonreactive and reactive lesions of gingiva: A comparative study using toluidine blue and immunohistochemical marker mast cell tryptase.

Background:Mast cells (MCs) are immune cells derived from a multipotent CD34 precursor. The most significant identifying feature of MCs is the presence of metachromatic granules. MCs are increased in oral reactive lesions and are possibly involved in pathogenesis of these lesions.Objectives:1. To compare the number of MCs between reactive and nonreactive lesions of gingiva using toluidine blue (TB) and mast cell tryptase (MCT) as a specific marker for MCs 2. To compare the staining specificity/efficacy of TB and MCT.Methodology:The study sample comprised 90 tissues which were divided into three groups: Group A comprised 30 cases of pyogenic granuloma (PG), Group B consisted of 30 cases of gingival hyperplasia (GH) and Group C comprised 30 cases of pericoronitis. Staining was done between 1% TB and immunohistochemistry (IHC) marker MCT.Results:A significant increase in number of MCs was observed in PG as compared to GH and pericoronitis. IHC marker MCT proved to be a more specific marker for MCs compared to TB.Conclusion:IHC marker MCT is a specific marker compared to TB. The position of MCs changed from juxtaepithelial in GH to deeper connective tissue in PG which was in correlation with the proliferating tissue that is epithelium in GH and blood vessel in PG.

Hidrox® and Chronic Cystitis: Biochemical Evaluation of Inflammation, Oxidative Stress, and Pain.

Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic bladder condition characterized by frequent urination, inflammation, oxidative stress, and pain. The aim of the study was to evaluate the anti-inflammatory and antioxidant effects of an oral administration of Hidrox® (10 mg/kg) in the bladder and spinal cord in a rodent model of IC/BPS. The chronic animal model of cystitis was induced by repeated intraperitoneal injections of cyclophosphamide (CYP) for five consecutive days. Treatment with Hidrox® began on the third day of the CYP injection and continued until the 10th day. CYP administration caused macroscopic and histological bladder changes, inflammatory infiltrates, increased mast cell numbers, oxidative stress, decreased expression of the tight endothelial junction (e.g., zonula occludens-1 (ZO-1) and occludin), and bladder pain. Treatment with Hidrox® was able to improve CYP-induced inflammation and oxidative stress via the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway. It was also able to reduce bladder pain which was aggravated by the activation of neuroinflammation in the central nervous system. In particular, Hidrox® reduced the brain-derived neurotrophic factor (BDNF), as well as the activation of astrocytes and microglia, consequently reducing mechanical allodynia. These results indicate that nutritional consumption of Hidrox® can be considered as a new therapeutic approach for human cystitis, increasing the conceivable potential of a significant improvement in the quality of life associated with a lowering of symptom intensity in patients with IC/BPS.

Reciprocal interactions between the gut microbiome and mammary tissue microenvironment promote distant regulation of breast tumor metastasis

Abstract Establishing commensal dysbiosis, defined as an inflammatory gut microbiome with low biodiversity, prior to breast tumor initiation enhances early dissemination of hormone-receptor positive (HR+) mammary tumor cells into the circulation, distal lymph nodes, and lungs. Here, we sought to define mammary tissue mediators of dysbiosis-induced tumor dissemination. Commensal dysbiosis increased mast cell numbers in the pre-malignant mammary tissue, with numbers remaining elevated in the presence of a tumor. During early tumor progression, increased mast cell numbers correlated with increased numbers of activated fibroblasts and collagen I protein levels in mammary tissues. Fibroblast activation and tissue remodeling are associated with enhanced breast tumor metastasis. Although mast cell degranulation is known to trigger fibrosis in other disease models, it is unknown whether mammary tissue mast cells influence dissemination of tumor cells. To investigate the role of mast cells during tumor dissemination, mice were treated with mast cell stabilizers ketotifen or cromolyn. Notably, inhibition of mast cell degranulation significantly reduced fibroblast activation and dissemination of tumor cells into the blood of dysbiotic animals. Collagen levels in mammary tissues from women diagnosed with HR+ breast cancer also correlated with mast cell abundance, suggesting mast cell-mediated fibroblast activation is relevant to human disease. Together, these data demonstrate that mast cells recruited into the pre-malignant mammary tissue in response to commensal dysbiosis orchestrate early dissemination of HR+ breast tumors through activation of tissue fibroblasts.

Small intestinal immunopathology and GI-associated antibody formation in hereditary alpha-tryptasemia

Hereditary alpha-tryptasemia (HαT) is characterized by elevated basal serum tryptase due to increased copies of the TPSAB1 gene. Individuals with HαT frequently present with multisystem complaints, including anaphylaxis and seemingly functional gastrointestinal (GI) symptoms. We sought to determine the prevalence of HαT in an irritable bowel syndrome cohort and associated immunologic characteristics that may distinguish patients with HαT from patients without HαT. Tryptase genotyping by droplet digital PCR, flow cytometry, cytometry by time-of-flight, immunohistochemistry, and other molecular biology techniques was used. HαT prevalence in a large irritable bowel syndrome cohort was 5% (N= 8/158). Immunophenotyping of HαT PBMCs (N≥ 27) revealed increased total and class-switched memory B cells. In the small bowel, expansion of tissue mast cells with expression of CD203c, HLA-DR, and FcεRI, higher intestinal epithelial cell pyroptosis, and increased class-switched memory B cells were observed. IgG profiles in sera from individuals with HαT (N= 21) significantly differed from those in individuals with quiescent Crohn disease (N= 20) and non-HαT controls (N= 19), with increased antibodies directed against GI-associated proteins identified in individuals with HαT. Increased mast cell number and intestinal epithelial cell pyroptosis in the small intestine, and class-switched memory B cells in both the gut and peripheral blood associated with IgG reactive to GI-related proteins, distinguish HαT from functional GI disease. These innate and adaptive immunologic findings identified in association with HαT are suggestive of subclinical intestinal inflammation in symptomatic individuals.