Mast cells mediate the microvascular inflammatory response to systemic hypoxia

2003 ◽  
Vol 94 (1) ◽  
pp. 325-334 ◽  
Author(s):  
Dawn R. S. Steiner ◽  
Norberto C. Gonzalez ◽  
John G. Wood
Keyword(s):  
Nitric Oxide ◽  
Mast Cell ◽  
Mast Cells ◽  
Inflammatory Response ◽  
Vascular Permeability ◽  
Cell Activation ◽  
Mast Cell Degranulation ◽  
Mast Cell Activation ◽  
Leukocyte Adherence ◽  
Systemic Hypoxia

Systemic hypoxia produces an inflammatory response characterized by increases in reactive O2 species (ROS), venular leukocyte-endothelial adherence and emigration, and vascular permeability. Inflammation is typically initiated by mediators released from activated perivascular cells that generate the chemotactic gradient responsible for extravascular leukocyte accumulation. These experiments were directed to study the possible participation of mast cells in hypoxia-induced microvascular inflammation. Mast cell degranulation, ROS levels, leukocyte adherence and emigration, and vascular permeability were studied in the mesenteric microcirculation by using intravital microscopy of anesthetized rats. The main findings were 1) activation of mast cells with compound 48/80 in normoxia produced microvascular effects similar, but not identical, to those of hypoxia; 2) systemic hypoxia resulted in rapid mast cell degranulation; 3) blockade of mast cell degranulation with cromolyn prevented or attenuated the hypoxia-induced increases in ROS, leukocyte adherence/emigration, and vascular permeability; and 4) mast cell degranulation during hypoxia was prevented by administration of the antioxidant lipoic acid and of nitric oxide. These results show that mast cells play a key role in hypoxia-induced inflammation and suggest that alterations in the ROS-nitric oxide balance may be involved in mast cell activation during hypoxia.

scholarly journals Mast cell activation is not required for induction of airway hyperresponsiveness by ozone in mice

1999 ◽  
Vol 86 (1) ◽  
pp. 202-210 ◽  
Author(s):  
N. Noviski ◽  
J. P. Brewer ◽  
W. A. Skornik ◽  
S. J. Galli ◽  
J. M. Drazen ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Airway Hyperresponsiveness ◽  
Essential Role ◽  
Cell Activation ◽  
Mast Cell Degranulation ◽  
Mast Cell Activation ◽  
Polymorphonuclear Cell ◽  
Pulmonary Parenchyma

Exposure to ambient ozone (O3) is associated with increased exacerbations of asthma. We sought to determine whether mast cell degranulation is induced by in vivo exposure to O3in mice and whether mast cells play an essential role in the development of pulmonary pathophysiological alterations induced by O3. For this we exposed mast cell-deficient WBB6F1- kitW/ kitW-v( kitW/ kitW-v) mice and the congenic normal WBB6F1(+/+) mice to air or to 1 or 3 parts/million O3for 4 h and studied them at different intervals from 4 to 72 h later. We found evidence of O3-induced cutaneous, as well as bronchial, mast cell degranulation. Polymorphonuclear cell influx into the pulmonary parenchyma was observed after exposure to 1 part/milllion O3only in mice that possessed mast cells. Airway hyperresponsiveness to intravenous methacholine measured in vivo under pentobarbital anesthesia was observed in both kitW/ kitW-vand +/+ mice after exposure to O3. Thus, although mast cells are activated in vivo by O3and participate in O3-induced polymorphonuclear cell infiltration into the pulmonary parenchyma, they do not participate detectably in the development of O3-induced airway hyperresponsiveness in mice.

Activation of mast cells by systemic hypoxia, but not by local hypoxia, mediates increased leukocyte-endothelial adherence in cremaster venules

2003 ◽  
Vol 95 (6) ◽  
pp. 2495-2502 ◽  
Author(s):  
Randy Dix ◽  
Teresa Orth ◽  
Julie Allen ◽  
John G. Wood ◽  
Norberto C. Gonzalez
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Selective Reduction ◽  
Mast Cell Activation ◽  
Phosphorescence Quenching ◽  
Inflammatory Cascade ◽  
Systemic Hypoxia ◽  
Quenching Method ◽  
Short Time

Systemic hypoxia, produced by lowering inspired Po2, induces a rapid inflammation in several microcirculations, including cremaster muscle. Mast cell activation is a necessary element of this response. Selective reduction of cremaster microvascular Po2(PmO2) with normal systemic arterial Po2(PaO2; cremaster hypoxia/systemic normoxia), however, does not elicit increased leukocyte-endothelial adherence (LEA) in cremaster venules. This could be due to a short time of leukocyte exposure to the hypoxic cremaster environment. Conversely, LEA increases when PaO2is lowered, while cremaster PmO2remains high (cremaster normoxia/systemic hypoxia). An alternative explanation of these results is that a mediator released from a central site during systemic hypoxia initiates the inflammatory cascade. We hypothesized that if this is the case, cremaster mast cells would be activated during cremaster normoxia/systemic hypoxia, but not during cremaster hypoxia/systemic normoxia. The microcirculation of rat cremaster muscles was visualized by using intravital microscopy. Cremaster PmO2was measured with a phosphorescence quenching method. Cremaster hypoxia/systemic normoxia (PmO27 ± 1 Torr, PaO287 ± 2 Torr) did not increase LEA; however, topical application of the mast cell activator compound 48/80 under these conditions did increase LEA. The effect of compound 48/80 on LEA was blocked by topical cromolyn, a mast cell stabilizer. LEA increased during cremaster normoxia/systemic hypoxia, (PmO264 ± 5 Torr, PaO233 ± 2 Torr); this increase was blocked by topical cromolyn. The results suggest that mast cell stimulation occurs only when PaO2is reduced, independent of cremaster PmO2, and support the idea of a mediator that is released during systemic hypoxia and initiates the inflammatory cascade.

scholarly journals Stress-Induced Mast Cell Activation in Glabrous and Hairy Skin

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Constantin Căruntu ◽  
Daniel Boda ◽  
Sorin Musat ◽  
Ana Căruntu ◽  
Eugen Mandache
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Prolonged Exposure ◽  
Mast Cell Degranulation ◽  
Mast Cell Activation ◽  
Glabrous Skin ◽  
Stress Exposure ◽  
Hairy Skin ◽  
The Impact

Mast cells play a key role in modulation of stress-induced cutaneous inflammation. In this study we investigate the impact of repeated exposure to stress on mast cell degranulation, in both hairy and glabrous skin. Adult male Wistar rats were randomly divided into four groups: Stress 1 day(n=8), Stress 10 days(n=7), Stress 21 days(n=6), and Control(n=8). Rats in the stress groups were subjected to 2 h/day restraint stress. Subsequently, glabrous and hairy skin samples from animals of all groups were collected to assess mast cell degranulation by histochemistry and transmission electron microscopy. The impact of stress on mast cell degranulation was different depending on the type of skin and duration of stress exposure. Short-term stress exposure induced an amplification of mast cell degranulation in hairy skin that was maintained after prolonged exposure to stress. In glabrous skin, even though acute stress exposure had a profound stimulating effect on mast cell degranulation, it diminished progressively with long-term exposure to stress. The results of our study reinforce the view that mast cells are active players in modulating skin responses to stress and contribute to further understanding of pathophysiological mechanisms involved in stress-induced initiation or exacerbation of cutaneous inflammatory processes.

scholarly journals Corticotropin-Releasing Hormone Induces Skin Mast Cell Degranulation and Increased Vascular Permeability, A Possible Explanation for Its Proinflammatory Effects*

Endocrinology ◽  
1998 ◽  
Vol 139 (1) ◽  
pp. 403-413 ◽  
Author(s):  
Theoharis C. Theoharides ◽  
Leena K. Singh ◽  
William Boucher ◽  
Xinzhu Pang ◽  
Richard Letourneau ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mast Cell ◽  
Mast Cells ◽  
Vascular Permeability ◽  
Evans Blue ◽  
Sensory Nerve ◽  
Mast Cell Degranulation ◽  
Nerve Endings ◽  
Sensory Nerve Endings ◽  
Evans Blue Extravasation

Abstract Mast cells are involved in atopic disorders, often exacerbated by stress, and are located perivascularly close to sympathetic and sensory nerve endings. Mast cells are activated by electrical nerve stimulation and millimolar concentrations of neuropeptides, such as substance P (SP). Moreover, acute psychological stress induces CRH-dependent mast cell degranulation. Intradermal administration of rat/human CRH (0.1–10 μm) in the rat induced mast cell degranulation and increased capillary permeability in a dose-dependent fashion. The effect of CRH on Evans blue extravasation was stronger than equimolar concentrations of the mast cell secretagogue compound 48/80 or SP. The free acid analog of CRH, which does not interact with its receptors (CRHR), had no biological activity. Moreover, systemic administration of antalarmin, a nonpeptide CRHR1 antagonist, prevented vascular permeability only by CRH and not by compound 48/80 or SP. CRHR1 was also identified in cultured leukemic human mast cells using RT-PCR. The stimulatory effect of CRH, like that of compound 48/80 on skin vasodilation, could not be elicited in the mast cell deficient W/Wv mice but was present in their +/+ controls, as well as in C57BL/6J mice; histamine could still induce vasodilation in the W/Wv mice. Treatment of rats neonatally with capsaicin had no effect on either Evans blue extravasation or mast cell degranulation, indicating that the effect of exogenous CRH in the skin was not secondary to or dependent on the release of neuropeptides from sensory nerve endings. The effect of CRH on Evans blue extravasation and mast cell degranulation was inhibited by the mast cell stabilizer disodium cromoglycate (cromolyn), but not by the antisecretory molecule somatostatin. To investigate which vasodilatory molecules might be involved in the increase in vascular permeability, the CRH injection site was pretreated with the H1-receptor antagonist diphenhydramine, which largely inhibited the CRH effect, suggesting that histamine was involved in the CRH-induced vasodilation. The possibility that nitric oxide might also be involved was tested using pretreatment with a nitric oxide synthase inhibitor that, however, increased the effect of CRH. These findings indicate that CRH activates skin mast cells at least via a CRHR1-dependent mechanism leading to vasodilation and increased vascular permeability. The present results have implications for the pathophysiology and possible therapy of skin disorders, such as atopic dermatitis, eczema, psoriasis, and urticaria, which are exacerbated or precipitated by stress.

scholarly journals Regulation of mast cell survival and function by tuberous sclerosis complex 1

Blood ◽  
2012 ◽  
Vol 119 (14) ◽  
pp. 3306-3314 ◽  
Author(s):  
Jinwook Shin ◽  
Hongjie Pan ◽  
Xiao-Ping Zhong
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Survival ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Cell Activation ◽  
Cytokine Production ◽  
Mast Cell Degranulation ◽  
Mtor Signaling ◽  
Mast Cell Activation

Abstract Mast cells play critical roles in allergic disorders and asthma. The importance of tuberous sclerosis complex 1/2-mammalian target of rapamycin (TSC1/2-mTOR) signaling in mast cells is unknown. Here, we report that TSC1 is a critical regulator for mTOR signaling in mast cells downstream of FcεRI and c-Kit, and differentially controls mast cell degranulation and cytokine production. TSC1-deficiency results in impaired mast cell degranulation, but enhanced cytokine production in vitro and in vivo after FcεRI engagement. Furthermore, TSC1 is critical for mast cell survival through multiple pathways of apoptosis including the down-regulation of p53, miR-34a, reactive oxygen species, and the up-regulation of Bcl-2. Together, these findings reveal that TSC1 is a critical regulator of mast cell activation and survival, suggesting the manipulation of the TSC1/2-mTOR pathway as a therapeutic strategy for mast cell-mediated diseases.

scholarly journals Identification of 5-Hydroxymethylfurfural (5-HMF) as an Active Component Citrus Jabara That Suppresses FcεRI-Mediated Mast Cell Activation

2020 ◽  
Vol 21 (7) ◽  
pp. 2472 ◽  
Author(s):  
Ryota Uchida ◽  
Michiko Kato ◽  
Yuka Hattori ◽  
Hiroko Kikuchi ◽  
Emi Watanabe ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Active Component ◽  
Cell Activation ◽  
Cytokine Production ◽  
Citrus Fruit ◽  
Mast Cell Degranulation ◽  
Mast Cell Activation ◽  
Active Components ◽  
Seasonal Allergies

Jabara (Citrus jabara Hort. ex Y. Tanaka) is a type of citrus fruit known for its beneficial effect against seasonal allergies. Jabara is rich in the antioxidant narirutin whose anti-allergy effect has been demonstrated. One of the disadvantages in consuming Jabara is its bitter flavor. Therefore, we fermented the fruit to reduce the bitterness and make Jabara easy to consume. Here, we examined whether fermentation alters the anti-allergic property of Jabara. Suppression of degranulation and cytokine production was observed in mast cells treated with fermented Jabara and the effect was dependent on the length of fermentation. We also showed that 5-hydroxymethylfurfural (5-HMF) increases as fermentation progresses and was identified as an active component of fermented Jabara, which inhibited mast cell degranulation. Mast cells treated with 5-HMF also exhibited reduced degranulation and cytokine production. In addition, we showed that the expression levels of phospho-PLCγ1 and phospho-ERK1/2 were markedly reduced upon FcεRI stimulation. These results indicate that 5-HMF is one of the active components of fermented Jabara that is involved in the inhibition of mast cell activation.

scholarly journals New Regulatory Roles of Galectin-3 in High-Affinity IgE Receptor Signaling

2016 ◽  
Vol 36 (9) ◽  
pp. 1366-1382 ◽  
Author(s):  
Monika Bambouskova ◽  
Iva Polakovicova ◽  
Ivana Halova ◽  
Gautam Goel ◽  
Lubica Draberova ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Mast Cell Degranulation ◽  
Negative Regulator ◽  
Mast Cell Activation ◽  
High Affinity ◽  
Galectin 3 ◽  
High Affinity Receptor ◽  
High Affinity Ige Receptor

Aggregation of the high-affinity receptor for IgE (FcεRI) in mast cells initiates activation events that lead to degranulation and release of inflammatory mediators. To better understand the signaling pathways and genes involved in mast cell activation, we developed a high-throughput mast cell degranulation assay suitable for RNA interference experiments using lentivirus-based short hairpin RNA (shRNA) delivery. We tested 432 shRNAs specific for 144 selected genes for effects on FcεRI-mediated mast cell degranulation and identified 15 potential regulators. In further studies, we focused on galectin-3 (Gal3), identified in this study as a negative regulator of mast cell degranulation. FcεRI-activated cells with Gal3 knockdown exhibited upregulated tyrosine phosphorylation of spleen tyrosine kinase and several other signal transduction molecules and enhanced calcium response. We show that Gal3 promotes internalization of IgE-FcεRI complexes; this may be related to our finding that Gal3 is a positive regulator of FcεRI ubiquitination. Furthermore, we found that Gal3 facilitates mast cell adhesion and motility on fibronectin but negatively regulates antigen-induced chemotaxis. The combined data indicate that Gal3 is involved in both positive and negative regulation of FcεRI-mediated signaling events in mast cells.

Human mast cells release the migraine-inducing factor pituitary adenylate cyclase-activating polypeptide (PACAP)

Cephalalgia ◽  
2017 ◽  
Vol 38 (9) ◽  
pp. 1564-1574 ◽  
Author(s):  
Angela J Okragly ◽  
S Michelle Morin ◽  
David DeRosa ◽  
Andrea P Martin ◽  
Kirk W Johnson ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Adenylate Cyclase ◽  
Cell Activation ◽  
Mast Cell Degranulation ◽  
Biologically Active ◽  
Mast Cell Activation ◽  
Human Mast Cells ◽  
Pituitary Adenylate Cyclase ◽  
Ige Mediated

Background Many patients with migraines suffer from allergies and vice versa, suggesting a relationship between biological mechanisms of allergy and migraine. It was proposed many years ago that mast cells may be involved in the pathophysiology of migraines. We set out to investigate the relationship between mast cell activation and known neurogenic peptides related to migraine. Methods Cultured human mast cells were assayed for the presence of neuropeptides and their receptors at the RNA and protein level. Immunohistochemistry analyses were performed on tissue resident and cultured mast cells. Mast cell degranulation assays were performed and pituitary adenylate cyclase-activating polypeptide (PACAP) activity was measured with a bioassay. Results We found that cultured and tissue resident human mast cells contain PACAP in cytoplasmic granules. No other neurogenic peptide known to be involved in migraine was detected, nor did mast cells express the receptors for PACAP or other neurogenic peptides. Furthermore, mast cell degranulation through classic IgE-mediated allergic mechanisms led to the release of PACAP. The PACAP released from mast cells was biologically active, as demonstrated using PACAP receptor reporter cell lines. We confirmed existing literature that mast cell degranulation can also be induced by several neurogenic peptides, which also resulted in PACAP release. Conclusion Our data provides a potential biological explanation for the association between allergy and migraine by demonstrating the release of biologically active PACAP from mast cells.

scholarly journals Effects of Toxin A from Clostridium difficile on Mast Cell Activation and Survival

1998 ◽  
Vol 66 (6) ◽  
pp. 2755-2761 ◽  
Author(s):  
Gloria M. Calderón ◽  
Javier Torres-López ◽  
Tong-Jun Lin ◽  
Bibiana Chavez ◽  
Manuel Hernández ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Clostridium Difficile ◽  
Inflammatory Response ◽  
Inflammatory Mediators ◽  
Cell Activation ◽  
Mast Cell Activation ◽  
Toxin A ◽  
Tnf Α ◽  
Vitro Effect

ABSTRACT Toxins A and B from Clostridium difficile are the main cause of antibiotic-associated diarrhea and pseudomembranous colitis. They cause fluid accumulation, necrosis, and a strong inflammatory response when inoculated in intestinal loops. Since mast cells are a rich source of inflammatory mediators, abundant in the gut, and known to be involved in C. difficile-induced enteritis, we studied the in vitro effect of toxin A on isolated mast cells. Normal rats sensitized by infection with Nippostrongilus brasiliensis were used to isolate peritoneal mast cells (PMC). PMC from naive rats were stimulated with calcium ionophore A23187 as a model of antigen-independent activation, and PMC from sensitized rats were stimulated with N. brasiliensis antigens to study immunoglobulin E-dependent mast cell activation. After 4 h, toxin A did not induce release of nitric oxide or histamine in naive PMC. However, 10 ng of toxin per ml caused a significant release of tumor necrosis factor alpha (TNF-α). In contrast, 1 μg of toxin per ml inhibited antigen or A23187-induced histamine release by PMC. Toxin A at 1 μg/ml for 4 h caused disruption of actin which aggregated in the cytoplasm and around the nucleus. After 24 h, chromatin condensation, cytoplasmic blebbing, and apoptotic-like vesicles were observed; DNA fragmentation was documented also. These results suggest that mast cells may participate in the initial inflammatory response toC. difficile infection by releasing TNF-α upon interaction with toxin A. However, longer exposure to toxin A affects the release of inflammatory mediators, perhaps because of the alteration of the cytoskeleton and induction of apoptosis. The impaired functions and survival of mast cells by C. difficile toxin A could hamper the capacity of these cells to counteract the infection, thus prolonging the pathogenic effects of C. difficiletoxins.

Anaphylaxis-induced mesenteric vascular permeability, granulocyte adhesion, and platelet aggregates in rat

1998 ◽  
Vol 275 (1) ◽  
pp. H274-H284 ◽  
Author(s):  
Geoffrey D. Withers ◽  
Paul Kubes ◽  
Geoffrey Ibbotson ◽  
R. Brent Scott
Keyword(s):  
Mast Cell ◽  
Platelet Aggregation ◽  
Vascular Permeability ◽  
Cell Activation ◽  
Leukocyte Adhesion ◽  
Mast Cell Degranulation ◽  
Mast Cell Activation ◽  
Induce Platelet Aggregation ◽  
Platelet Aggregate ◽  
Platelet Aggregates

This study investigates the response of small venules to IgE-dependent, antigen-mediated mast cell activation. Intravital microscopy was utilized to visualize 25- to 40-μm mesenteric venules, mast cell degranulation (on-line detection), vascular permeability changes (albumin leakage), leukocyte adhesion, and the formation of platelet aggregates in rats sensitized with 10 μg of intraperitoneal egg albumin (EA) in saline- or sham-sensitized (saline alone) rats. Sensitized rats challenged with EA (1 mg/ml superfusing mesentery), but not sensitized rats challenged with BSA or sham-sensitized rats challenged with EA, exhibited mast cell degranulation with significant time-dependent increases in vascular permeability (inhibited by diphenhydramine, salbutamol, and indomethacin), leukocyte adhesion (inhibited by Web-2086), and the formation of cellular aggregates (platelet), which were associated with intermittent obstruction of venular flow. Anti-platelet antibody, but not anti-neutrophil antibody or fucoidin (selectin antagonist), prevented platelet aggregate formation. Compound 48/80-induced mast cell degranulation caused similar changes in permeability (via different mediators) and leukocyte adhesion but did not induce platelet aggregation. EA-induced platelet aggregation was not inhibited by any of the mediators tested, and platelets isolated from sensitized rats failed to aggregate in response to direct EA challenge, suggesting release of an unidentified inflammatory mediator as the factor initiating platelet aggregation.

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