Interactions of mast cells and leukocytes in increased vascular permeability in the focus of inflammation]

On the model of acute infectious peritonitis in rats it is shown that the mast cell depletion affected the inflammatory focus vascular permeability mainly in the immediate phase of its increase. Leukopenia inhibited the permeability both in the immediate and delayed phases. The combined depletion of mast cells and leukocytes not only inhibited the degree of vascular permeability increase but strongly affected its kinetics during exudative phase of peritonitis. The results indicate that in the natural conditions of inflammation the mast cell-leukocyte interaction in the vascular permeability increase takes place.     

Connections between the mast cell system of a focus of inflammation and the zona fasciculata of the adrenal cortex

At aseptic inflammation developing around a solid foreign body and proceeding both under common conditions and on the background of disturbed inactivation of free amines as a result of monoaminoxidase blockade with vetrasin or devastation of amine tissue depots with reserpine it has been stated that indices of the adrenal cortex activity (hyperemia, contents of ascorbic acid and corticoids) and those of the mast cells system in the inflammatory focus (amount of the cells, their size, contents of glycosaminoglycans, RNA, tryptophan and histidine) are subjected to certain fluctuations during inflammation. Increasing activity of the adrenal cortex fascicular zone and renewal of the mast cell population in the inflammatory focus are directly proportional to the degree of a disturbed deposition of free amines in the organism. Certain positive correlations prevail in cooperation of the adrenal cortex activity, decomposition rate of large (mature) mast cells and migration into the inflammatory focus of small (immature) forms of these cells.     

P2 receptor-mediated signaling in mast cell biology

Mast cells are widely recognized as effector cells of allergic inflammatory reactions. They contribute to the pathogenesis of different chronic inflammatory diseases, wound healing, fibrosis, thrombosis/fibrinolysis, and anti-tumor immune responses. In this paper, we summarized the role of P2X and P2Y receptors in mast cell activation and effector functions. Mast cells are an abundant source of ATP which is stored in their granules and secreted upon activation. We discuss the contribution of mast cells to the extracellular ATP release and to the maintenance of extracellular nucleotides pool. Recent publications highlight the importance of purinergic signaling for the pathogenesis of chronic airway inflammation. Therefore, the role of ATP and P2 receptors in allergic inflammation with focus on mast cells was analyzed. Finally, ATP functions as mast cell autocrine/paracrine factor and as messenger in intercellular communication between mast cells, nerves, and glia in the central nervous system.     

Mast cells in inflammatory arthritis

Mast cells are present in limited numbers in normal human synovium, but in rheumatoid arthritis and other inflammatory joint diseases this population can expand to constitute 5% or more of all synovial cells. Recent investigations in a murine model have demonstrated that mast cells can have a critical role in the generation of inflammation within the joint. This finding highlights the results of more than 20 years of research indicating that mast cells are frequent participants in non-allergic immune responses as well as in allergy. Equipped with a diversity of surface receptors and effector capabilities, mast cells are sentinels of the immune system, detecting and delivering a first response to invading bacteria and other insults. Accumulating within inflamed tissues, mast cells produce cytokines and other mediators that may contribute vitally to ongoing inflammation. Here we review some of the non-allergic functions of mast cells and focus on the potential role of these cells in murine and human inflammatory arthritis.     

Mast cells in inflammatory arthritis

Mast cells are present in limited numbers in normal human synovium, but in rheumatoid arthritis and other inflammatory joint diseases this population can expand to constitute 5% or more of all synovial cells. Recent investigations in a murine model have demonstrated that mast cells can have a critical role in the generation of inflammation within the joint. This finding highlights the results of more than 20 years of research indicating that mast cells are frequent participants in non-allergic immune responses as well as in allergy. Equipped with a diversity of surface receptors and effector capabilities, mast cells are sentinels of the immune system, detecting and delivering a first response to invading bacteria and other insults. Accumulating within inflamed tissues, mast cells produce cytokines and other mediators that may contribute vitally to ongoing inflammation. Here we review some of the non-allergic functions of mast cells and focus on the potential role of these cells in murine and human inflammatory arthritis.     

肥大细胞在动脉粥样硬化形成中的作用

动脉粥样硬化,是冠心病的病理基础,被认为是一种慢性炎症性疾病,涉及如巨噬细胞和T淋巴细胞等许多炎性细胞。肥大细胞是一种重要的免疫细胞,其功能主要是在超敏反应方面的作用。有病理学研究表明：肥大细胞在动脉粥样硬化斑块周围表达增加,这表明肥大细胞可能与疾病的进展有关。最近的研究表明,肥大细胞在动脉粥样硬化中确实起着重要的作用。本文通过总结肥大细胞在动脉粥样硬化形成中的作用,为在疾病进程中,通过调节肥大细胞功能来改善动脉粥样硬化的这种治疗方式的可能性提供依据。     

肥大细胞在动脉粥样硬化形成中的作用

动脉粥样硬化,是冠心病的病理基础,被认为是一种慢性炎症性疾病,涉及如巨噬细胞和T淋巴细胞等许多炎性细胞。肥大细胞是一种重要的免疫细胞,其功能主要是在超敏反应方面的作用。有病理学研究表明:肥大细胞在动脉粥样硬化斑块周围表达增加,这表明肥大细胞可能与疾病的进展有关。最近的研究表明,肥大细胞在动脉粥样硬化中确实起着重要的作用。本文通过总结肥大细胞在动脉粥样硬化形成中的作用,为在疾病进程中,通过调节肥大细胞功能来改善动脉粥样硬化的这种治疗方式的可能性提供依据。     

Secretogranin III directs secretory vesicle biogenesis in mast cells in a manner dependent upon interaction with chromogranin A

Mast cells are granular immunocytes that reside in the body's barrier tissues. These cells orchestrate inflammatory responses. Proinflammatory mediators are stored in granular structures within the mast cell cytosol. Control of mast cell granule exocytosis is a major therapeutic goal for allergic and inflammatory diseases. However, the proteins that control granule biogenesis and abundance in mast cells have not been elucidated. In neuroendocrine cells, whose dense core granules are strikingly similar to mast cell granules, granin proteins regulate granulogenesis. Our studies suggest that the Secretogranin III (SgIII) protein is involved in secretory granule biogenesis in mast cells. SgIII is abundant in mast cells, and is organized into vesicular structures. Our results show that over-expression of SgIII in mast cells is sufficient to cause an expansion of a granular compartment in these cells. These novel granules store inflammatory mediators that are released in response to physiological stimuli, indicating that they function as bona fide secretory vesicles. In mast cells, as in neuroendocrine cells, we show that SgIII is complexed with Chromogranin A (CgA). CgA is granulogenic when complexed with SgIII. Our data show that a novel non-granulogenic truncation mutant of SgIII (1-210) lacks the ability to interact with CgA. Thus, in mast cells, a CgA-SgIII complex may play a key role in secretory granule biogenesis. SgIII function in mast cells is unlikely to be limited to its partnership with CgA, as our interaction trap analysis suggests that SgIII has multiple binding partners, including the mast cell ion channel TRPA1.     

The role of mast cells in virus-induced inflammation in the murine central nervous system

The mononuclear inflammatory response to Sindbis virus infection of the central nervous system is analogous to the cutaneous delayed-type hypersensitivity reaction. It is dependent on sensitized T cells for initiation, but many of the cells present are nonsensitized bone marrow-derived cells. Tissue mast cells have been shown to be important for the development of the delayed-type hypersensitivity reaction in the skin where capillary endothelial cells are joined by tight junctions. To determine whether mast cells are also important for the development of an immune-mediated inflammatory response across the endothelial tight junctions of the blood-brain barrier, the development of mononuclear inflammation in the central nervous system of reserpine-treated mice and mast cell-deficient mice (WBB6F1-W/Wv) was studied after infection with Sindbis virus. Three central nervous system compartments, the cerebrospinal fluid, the meninges, and the brain parenchyma, were evaluated for inflammation by counting the number of cells present, by grading the histopathologic lesions, and by labeling infiltrating cells with 125IUDR. By all parameters inflammation was reduced when mice were treated with reserpine or were deficient in mast cells. Antigen-specific humoral and cellular immune responses were depressed and virus clearance delayed in reserpine-treated mice, but not in mast cell deficient mice. It is concluded that the vasoactive amines released by mast cells in the central nervous system play a facilitating role in the development of the inflammatory response to Sindbis virus.     

Influence of a macrolide antibiotic, roxithromycin, on mast cell growth and activation in vitro

BACKGROUND: Long-term administration of macrolide antibiotics is recognized to be able to favorably modify the clinical condition of inflammatory diseases, such as diffuse panbronchiolitis and cystic fibrosis. However, the precise mechanisms by which macrolide antibiotics could improve clinical conditions of the patients are not well understood. AIM: The present study was designed to examine the influence of macrolide antibiotics on effector cell functions responsible for inflammation through the choice of roxithromycin (RXM) and mast cell. METHODS: Mast cells were induced by long-term culture of splenocytes from BALB/c mice. RXM was added to the cultures at seeding and then every 4-5 days, when the culture medium was replaced with a fresh one. The influence of RXM on mast cell growth was evaluated by counting the number of cells grown on the 16th day. We also examined the influence of RXM on mast cell activation by examining histamine release and inflammatory cytokine secretion. RESULTS AND CONCLUSION: RXM could not inhibit mast cell growth, even when splenocytes were exposed to 100 microg/ml of RXM throughout the entire culture periods. RXM also could not suppress histamine release from cultured mast cells in response to non-immunological and immunological stimulations. However, RXM could suppress inflammatory cytokine, interleukin-1beta, interleukin-6, granulocyte macrophage-colony stimulating factor and tumor necrosis factor-alpha, secretions induced by concanavalin A stimulation at a concentration of as little as 0.5 microg/ml. These results may suggest that RXM modulated the ability of mast cells to secrete inflammatory cytokines and results in improvement of clinical condition of chronic inflammatory diseases.     

Age-related changes in mast cells and eosinophils of human dermis

In this study, quantitative analysis of inflammatory effectors—mast cells and eosinophils—in derma of people of different ages is performed. The study shows that mast cell quantity in derma increases with age. Eosinophils are rarely observed in human dermis. There are no age-correlated changes of dermal eosinophils quantity observed. Age-correlated dermal fibroblast quantity is established. PCNA+ (proliferating cells nuclear antigen) fibroblast percentage demonstrating their proliferative pool also reliably decreases with age. Results of correlation analysis show that age-correlated increase in mast cells’ quantity is reliably (p < 0.05) correlated with decrease in total number and percentage of PCNA+ fibroblasts in derma. Consequently, age-correlated increase in dermal mast cell may be proposed to be one of the inflammatory and aging mechanisms. Mast cells, whose number increases with aging, may influence dermal fibroblast number with aging.     

The molecular role of mast cells in atherosclerotic cardiovascular disease

Human atherosclerosis has many characteristics of an inflammatory disorder. Recent data suggest that mast cells might be important in the pathogenesis of atherosclerotic disease. By secretion of pro-inflammatory cytokines, mast cells can assist in the recruitment of monocytes and lymphocytes into vascular tissue, thereby propagating the inflammatory response. Mast cell enzymes might activate pro-metalloproteinases, thereby destabilizing atheromatous plaques. Mast cells can facilitate foam cell formation by promoting cholesterol accumulation. However, mast cell tryptase could slow thrombus formation at sites of plaque rupture by interfering with coagulation. Therefore, mast cells can modulate coronary artery disease by both facilitatory and inhibitory pathways.     

Participation of mast cells in chronic otitis media

In the pathogenesis of chronic otitis media (COM), much attention is paid to the molecular mechanisms of local inflammatory reactions in which mast cells (MCs) may be involved due to their role not only in allergic but also inflammatory processes. The aim of this study was to assess the density of mast cells in chronic otitis media in relationship to different clinical courses of COM, bacterial infections and types of disease. The MCs expression was measured immunohistochemically in paraffin-embedded granulation tissue specimens taken during surgery, by staining with a monoclonal antibody against tryptase. The density of tryptase-positive mast cells was lower in tissue samples from the group with a good clinical course than in those from the group with poor healing and recurrence (p = 0.006). There were no differences between the groups of patients with granulomatous and cholesteatomatous chronic otitis media (p = 0.66) or between the groups of patients with and without bacterial infection (p = 0.30), although the density of mast cells was lower for those with Pseudomonas aeruginosa/Proteus sp./ /Staphylococcus MRSA infection. In conclusion, the expression of mast cells in chronic otitis media granulation tissue was found to differ depending on the clinical course of the disease, but not on bacterial infection or type of COM. This may suggest that mast cells contribute to the maintenance of the inflammatory process, but not to antibacterial defense in chronic otitis media.     

Mast cells and metabolic syndrome

Mast cells are critical effectors in the development of allergic diseases and in many immunoglobulin E-mediated immune responses. These cells exert their physiological and pathological activities by releasing granules containing histamine, cytokines, chemokines, and proteases, including mast cell-specific chymase and tryptase. Like macrophages and T lymphocytes, mast cells are inflammatory cells, and they participate in the pathogenesis of inflammatory diseases such as cardiovascular complications and metabolic disorders. Recent observations suggested that mast cells are involved in insulin resistance and type 2 diabetes. Data from animal models proved the direct participation of mast cells in diet-induced obesity and diabetes. Although the mechanisms by which mast cells participate in these metabolic diseases are not fully understood, established mast cell pathobiology in cardiovascular diseases and effective mast cell inhibitor medications used in pre-formed obesity and diabetes in experimental models offer hope to patients with these common chronic inflammatory diseases. This article is part of a Special Issue entitled: Mast cells in inflammation.     

Morphometric evaluation of murine pulmonary mast cells in experimental hemorrhagic shock

Respiratory failure resulting frequently in death is one of the complications in the course of post-hemorrhagic changes. A systemic inflammatory reaction plays a significant role in the pathogenesis of this syndrome. Mast cells also contribute to this effect. To broaden our knowledge of the pathogenesis of respiratory insufficiency, we evaluated morphometrically lung mast cells in hemorrhagically shocked rats. Lung sections were stained with alcian blue and safranin, and four separate locations were distinguished: under the lung pleura, around the bronchi and the large vessels, and in the interalveolar septa. A decrease in the area and volume of mast cells and an increase in their circularity index in interalveolar septa and around the bronchi was observed. An enlargement of mast cells around lung vessels was also found. There were no changes in the morphometric parameters of mast cells under pleura. The results suggest an activation and degranulation of mast cells and a role in the inflammatory process causing acute lung injury in hemorrhagic shock.     

Immunoglobulin E-independent activation of mast cell is mediated by Mrg receptors

Mast cells play a central role in inflammatory and allergic reactions by releasing inflammatory mediators through two main pathways, immunoglobulin E-dependent and -independent activation. In the latter, mast cells are activated by a diverse range of basic molecules, including peptides and amines such as substance P, neuropeptide Y, and compound 48/80. These secretagogues are thought to activate the G proteins in mast cells through a receptor-independent mechanism. Here, we report that the basic molecules activate G proteins through the Mas-related gene (Mrg) receptors on mast cells, leading to mast cell degranulation. We suggest that one of the Mrg receptors, MrgX2, has an important role in regulating inflammatory responses to non-immunological activation of human mast cells.     

TNF-alpha is crucial for the development of mast cell-dependent colitis in mice

Inflammatory bowel disease (IBD) describes chronic inflammatory conditions of the gastrointestinal tract, and TNF-alpha plays a pivotal role in mediating the response. The proinflammatory cytokine TNF-alpha is rapidly released by mast cells after degranulation. In the present study, we hypothesized TNF-alpha to be an important player in our recently described mast cell-dependent murine model for IBD. The effect of neutralizing anti-TNF-alpha MAb was studied on colonic hypersensitivity in mice induced by a skin application of dinitrofluorobenzene (DNFB) followed by an intrarectal challenge with dinitrobenzene sulfonic acid. Features of the colonic hypersensitivity response included diarrhea, mast cell infiltration and activation, infiltration of inflammatory cells in the colon, colonic patch hypertrophy, and increased mast cell-derived TNF-alpha levels in the colon. Anti-TNF-alpha MAb could effectively abrogate diarrhea in DNFB-sensitized mice 72 h after the challenge. The numbers of colonic patches and total tissue damage scores were reduced by anti-TNF-alpha MAb treatment in DNFB-sensitized mice 72 h after the challenge. Mast cell infiltration and activation remained unaffected by neutralizing anti-TNF-alpha MAb. Treatment with the corticosteroid dexamethasone, a frequently used therapeutic treatment in IBD, resulted in a reduction of diarrhea, cellular infiltration, and total tissue damage scores to the same extent as anti-TNF-alpha MAb. Additionally, dexamethasone treatment could also reduce total TNF-alpha levels in the colon, mast cell numbers, and mast cell activation in both vehicle- and DNFB-sensitized mice 72 h after the challenge. These findings suggest that TNF-alpha can play an instrumental role in causing inflammatory responses in the present murine model for IBD downstream from mast cell activation.     

Purinergic signaling in inflammatory cells: P2 receptor expression, functional effects, and modulation of inflammatory responses

Extracellular ATP and related nucleotides promote a wide range of pathophysiological responses via activation of cell surface purinergic P2 receptors. Almost every cell type expresses P2 receptors and/or exhibit regulated release of ATP. In this review, we focus on the purinergic receptor distribution in inflammatory cells and their implication in diverse immune responses by providing an overview of the current knowledge in the literature related to purinergic signaling in neutrophils, macrophages, dendritic cells, lymphocytes, eosinophils, and mast cells. The pathophysiological role of purinergic signaling in these cells include among others calcium mobilization, actin polymerization, chemotaxis, release of mediators, cell maturation, cytotoxicity, and cell death. We finally discuss the therapeutic potential of P2 receptor subtype selective drugs in inflammatory conditions.     

Mast cells in the focus of an acute infectious inflammation]

On the model of E. coli-induced acute infectious peritonitis in rats it is established that the mast cell reaction and histamine level increase in exudate and inflamed mesentery tissue are biphase and are observed predominantly following the inflammatory agent action, in the period corresponding to the immediate phase of peritoneal cavity vessel permeability increases. The preliminary elimination of mast cells significantly inhibits a rise in the vascular permeability in the immediate phase and slightly affects the delayed phase, thus prolonging exudation. At the same time the dynamics of free histamine indicates its direct involvement in mediation and/or modulation as well as in subsequent inflammatory events. The common rules of mast cell involvement and vascular permeability increase in infectious and aseptic inflammation have been shown.