Activation of the metalloproteases breaks down extracellular matrix proteins and remodels the connective tissue matrix. Chymase cleaves fibronectin and collagen by activation of MMPs.
Histamine and heparin are also stored in prepackaged granules and are involved with vascular permeability and smooth muscle contraction.
Histamine is the most important mediator released from the mast cell involved with an allergic response. Histamine is derived from the amino acid histidine and works through three different receptors H1, H2, H3. Stimulation of H1 receptors by the binding of histamine induces the classic allergic reaction.
H1 receptors are found on smooth muscle cells and endothelial cells. Activation of H1 receptors on endothelial cells results in increased vascular permeability and activation of smooth muscle cells resulting in contraction, constriction of airways, and mucous secretion 8. Leukocytes can bind to these adhesion molecules and then are brought to the site of inflammation 36 , Other molecules are synthesized and released after the mast cells have been activated.
CCL3 is a chemotactic factor for macrophages and neutrophils 1. Eicosanoids prostaglandins, leukotrienes, and thromboxanes are produced by catalytic conversion of arachidonic acid by the action of phospholipase A2 on membrane phospholipids. Mast cells express COX1 and COX2, which converts arachidonic acid into prostaglandins and thromboxanes with the action of specific isomerases Prostaglandins increase vascular permeability and attract neutrophils.
Leukotrienes are involved with smooth muscle contraction, airway constriction, and mucous secretion Eicosanoids act at the local area of mast cell degranulation. Platelet-activating factor is released after mast cell activation that acts as a chemotactic factor for leukocytes, and activates neutrophils, eosinophils, and platelets All of the mediators released upon activation results in increased vascular permeability, smooth muscle contraction, and airway constriction.
These adaptations can remove parasites from the gastrointestinal tract. Due to the increased vascular permeability, increased fluid in the tissue can enhance elimination of parasites. IgE-mediated mast cell activation would result in physical expulsion of parasites. However, developed countries rarely have parasite infections. Persistent mast cell degranulation resulting from recurrent responses to innocuous substances leads to allergies, asthma, and food allergies.
Mast cell degranulation also occurs from grass, pollen, or shellfish-derived allergens. It is of interest that developing countries do not have a high prevalence of allergies or asthma potentially due to childhood exposure to a variety of environmental PAMPs and subsequent desensitization 8.
Mast cells are important cells of the immune system. Mast cells mediate microvascular inflammatory response to systemic hypoxia caused by a reduction in the level of inspired oxygen During hypoxia, leukocytes interact with endothelial adhesion molecules, resulting in leukocyte rolling and adherence within systemic venules, and eventually leukocyte emigration into the tissue.
This microvascular inflammatory response was also associated with increased vascular permeability to plasma proteins during systemic hypoxia Steiner et al. The mechanism responsible for mast cell activation during systemic hypoxia is complex, and is partially dependent on increased generation of ROS. Administration of the antioxidant lipoic acid prevents hypoxia-induced mast cell degranulation Mast cell activation also contributes to increased ROS generation during systemic hypoxia, as dihydrorhodamine-dependent fluorescence in venular endothelium was attenuated by cromolyn.
Although decreased oxygen levels in culture media have been shown to increase ROS generation in various cells in vitro 43 , decreased tissue oxygen levels in systemic organs are not the major cause of mast cell degranulation in vivo. Dix et al. A local reduction in tissue oxygen levels to that seen during systemic hypoxia did not cause mast cell degranulation or increased leukocyte adherence within cremaster venules During systemic hypoxia, however, these events occurred in the cremaster even though the tissue oxygen levels were maintained at normal levels.
After demonstrating that a proinflammatory mediator was released into the circulation during systemic hypoxia that caused mast cell degranulation and microvascular inflammation, we began a series of studies to find the source of this mediator as well as its identity. Following a reduction in inspired oxygen, the first organ to become hypoxic is the lungs. Chao et al. Tissue oxygen levels decrease in the organ during the ischemic phase, but microvascular inflammation does not develop until the reperfusion phase During the ischemic phase, vasodilators accumulate within the tissue resulting in higher than normal blood flow for a period of time when blood flow is restored to the organ.
During the reperfusion phase, increased generation of ROS occurs resulting in mast cell activation. During reperfusion, complement molecules C3a and C5a cause mast cell degranulation when activating G-protein-coupled receptors GPCR on the mast cell surface Additionally, reactive oxygen species are generated when tissue is reperfused, which activates intracellular pathways causing mast cell degranulation Intracellular and extracellular pathways converge and result in phospholipase C-mediated production of IP3 and DAG, causing calcium release from the endoplasmic reticulum and activation of protein kinase C, leading to degranulation of the mast cell 50 , Mast cells release mediators that increase both leukocyte adhesion to the venular endothelium and vascular permeability during reperfusion These effects are mediated by various substances released by mast cells, such as histamine, tryptase, and chymase Yang et al.
Rat livers were subjected to 1 h ischemia followed by 24 h of reperfusion. Mast cell degranulation was monitored by toluidine blue staining and assessment of mast cell tryptase. Mast cell degranulation was highest at 2 h of reperfusion, while liver damage was greatest after 6 h of reperfusion.
Activated cardiac mast cells release renin, which converts angiotensinogen to angiotensin 1, which is then formed to angiotensin 2 by angiotensin-converting enzyme ACE. Angiotensin 2 enhances the release of norepinephrine from nerve endings and can lead to arrhythmias It is possible to inhibit mast cells by either inhibiting degranulation or blocking the action of the components that are released during mast cell degranulation Histamine antagonists, ACE inhibitors, and angiotensin 2 receptor blockers are all drugs that inhibit components produced by mast cells.
Other drugs that block individual components released during mast cell degranulation are still being investigated Possible targets for inhibition include protein kinase C, which is an important enzyme in the degranulation pathway Atherosclerosis is an inflammatory process that involves innate and adaptive immunity During atheroma formation, increased numbers of T cells and macrophages are recruited to the vessel wall Microbial products can contribute to plaque growth.
Angiotensin II has been shown to induce cytokine expression in atheroma-related cells Leukocytes are targeted to the site of atheroma from chemokines. Mast cells are recruited to the site of atheroma by eotaxin Macrophages and T cells outnumber mast cells in the atheroma. However, mast cells are important in activation of plaques due to their proteases, which are released leading to plaque rupture and acute coronary syndromes Mast cells are also able to degrade the extracellular matrix of cells in the atheroma and modify lipoproteins When a plaque is physically disrupted, a thrombus can form.
Rupture of the fibrous cap of the plaque allows tissue factor from within the intima to come in contact with coagulation factors. Mast cell proteases degrade collagen in the fibrous cap of the plaque, which can lead to plaque rupture Unstable angina and myocardial infarctions are caused by rupture of atherosclerotic plaques Mast cells play a large role in the pathogenesis of plaque rupture and accumulate in the rupture prone region or human atheromas.
Activated mast cells release tryptase and chymase, which are proteases that are found at the rupture site. Plaque destabilization in coronary arteries can occur from inflammatory response caused by mast cells.
It is known that systemic activation of mast cells occurs during atherogenesis and results in increased progression of plaques in apoE-deficient mice Mast cell stabilization by cromolyn has been shown to prevent pathophysiological events, such as plaque rupture Systemic mast cell activation leads to plaque progression during atherogenesis as seen with treatment with dinitrophenyl-albumin DNP , which causes activation in antigen-sensitized mast cells.
When mast cells were challenged with DNP in mice, there was an increase in hemorrhage in the plaque. These findings are not seen in mast cells pretreated with cromolyn. This is consistent with findings in humans by Laine et al. Macrophage apoptosis was most often seen in the center of the atheroma. This leads to increase size of the necrotic core and release of apoptotic microbodies, which increase instability of the plaque and increase thrombosis.
Protease inhibitors prevented macrophage apoptosis induced by mast cells. Additionally, macrophage apoptosis was completely inhibited by a H1 receptor antagonist. Mice treated with DNP also had increased vascular permeability, capillary leakage, and increased leukocyte adhesion in the atherosclerotic plaques. Mast cell stabilization with cromolyn prevented acute coronary syndromes Inflammatory cells, such as mast cells, neutrophils, NK cells, monocytes, macrophages and dendritic cells, play a key role in the development and progression of atherosclerosis Inflammatory cells respond to tissue injury, which results in an inflammatory process.
Mast cells are found in all vascularized tissues except for the central nervous system and the retina. Mast cells are located in the intima of carotid arteries and in the shoulder region of atherosclerotic plaques.
Reduction in lipid deposition was caused by a decrease in FceRIa-mediated mast cell activation and a decrease in inflammatory mediator release. Mast cells have also been shown to activate TLR4 that leads to smooth muscle cell apoptosis in the plaque resulting in plaque destabilization Mast cell tryptase plays a role in leukocyte recruitment. Tryptase can break down fibronectin and collagen type IV, which can result in plaque rupture and thrombosis. Mast cell chymase can also cause smooth muscle cell apoptosis resulting in destabilization of the plaque Mast cells are also found in the media and adventitia of the aorta and contribute to development of aneurisms.
Risk factors for abdominal aortic aneurisms AAA are male gender, advanced age, history of smoking, and atherosclerosis. In AAA, there is inflammation in the media and adventitia of the aorta versus atherosclerotic disease, which is mostly found in the intima. During development of AAA, there is an imbalance of the matrix buildup and breakdown, which leads to weakening of the wall of the aorta and dilation of the aorta. There are many important cells involved in the development of AAA, which are neutrophils, smooth muscle cells, and aortic mast cells Mast cells are involved in degradation of the extracellular matrix by activation of metalloproteases , apoptosis of smooth muscle cells, and activation of the renin angiotensin system.
Experimentally induced AAA in animals can be done with intra-aortic elastase infusion, topical treatment of aorta with CaCl 2 , or angiotensin infusion Sun et al. Histamine, a major mediator of mast cells, activates JNK pathways. Tissue repair in AAA depends on smooth muscle cells that make collagen.
Granzyme B, also released by mast cells, can induce smooth muscle cell apoptosis Additionally, chymase released by mast cell inhibits collagen synthesis from smooth muscle cells. Drug targeting of mast cell mediators of AAA could help in treatment by inhibiting the growth of small AAA before they require surgery Increased numbers of mast cells are seen during the progression of atherosclerosis They are predominately seen in the intima and adventitia.
Mast cells are recruited to the plaque via chemokine CCL, which is expressed in the plaque, and CCR-2 which is expressed on the mast cell surface. Mast cells in plaque are located near microvessels 77 , When mast cells degranulate, they release histamine and matrix degrading proteases, which can cause microvessel leakiness and rupture leading to intraplaque hemorrhage.
Mast cell activation during atherosclerosis was shown to increase the size of the plaque in the brachiocephalic artery of apoE-deficient mice This response was prevented by administration of cromolyn.
Another study showed that mast cell deficiency inhibited development of atherosclerotic plaque in LDL receptor-deficient mice Mast cells can be seen as effector cells to induce plaque formation and progression.
Overexpression of mast cell tryptase in mice had a greater risk of intraplaque hemorrhage Additionally, a patient cohort study found that serum chymase levels were higher in patients with coronary heart disease. Chymase can modify HDL, affect cholesterol efflux ability, and also enhance the production of Angiotensin II, which is a proatherogenic factor.
Chymase also induces apoptosis of vascular smooth muscle cells and endothelial cells 80 — Activation of mast cells promotes enhanced lipid uptake by macrophages. Heparin-bound LDL is phagocytosed by macrophages to form foam cells 83 , Mast cell activation during plaque development leads to progression and increased leukocyte infiltration and lipid accumulation.
The resulting leakiness of microvessels in advanced unstable lesions can lead to hemorrhage of the plaque or rupture of the fibrous cap. This can then result in thrombosis and acute cardiovascular events. Mast cell activation in the plaque can be through IgE-dependent or IgE-independent pathways. IgE levels are high in patients with angina pectoris However, another study showed that plasma IgE levels did not correlate with disease progression or mast cell numbers in Western populations This suggests that mast cell activation in the progression of atherosclerotic plaques may be initiated by another mechanism, such as plaque lipids, which can activate mast cells in the vessel wall.
Another mechanism of activation is through C5a activation via C5aR on mast cells. Activated complement is found within the plaque. Activation of mast cells with C5a resulted in an increase in vein graft atherosclerosis, which was inhibited by cromolyn Activation of mast cells can be accomplished via neuropeptides, such as substance P, as mast cells are in close proximity to nerve fibers. Use of mast cell stabilizers for halting plaque progression would be a reasonable treatment option Mast cells are increased in coronary arteries during spasm and in the rupture prone shoulders of coronary atheromas Risk factors, such as oxidized LDL, reactive oxygen species, complement 5a, substance P, endothelin-1, and thrombin can activate mast cells 87 — Mast cells synthesize and secrete histamine, proteases, prostaglandin D2, leukotrienes, heparin, and a variety of cytokines, many of which are implicated in CVD 36 , 93 — Furthermore, mast cells enhance endothelial inflammatory responses through upregulation of innate immune mechanisms , The clinical significance of mast cells in CVD is evident from their increased presence in the adventitia of coronary arteries of patients with atherosclerosis 98 , — An increase in the number of mast cells is also found to be associated with thrombus formation Endothelial cells can endocytose MCG in vitro , and in vivo MCGs are also involved in the induction of human microvascular endothelial cell proliferation , LDL uptake by macrophages, and foam cell formation , Although these findings suggest an important role for mast cells in CVD, the mechanism by which mast cell products promote atherogenesis and CVD is not well understood.
Histamine is a major secretory product of the mast cell and is recognized for its role in the regulation of vasodilation and bronchoconstriction , Histamine also regulates functions of monocytes and macrophages , , eosinophils , , T cells , neutrophils, and endothelial cells , GRKs are a group of seven mammalian serine and threonine protein kinases GRK2 is one of the members of this group that is known to desensitize H1R and limits its signaling , Endothelial cells and smooth muscle cells highly express H1R and this receptor facilitates histamine-mediated inflammatory and hypersensitivity responses , The clinical significance of mast cell-derived histamine in CVD is evident from the finding that coronary arteries of patients with ischemic heart disease contain more mast cells and histamine than normal vessels , and patients with variant angina have elevated levels of histamine in their coronary circulation Reports have suggested that histamine induces smooth muscle cell migration and proliferation , , and regulates intimal thickening model Histamine also increases endothelial cell responses to TLR2 and TLR4 ligands by increasing the expression of these two innate immune receptors , , Figure 2.
Scheme showing the synergistic activation of inflammatory response in endothelial cells by mast cell-derived histamine and bacterial products.
A Histamine secreted by the mast cell stimulates H1R on endothelial cells. Therefore, it is unclear whether H1R signaling of histamine is proatherogenic or cardioprotective. Some studies show that H1 antihistamines reduce atherogenesis in apoE-deficient mice , Raveendran et al.
Increased atheroma formation and lesion area were noted in mice with low doses of cetirizine or fexofenadine. This was not associated with increased macrophage, mast cell, or T lymphocyte count. Reduction in the number of mast cells may be due to increased degranulation.
However, high doses of cetirizine and fexofenadine did not increase atherosclerosis compared to the control. Ingestion of H1 antihistamines did not alter H1R expression in the plaque area as determined by immunofluorescence.
At high doses, the antihistamines may bind to other receptors, such as H4R, which may result in the different response seen than binding H1R. Therefore, antihistamines continue to show a mixed picture with respect to atherosclerosis It should be noted that the vasodilatory effects of histamine may promote lipid accumulation in the vessel wall.
In summary, mast cells play a key role in regulation of normal physiological processes as well as in many pathophysiological settings. Considerable progress has been made in our understanding of these immune cells in recent years. Additional efforts to define the complex interactions of mast cells will potentially lead to novel clinical approaches for many pathological conditions.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Schwartz LB. Methods Mol Biol — PubMed Abstract Google Scholar. Coordinated regulation of NK receptor expression in the maturing human immune system. J Immunol 10 —9. Bradding P. Allergen immunotherapy and mast cells. Histamine and selective H4R agonists were shown to induce the shape change of eosinophils, an effect that maybe blocked by selective H4R antagonists 5.
Treatment with JNJ H4R antagonist resulted in a statistically significant inhibition of eosinophil shape change. These results showed that administration of H4R antagonists may have an impact on eosinophil function Finally, the activation of H4R involves several signaling cascades for the release of various allergic inflammatory mediators.
ERK is a member of MAPK family and mediates the proliferation, differentiation, anti-apoptosis, regulation, and cytokine expression at gene level.
In addition to H1R, H4R is considered as a novel drug target for the treatment of allergy and inflammation. Recently, the H4R antagonists such as JNJ and JNJ have been extensively used as a tools to understand the pathophysiological involvement of H4R and have been studied extensively in both cell culture and in vivo animal models , Furthermore, H4R antagonists have been used to explore the role of H4R in allergic inflammatory disorders, such as allergic asthma, allergic rhinitis, and chronic pruritus Mast cells play an active role in various allergic diseases such as acute pruritus, atopic dermatitis, allergic asthma, allergic rhinitis, and pulmonary fibrosis , H 1 -antihistamines, such as azatadine, cetirizine, and mizolastine are used for the treatment mast cell activated diseases Cimetidine, ranitidine, famotidine, and nizatidine are H2R selective antihistamines that reduce gastric acid secretion H3R antihistamines include thioperamide, clobenpropit, BF2.
JNJ is a selective H4R antihistamine that is widely used in inflammation and pruritus H 1 -antihistamines are a standard treatment for mast cell-mediated allergic diseases. There is increasing evidence that histamine binding to H4 receptors exacerbates allergy and inflammation. Indeed, mast cells themselves have H4 receptors which when stimulated increased degranulation and cytokine production.
Therefore, antihistamines targeting both the H1 and H4 receptor could be an effective treatment for mast cell-mediated allergic diseases Pharmacological properties of H4R have been exhibited by various H4R transfected cells 87 , 89 , 99 , , However, some H3R ligands such as imetit, clobenpropit, thioperamide, and R -methylhistamine are also able to bind to the H4R with different affinities.
Currently, a number of H4R antagonists have been developed but only a few are undergoing clinical trials. JNJ , a potent and selective H4R antagonist, has shown impressive results in different allergic inflammatory diseases such as dermatitis, asthma, pruritus, and arthritis , Interestingly, the combination therapy of this H4R antagonist and the H1R antihistamine, cetirizine, showed a more beneficial effect in the treatment of pruritus as compared with H1R alone — Furthermore, a study was carried out by using JNJ to treat persistent asthma NCT , but no results have yet been reported.
However, a study in rheumatoid arthritis NCT was terminated due to issues related to efficacy. The recent developments in research on histamine pathway underscore the importance of histamine in allergic inflammation through its effects on the H1R and H4R. Although, drugs targeting H1R are being explored for the treatment of various mast cell-associated allergic disorders, they are not always clinically effective.
Several H4R antagonists have entered the later stages of clinical trials for a different range of allergic and inflammatory diseases. However, their clinical efficacy reports are not yet published. Furthermore, there appears to be some overlap in function between H1R and H4R, opening up the possibility for using synergistic strategies for therapeutic approaches.
As such, we suggest the combination therapies by using both H4R together with H1R antagonists may provide a potential benefit in the treatment of various allergic and inflammatory diseases. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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J Allergy Clin Immunol — Molecular and biochemical pharmacology of the histamine H4 receptor. Singh M, Jadhav HR. Histamine H3 receptor function and ligands: recent developments. Mini Rev Med Chem — Thurmond RL. Fig 1 : Following is a diagram of a mast cell. There are blue granules inside the cell. These granules contain histamine. Fig 2 : This is diagram of an anaphylactic reaction allergic type of inflammation. Here we can see the release of Histamine from mast cell.
Fig 3 : following is a diagram of a basophil. Here we can see the granules which store histamine to release during inflammation. During the inflammatory response, what cells release histamine?
Saikat R.
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