The H4-receptor has also been shown to be involved in allergy and inflammation 38 , H4R-mediated mast cell activation can regulate a powerful inflammatory cascade by releasing several inflammatory mediators; these mediators may stimulate the migration of different inflammatory cells into the inflammatory site Likewise, the activation of H1R also regulates allergic responses by enhancing the migration of Th2 cells toward the allergen during lung inflammation A more detailed summary of histamine receptor expression is shown in Table 1.
The H1R is ubiquitously expressed and is involved in allergy and inflammation. H1R is expressed in many tissues and cells, including nerves, respiratory epithelium, endothelial cells, hepatic cells, vascular smooth muscle cells, dendritic cells, and lymphocytes 8 , As a consequence, histamine elicits the contraction of smooth muscle of the respiratory tract, increases vascular permeability, and induces the production of prostacyclin and platelet activating factor by activating H1R Figure 1 Thus, almost all immediate hypersensitivity reactions, including symptoms observed in the skin, such as erythema, pruritus, and edema, may be elicited by the activation of H1R Figure 1.
Schematic representation of the expression of histamine receptors on mast cells and their potential response to histamine: binding of histamine to H1R induces vasodilatation, bronchoconstriction, platelet aggregation, and mucus hyper-secretion. Stimulation of H2R by histamine causes gastric acid secretion, increase heart rate, and cardiac output. Activation of H3R is involved in sleep-wake cycle, cognition, homeostatic regulation of energy levels, and neurotransmission.
Activation via H1R may also enhance both Th1- and Th2-type immune responses Similarly, Bryce et al. They also demonstrated that histamine may act as a chemotactic factor for Th2 cells, stimulating their migration into lung tissues In addition, IL-3 activation can increase H1R expression on Th1 cells 61 , 62 , and histamine can enhance B cell proliferation, which is absent in H1R-deficient mice The role of H1R activation in asthma may be further corroborated by observations showing that use of H1R-antagonists can significantly decrease asthma symptoms and improve pulmonary function in persistent asthma 58 , 64 , Histamine H1 receptor is also expressed in dermal dendritic cells and keratinocytes in the skin tissue, and histamine increases the NGF production via H1R in human keratinocytes It also upregulates the antigen-presenting capability of dendritic cells, and leads to Th1 polarization through H1R Histamine induces IL production, which plays an important and crucial role in pruritus and skin barrier function in allergic dermatitis Administration of an H1R antagonist decreased IL levels in the serum of atopic dermatitis patients These data therefore suggest that H1R activation by histamine has the ability to induce various symptoms related with allergic skin diseases such as pruritus and atopic dermatitis.
Activation of the receptor can induce airway mucus production, vascular permeability, and secretion of gastric acid Furthermore, the H2R is importantly accountable for the relaxation of the airways, uterus, and smooth muscle cells in the blood vessels. Moreover, the H2R is involved in the activation of the immune system, such as Th1 cytokine production, reduction of basophil degranulation, T-cell proliferation, and antibody synthesis 71 , It is important for homeostatic regulation of energy levels, sleep-wake cycle, cognition, and inflammation 76 Figure 1.
H3R-deficient mice exhibit altered behavior and locomotion 77 and display a metabolic syndrome characterized by obesity, hyperphagia, and increased leptin and insulin levels 78 , These investigators also showed that H3R can be involved in blood—brain barrier function. The H3R has also been associated with rhinitis This is likely because it is expressed on presynaptic nerves in the peripheral sympathetic adrenergic system and also on nasal sub-mucosal glands.
Stimulation of H3R suppressed norepinephrine release at presynaptic nerve endings and stimulated nasal sub-mucosal gland secretion Currently, several H3R ligands are available, but not in clinical use. H3R antagonists, such as clobenpropit and thioperamide, were extensively used as a research tools and few early stage clinical trial reports are also available for H3R antagonists However, these antagonists are used to treat obesity, myocardial ischemic arrhythmias, cognition disorders, and insomnia H4R mediates the pro-inflammatory responses of histamine in both autocrine and paracrine manners.
Histamine enhances adhesion molecule expression, cell shape change, and cytoskeletal rearrangement via H4R, leading to the increased migration of eosinophils 5. Histamine H4R stimulation of mast cells may have three positive effects. First, it increases chemotaxis of mast cells thus encouraging their accumulation at the site of an allergic response 6.
Third, it mobilizes intracellular calcium to either prime mast cells for activation or, indeed, induce degranulation. These effects have been studied using histamine, the H4R-agonist 4-methylhistamine, the H4R-antagonists thioperamide or JNJ and mast cells from H4R-deficient mice.
Basophils also express H4R on their surface and release histamine following antigen stimulation However, basophils and mast cells differ in several important aspects, such as anatomical localization, the production of cytokines, and antigen-presenting activity.
Histamine, acting via H4R, induces chemotaxis of bone marrow-derived basophils. H4R may play significant roles in basophil regulation in allergic dermatitis H4R may be involved in the pathogenesis of allergy and inflammation by activating Th2 as well as Th17 cells 68 , Stimulation of H4R can also enhance the migration of eosinophils and the recruitment of mast cells leading to the amplification of immune responses and chronic inflammation.
Similarly, H4R are involved in T cell differentiation and dendritic cell activation and its immunomodulatory function 6. 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.
Rothenberg ME. N Engl J Med — Kay AB. Allergy and allergic diseases. First of two parts. N Engl J Med —7. Nature —6. Identification, purification, and characterization of a mast cell-associated cytolytic factor related to tumor necrosis factor. Histamine induces cytoskeletal changes in human eosinophils via the H 4 receptor.
Br J Pharmacol — Histamine H4 receptor mediates chemotaxis and calcium mobilization of mast cells. J Pharmacol Exp Ther — Identification of a histamine H4 receptor on human eosinophils — role in eosinophil chemotaxis. J Recept Signal Transduct Res — A potent and selective histamine H4 receptor antagonist with anti-inflammatory properties.
Inflamm Res — Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors. Nature —5. Histamine upregulates Th1 and downregulates Th2 responses due to different patterns of surface histamine 1 and 2 receptor expression.
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Br J Pharmacol Suppl 1 :S— Apoptosis in the airways: another balancing act in the epithelial program. Changes in VE-cadherin localization, internalization or disassembly, induce endothelial barrier disruption. Fig 5C shows that similar results were obtained by en face immunostaining of the pulmonary artery. Again, treatment with bradykinin 0. These results suggested that histamine disrupted vascular endothelial barrier function through an NO-independent signaling pathway.
Endothelial barrier function was evaluated in vitro assay by measuring TER. A low concentration of histamine 0. During allergic inflammation, activated mast cells release a large amount of histamine, leading to vascular hyperpermeability [ 15 , 16 ]. Since vascular hyperpermeability is closely associated with various allergic symptoms such as urticaria, conjunctivitis, and nasal congestion, understanding the mechanism underlying histamine-induced vascular hyperpermeability will provide novel therapeutic insights into allergic diseases.
Several groups have previously reported that histamine disrupted the endothelial barrier [ 11 , 17 , 18 ]. However, many of these studies focused on cell-based in vitro systems and the precise mechanism involved in vivo still remained unclear. Vasoconstrictors are currently used to treat rhinitis [ 2 ]. Our observations supported the effectiveness of these treatments and implied that they may also have therapeutic efficacy for other allergic symptoms, including urticaria.
Previous studies suggested that increased blood flow elevated the hemodynamic forces on the vascular wall in the form of shear stress and intravascular hydrostatic pressure, thus compromising its barrier function. Orsenigo et al.
Other researchers indicated that an increase in intraluminal hydrostatic pressure intensified the outward transfer of plasma components [ 1 ]. The present study showed that histamine simultaneously increased blood flow, altered VE-cadherin localization, and caused vascular hyperpermeability. NOS-inhibition or vascular contraction were found to decrease blood flow, inhibiting vascular leakage without affecting VE-cadherin localization.
We previously reported that an inflammatory mediator, prostaglandin E 2 , or the vasorelaxant, isoproterenol, elicited vascular hyperpermeability by increasing blood flow while causing VE-cadherin accumulation at intercellular boundaries, indicating enhancement of the endothelial barrier [ 13 ].
Although it is still unclear how increased hemodynamic force causes the extravasation of plasma components, these observations support the idea that vascular dilation and the subsequent increase in blood flow are major in vivo determinants of vascular hyperpermeability.
We revealed that histamine induced hyperpermeability of venulae, while only elevating blood flow in arteries. This result was consistent with previous in vivo studies showing that leukotriene mainly increased vascular permeability in venulae [ 20 ]. Compared with arteries and large veins, venulae have a thinner vessel wall and smooth muscle layer. The structural weakness of venulae may be responsible for their permeability.
In addition, the venous endothelial layer is reported to be more permeable than that of arteries because it expresses fewer cell-cell adhesion proteins [ 21 ].
This is one potential explanation for our observation that histamine induced increased arterial blood flow and increased permeability of venulae. Endothelial barrier function is also critical for vascular permeability. Mikelis et al. These results suggest that endothelial barrier disruption as well as blood flow increase is included in the histamine-induced vascular leakage. Several inflammatory substances such as bradykinin are known to induce vascular hyperpermeability by disrupting this barrier in isolated endothelial cells [ 23 ].
Consistent with these reports, we found that histamine disrupted adherence junction assembly in vivo and in vitro. Activation of these kinases induces drastic cytoskeletal rearrangement, including actin stress fiber formation and myosin light chain phosphorylation. Both of these effects result in adherens junction disassembly and endothelial hyperpermeability in human pulmonary artery endothelial cells [ 24 ].
NO is another well-known regulator of endothelial barrier function. Several barrier-disrupting substances, including platelet-activating factor and VEGF, exert their actions through effects on endothelial NO production, causing adherens junction destabilization [ 6 , 25 , 26 ]. However, our in vivo observations showed that inhibition of NO did not restore histamine-induced changes in VE-cadherin localization, even though it completely blocked vascular dilation and leakage.
In vitro experiments showed that L -NAME only slightly attenuated the histamine-induced endothelial barrier disruption, even at a high concentration 3 mM.
Histamine-induced NO production may therefore only partially affect the properties of the endothelial barrier, whilst strongly inducing vasodilation. Further investigation is required to clarify this discrepancy. Vascular mural cells and endothelial cells work together to control a range of vascular functions.
Since the structure and cellular components of the vasculature vary by tissue type and site, comprehensive in vivo studies focusing on both functions are required to fully elucidate the pathophysiological implications of vascular permeability.
PCA reaction decreased histamine content in the ear. A Typical photographs of mouse ears. Effect of diphenhydramine or cimetidine on histamine-induced vascular hyperpermeability. C Typical photographs. EGFP mice were kindly donated by Prof. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
National Center for Biotechnology Information , U. PLoS One. Published online Jul 9. Yulia Komarova, Editor. Author information Article notes Copyright and License information Disclaimer.
Competing Interests: The authors have declared that no competing interests exist. Received Mar 26; Accepted Jun This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
This article has been cited by other articles in PMC. S2 Fig: Endogenous and exogenous histamine induced ear swelling. Abstract Histamine is a mediator of allergic inflammation released mainly from mast cells. Introduction In allergic inflammation, antigen-stimulated mast cells release a range of mediators that can be subdivided into the preformed mediators, the synthesized lipid mediators, and the cytokines and chemokines.
Materials and Methods Ethics Statement All animal experiments were approved by the institutional animal care and use ethical committees of the University of Tokyo approval no. Reagents The following reagents were obtained from the indicated suppliers: Evans blue, bradykinin, anti-dinitrophenol IgE and L-phenylephrine hydrochloride Sigma-Aldrich, St. Passive cutaneous anaphylaxis test Passive cutaneous anaphylaxis PCA tests were performed as described previously [ 12 ], with slight modification.
Blood flow velocity and volume measurements Blood flow velocity B vel was calculated by measuring the velocity of EGFP-tagged blood cells in the mouse ear vessel.
Laser doppler velocimeter measurements After the mice had been anaesthetized, histamine was treated percutaneously. Measurement of vascular contraction The mouse mesenteric artery was excised and placed in physiological saline solution containing Open in a separate window.
Fig 1. H1 receptor activation increased vascular permeability. Two types of vasculature are in mouse ear Whole-mount immunostaining revealed two types of vasculature in the mouse ear Fig 2A.
Fig 2. Two types of vasculature are in mouse ear. Histamine increased vascular diameter and blood flow volume via H1 receptor activation We next observed the local vascular dynamics in the ear using in vivo imaging. Fig 3. Histamine increased blood flow volume. Histamine-induced NO-dependent vascular relaxation increased vascular permeability We next examined the effects of histamine on vascular relaxation and contraction using an isolated rat mesenteric artery preparation.
Fig 4. L-NAME or phenylephrine pretreatment inhibited histamine-induced hyperpermeability and vascular relaxation. Histamine disrupted the endothelial barrier in vivo We next assessed the effect of histamine on endothelial barrier formation by observing intercellular adherens junctions.
Fig 5. Histamine regulated endothelial barrier function in vivo. Mast cells have surface receptors that bind immunoglobulin E, and when antigen crosslinks IgE on the mast cell surface, they respond by secreting histamine, along with a variety of other bioactive mediators. Histamine is best known as a mediator of allergic reactions, but it is now recognized to participate in numerous other normal and pathologic processes. The sensitivity and response of a particular cell to histamine depends upon which type of histamine receptor is present on that cell.
An interesting illustration of the systemic effects of histamine is scombroid fish poisoning. Essentially histamine poisoning, this disorder is seen following consumption of fish, commonly tuna or mackerel, that have spoiled and within which bacteria have generated abundant quantities of histamine from histidine in muscle protein.
Consumption of such spoiled fish results in the rapid development of a variety of clinical signs, including headache, sweating, diarrhea, a flushed face, and vomiting, all resulting from systemic exposure to histamine. The lesson here: keep fish refrigerated! Histamine playes a pivotal role in many types of allergic and inflammatory processes, including both acute and delayed hypersensitivity reactions.
The source of histamine in such cases is tissue mast cells. The magnitude of such problems depends on the route of exposure local versus systemic , sites of exposure e.
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