Mechanisms underlying vascular hyperpermeability in allergic inflammation
論文ID: 2025-010
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論文ID: 2025-010
In allergic inflammation (type I hypersensitivity), the antigen-antibody reaction triggers mast cell degranulation. Inflammatory mediators released by activated mast cells induce vascular hyperpermeability, leading to pronounced inflammation. Understanding these mechanisms is essential for developing novel therapeutic strategies. Vascular permeability is primarily regulated by blood flow and endothelial barrier function. In this review, we summarize how mediators such as histamine, platelet-activating factor, bradykinin, prostaglandin D2, and tumor necrosis factor-α modulate vascular permeability, with a focus on their effects on blood flow and endothelial barrier function in allergic inflammation.
In allergic inflammation, the antigen-antibody reaction triggers mast cell degranulation, releasing inflammatory mediators such as histamine, platelet-activating factor, bradykinin, and prostaglandin D2. Histamine increases blood flow, bradykinin induces histamine-independent hyperpermeability, and prostaglandin D2 enhances barrier function. As detailed mechanisms have been clarified, continued research is essential for developing improved allergy therapies.
Type I hypersensitivity, including urticaria, rhinitis, food allergies, and anaphylactic shock, involves antigen-antibody interactions with mast cells. These reactions are driven by the inflammatory mediators released during mast cell degranulation [1]. Antihistamines and steroids are commonly used to alleviate symptoms; however, they often fail to provide complete relief and may cause adverse effects. A deeper understanding of the complex mechanisms underlying type I hypersensitivity is essential for developing more effective treatments.
Under resting conditions, fluid and protein leakage from the blood vessels is tightly regulated to maintain tissue homeostasis [2]. During type I hypersensitivity, mast cell degranulation releases inflammatory mediators and stimulates the vascular endothelial cells. Increased intracellular Ca2+ concentration promotes the secretion of endothelium-dependent relaxing factors such as nitric oxide (NO), leading to increased blood flow. Additionally, Rho kinase activation in vascular endothelial cells weakens adhesive junctions and disrupts the endothelial barrier function [2]. These two factors—enhanced blood flow and barrier disruption—lead to vascular hyperpermeability, resulting in fluid and protein leakage into peripheral tissues. In this review, we discuss key inflammatory mediators in type I hypersensitivity: histamine, platelet-activating factor (PAF), bradykinin, prostaglandin D2 (PGD2), and tumor necrosis factor-α (TNF-α).
Histamine is a major mediator of type I hypersensitivity, and its receptor, the H1 receptor (H1R), is a primary target for current treatments. The H1R is a Gq protein-coupled receptor expressed in vascular endothelial cells. Its activation increases intracellular Ca2+ levels by inducing Ca2+ release from the endoplasmic reticulum or promoting Ca2+ influx through nonselective cation channels. This results in NO-dependent vascular smooth muscle relaxation and increased blood flow [3, 4]. In vitro, histamine activates Rho kinase, induces stress fiber formation, and disrupts the endothelial barrier [5]. In vivo, histamine-induced hyperpermeability is reduced by more than half following NO inhibition [3]. However, NO inhibition almost completely suppresses histamine-induced vascular relaxation without affecting endothelial barrier disruption. These findings suggest that the NO-dependent increase in blood flow plays a more significant role than barrier disruption in histamine-induced vascular hyperpermeability in vivo.
In neurons, histamine-induced Ca2+ influx is mediated by the transient receptor potential vanilloid (TRPV) 1 channels [6]. TRPV channels are also expressed in vascular endothelial cells and may contribute to the histamine-induced Ca2+ influx and subsequent vascular hyperpermeability.
PAF is a bioactive lipid released from mast cells. Its receptor is a Gq- and Gi-protein-coupled receptor, and its activation induces platelet aggregation and vascular hyperpermeability [7, 8]. Rupatadine, an inhibitor of both H1R and PAF receptors, is currently used to treat type I hypersensitivity [9, 10].
PAF incubation of human umbilical vein endothelial cells induces vascular endothelial disruption [11]. In ferrets, PAF treatment induces contraction in pulmonary veins but relaxation in pulmonary arteries [12]. This arterial relaxation is suppressed by endothelial nitric oxide synthase (eNOS) inhibition. PAF-induced anaphylactic shock is also mediated by eNOS, although the detailed mechanisms remain unclear [13].
The thromboxane A2 (TXA2) receptor, another Gq protein-coupled receptor, also induces platelet aggregation. We previously reported that TXA2 decreases blood flow while simultaneously disrupting the endothelial barrier. As capillaries consist of a single endothelial cell layer, TXA2 treatment results in vascular hyperpermeability [14]. PAF-induced vascular hyperpermeability may involve a similar mechanism, which warrants further investigation.
Bradykinin is a pro-inflammatory peptide hormone derived from heparin, a mast cell-derived mediator. Its receptors, bradykinin receptors B1 and B2, couple to Gq and Gi proteins [15]. Bradykinin stimulation of rat coronary vessels induces vasodilation [16], and bradykinin stimulation of human umbilical vein endothelial cells induces hyperpermeability [17]. In a passive cutaneous anaphylaxis mouse model, IgE-antigen (Ag) stimulation induced vascular leakage, which was partially reduced in coagulation factor XII-deficient (F12−/−) mice. These mice exhibited impaired contact system-driven bradykinin formation. Similarly, IgE-Ag-induced vascular leakage was partially attenuated in Bdkrb2−/− mice, which lack bradykinin receptor B2. In contrast, the histamine-induced vascular leakage in Bdkrb2−/− and F12−/− mice was comparable to that observed in wild-type mice [18]. These findings suggest that vascular hyperpermeability during passive cutaneous anaphylaxis is partially bradykinin-dependent and independent of histamine.
Various arachidonic acid metabolites regulate vascular permeability. PGD2 is known well for its contribution to type I hypersensitivity. In a mouse model of food allergy, we found that hematopoietic PGD synthase deficiency led to mast cell hyperplasia in the intestine [19], enhanced mast cell degranulation-induced vascular hyperpermeability, and exacerbated anaphylactic shock symptoms. This effect is mediated by the activation of endothelial D-prostanoid 1 (DP1), a receptor for PGD2 [20]. DP1 activation enhances endothelial barrier function through cAMP/PKA/Tiam1/Rac1 signaling [21], but does not affect vascular diameter or blood flow. Although PGD synthase and DP1 inhibitors are not yet clinically used, future developments are anticipated.
TNF-α is a major pro-inflammatory cytokine released by immune cells such as mast cells, macrophages, and T cells during allergic responses [22]. Although TNF-α induces contraction in rat aorta [23], it also increases vascular permeability via endothelial barrier disruption [24, 25]. This is characterized by the loss of tight junction integrity, which is mediated through NF-κB activation [26]. Mouse models have shown that TNF-α contributes to allergic inflammation, including rhinitis [27] and asthma [28]. Moreover, TNF-α acts synergistically with other mediators, including histamine [29] and PAF [30], to amplify inflammatory responses.
In this review, we discussed the bioactive substances that regulate vascular hyperpermeability in type I hypersensitivity (Table 1). Although their involvement in vascular permeability has been reported, the detailed mechanisms through which they regulate this process and contribute to pathological conditions remain unclear. Further studies to elucidate these mechanisms will contribute to the development of new treatments for type I hypersensitivity.
| Mediators | Receptor (G protein) | Blood flow | Endothelial barrier | Vascular permeability |
|---|---|---|---|---|
| Histamine | H1 (Gq) | Increase (Delation of rat mecentric artery contraction [3]) | Disruption (Disruption of endothelial adherence junction in mouse ear [3]) | Increase (Dye extravasation in mouse ear [3]) |
| PAF | PAF (Gq, Gi) | Increase (Dilation of ferret pulmonary artery tension [12]) | Disruption (Barrier disruption of human umbilical vein endothelial cells [11]) | Increase (Dye extravasation in rat lung [8]) |
| Bradykinin | B1, B2 (Gq, Gi) | Increase (Dilation of rat coronary vessel [16]) | Disruption (Barrier disruption of human umbilical vein endothelial cells and retinal capillary endothelial cells [17]) | Increase (Dye extravasation in mouse dosal skin [18]) |
| PGD2 | DP1 (Gs) | No effect (No change of mouse ear vessels [21]) | Enhancement (Barrier enhancement of human umbilical vein endothelial cells [21]) | Decrease (Dye extravasation in mouse ear [21]) |
| TNF-α | TNFR1, 2 (not G protein) | Decrease (Contraction of rat aorta [23]) | Disruption (Disruption of endothelial tight junction in bovine aortic endothelial cells [25]) | Increase (Dye extravasation in mouse lung [24]) |
This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (20H05678 and 25H00430) and the Adaptable and Seamless Technology Transfer Program through Target-driven R&D (A-STEP) from the Japan Science and Technology Agency (JST, JPMJTR22UF), Japan Racing Association, and Joint Research of the Exploratory Research Center on Life and Living Systems (ExCELLS) to Takahisa Murata.
The authors declare no conflict of interest related to this review.
