RESUMO
Histamine is a major inflammatory molecule released from the mast cell, and is known to activate endothelial cells. However, its ability to modulate endothelial responses to bacterial products has not been evaluated. In this study we determined the ability of histamine to modulate inflammatory responses of endothelial cells to Gram-negative and Gram-positive bacterial cell wall components and assessed the role of Toll-like receptors (TLR) 2 and 4 in the co-operation between histamine and bacterial pathogens. Human umbilical vein endothelial cells (HUVEC) were incubated with lipopolysaccharide (LPS), lipoteichoic acid (LTA), or peptidoglycan (PGN) in the presence or absence of histamine, and the expression and release of interleukin-6 (IL-6), and NF-kappaB translocation were determined. The effect of histamine on the expression of mRNA and proteins for TLR2 and TLR4 was also evaluated. Incubation of HUVEC with LPS, LTA and PGN resulted in marked enhancement of IL-6 mRNA expression and IL-6 secretion. Histamine alone markedly enhanced IL-6 mRNA expression in HUVEC, but it did not stimulate proportional IL-6 release. When HUVEC were incubated with LPS, LTA, or PGN in the presence of histamine marked amplification of both IL-6 production and mRNA expression was noted. HUVEC constitutively expressed TLR2 and TLR4 mRNA and proteins, and these were further enhanced by histamine. The expression of mRNAs encoding MD-2 and MyD88, the accessory molecules associated with TLR signalling, were unchanged by histamine treatment. These results demonstrate that histamine up-regulates the expression of TLR2 and TLR4 and amplifies endothelial cell inflammatory responses to Gram-negative and Gram-positive bacterial components.
Assuntos
Bactérias/imunologia , Células Endoteliais/imunologia , Histamina/imunologia , Glicoproteínas de Membrana/imunologia , Receptores de Superfície Celular/imunologia , Proteínas Adaptadoras de Transdução de Sinal , Antígenos de Diferenciação/análise , Antígenos de Superfície/análise , Parede Celular/imunologia , Células Cultivadas , Antagonistas dos Receptores Histamínicos H1/imunologia , Humanos , Interleucina-6/imunologia , Lipopolissacarídeos/imunologia , Antígeno 96 de Linfócito , Glicoproteínas de Membrana/análise , Fator 88 de Diferenciação Mieloide , NF-kappa B/imunologia , Peptidoglicano/imunologia , RNA Mensageiro/análise , Receptores de Superfície Celular/análise , Receptores Imunológicos/análise , Ácidos Teicoicos/imunologia , Receptor 2 Toll-Like , Receptor 4 Toll-Like , Receptores Toll-Like , Regulação para Cima/imunologiaRESUMO
The primary mechanism of antihistamine action in the treatment of allergic diseases is believed to be competitive antagonism of histamine binding to cellular receptors (specifically, the H1-receptors), which are present on nerve endings, smooth muscles, and glandular cells. This notion is supported by the fact that structurally unrelated drugs antagonize the H1-receptor and provide clinical benefit. However, H1-receptor antagonism may not be their sole mechanism of action in treating allergic rhinitis. On the basis of in vitro and animal experiments, drugs classified as H1-receptor antagonists have long been recognized to have additional pharmacological properties. Most first-generation H1-antihistamines have anticholinergic, sedative, local anaesthetic, and anti-5-HT effects, which might favourably affect the symptoms of the allergic response but also contribute to side-effects. These additional properties are not uniformly distributed among drugs classified as H1-receptor antagonists. Azatadine, for example, inhibits in vitro IgE-mediated histamine and leukotriene (LT) release from mast cells and basophils. In human challenge models, terfenadine, azatadine, and loratadine reduce IgE-mediated histamine release. Cetirizine reduces eosinophilic infiltration at the site of antigen challenge in the skin, but not the nose. In a nasal antigen challenge model, cetirizine pretreatment did not affect the levels of histamine and prostaglandin D2 recovered in postchallenge lavages, whereas the levels of albumin, N-tosyl-L-arginine methyl ester (TAME) esterase activity, and LTs were reduced. Terfenadine, cetirizine, and loratadine blocked allergen-induced hyperresponsiveness to methacholine. In view of the complexity of the pathophysiology of allergy, a number of H1 antagonists with additional properties are currently under development for allergic diseases. Mizolastine, a new H1-receptor antagonist, has been shown to have additional actions that should help reduce the allergic response. In animal models, mizolastine inhibits antigen-induced eosinophil infiltration into mouse skin and into the nasal cavity of guinea-pigs. Mizolastine also significantly inhibits antigen-induced neutrophil infiltration into the bronchoalveolar lavage fluids of guinea-pigs. In addition, it inhibits arachidonic acid-induced paw oedema in rats without affecting carrageenin-induced rat paw oedema, suggesting an effect on LT generation. In man, mizolastine inhibits early and late antigen-induced soluble intercellular adhesion molecule 1 (ICAM-1) levels in skin blisters. It also inhibits anaphylactic release of histamine from rodent mast cells, LTC4 and LTB4 release from mouse bone-marrow-derived mast cells, LTC4 release from rat intestinal mast cells, and 5-lipoxygenase activity of polymorphonuclear neutrophils of guinea-pig intestines and rat basophilic leukaemia cells. It is clear that a number of H1-antihistamines have multiple effects on the allergic inflammatory response. It is equally clear that these antiallergic effects are not uniformly shared among all drugs of this class. The assessment of the clinical significance of these results and research regarding the parts of the molecules responsible for these activities are underway.
Assuntos
Antialérgicos/imunologia , Antagonistas dos Receptores Histamínicos H1/imunologia , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/imunologia , Animais , Antialérgicos/uso terapêutico , Benzimidazóis/imunologia , Benzimidazóis/uso terapêutico , Modelos Animais de Doenças , Humanos , Receptores Histamínicos H1/imunologia , Rinite/tratamento farmacológico , Rinite/imunologiaRESUMO
Urticaria is a common disorder that adversely affects quality of life; work-related and recreational activities are restricted, while rest, sleep, and emotions are seriously disturbed in a significant proportion of patients. The pathogenic mechanisms vary, but cutaneous mast-cell activation with release of histamine and other vasoactive or proinflammatory mediators is thought to be the final common pathway for lesion induction in most cases. A subsequent, but incompletely understood, late-phase allergic reaction seems to prolong the inflammatory process, particularly in certain chronic forms of the disorder. Although histamine is considered an important mediator of urticaria, additional substances, including the cysteinyl leukotrienes (LTs), are putative mediators of the immediate urticarial responses and the inflammatory events that follow in some types of urticaria. A second-generation antihistamine, mizolastine, which exhibits dual activity with selective H1-receptor antagonism and, as shown in animal studies, anti-5-lipoxygenase activity, represents an advance in the treatment of urticaria. It has rapid, potent and sustained action. At the recommended 10-mg dose, mizolastine suppresses the histamine-induced wheal reaction as early as 1 h after oral administration. Compared to placebo, mizolastine significantly reduces overall patient discomfort and pruritus in patients with chronic idiopathic urticaria. Double-blind, placebo-controlled studies have also shown mizolastine to be at least as effective as other second-generation antihistamines. Furthermore, with long-term use of mizolastine over 1 year, a reduction in pruritus and the number of urticarial episodes was maintained with no evidence of tachyphylaxis or tolerance. Mizolastine has also been shown to be an effective treatment for cold-induced urticaria, causing significant delay in the whealing response to the ice-cube test and also reducing the wheal diameter.
Assuntos
Antialérgicos/uso terapêutico , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Urticária/tratamento farmacológico , Urticária/imunologia , Doença Aguda , Antialérgicos/imunologia , Antialérgicos/farmacologia , Benzimidazóis/imunologia , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Doença Crônica , Ensaios Clínicos como Assunto , Temperatura Baixa/efeitos adversos , Histamina/imunologia , Antagonistas dos Receptores Histamínicos H1/imunologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Humanos , Leucotrienos/imunologia , Inibidores de LipoxigenaseRESUMO
Se realizó un estudio prospectivo, y al azar, en 40 pacientes, con ebastina vs terfenadina; para evaluar la eficacia de ambos como antihistamínicos de segunda generación en el tratamiento de la rinitis alérgica. Se administró la ebastina en 10 mg en ayunas, en pacientes de 5 a 10 años y de 20 mg de 11 a 15 años de edad, una vez al día. La terfenadina se administró 60 mg en pacientes de 5 a 10 años y 120 mg de 11 a 15 años de edad, una vez al día. La ebastina fue más eficaz en el control de los síntomas (rinorrea, obstrucción nasal, estornudos, prurito nasal y oftálmico) más que la terfenadina desde el séptimo día de tratamiento hasta su conclusión (p. 0.05). La tolerancia de la ebastina fue buena, aunque un número pequeño de pacientes (1.5 por ciento) presentaron síntomas colaterales tales commo somnolencia, cefalea y náusea. Ambas dosis de ebastina (10 o 20 mg según la edad del paciente) tuvieron tasas de eficacia global, significativamente mejores que la terfenadina (P 0.05 por ciento)