Polysaccharides are receiving increased attention due to their clinical applications in tissue engineering, vaccine development, nutritional supplementation and antimicrobial biopolymer engineering. The most abundant polysaccharides include fungal cell wall components chitin and β-1,3-glucans. Recent evidence has shown that these polysaccharides modulate airway inflammation, making them the basis of several drug discovery platforms. Small to intermediate chitin fragments ( < 70 μm) are protective in allergic inflammatory models, skewing T cell immunity towards Th1 responses, and reducing the production of Th2 cytokines. As such, chitin prevents the development of the quintessential features of asthmatic disease including chronic airway inflammation, airway hyperresponsiveness and pathological remodeling changes in mouse models of allergy. In contrast, the in vivo effects of β-glucans in animal models of airway inflammation are often contradictory, and the number of human studies is limited. β-1,3-glucans are both proand anti-inflammatory, preventing and enhancing allergic inflammation depending on the preparation, purity and species origin of the β-glucans. This review summarizes recent studies of chitin and β-glucans in models of atopy and airway inflammation and examines the possible reasons for the apparently contradictory observations. Recent relevant patents are also highlighted. Keywords: Chitin, β-glucan, allergy, asthma, inflammation, airway, Dectin-1, TLR2.
Cysteinyl leukotrienes (CysLT) are potent inflammatory lipid molecules that mediate some of the pathophysiological responses associated with asthma such as bronchoconstriction, vasodilation and increased microvascular permeability. As a result, CysLT receptor antagonists (LRA), such as montelukast, have been used to effectively treat patients with asthma. We have recently shown that mast cells are necessary modulators of innate immune responses to bacterial infection and an important component of this innate immune response may involve the production of CysLT. However, the effect of LRA on innate immune receptors, particularly on allergic effector cells, is unknown. This study determined the effect of CysLT on toll-like receptor (TLR) expression by the human mast cell line LAD2. Real-time PCR analysis determined that LTC4, LTD4 and LTE4 downregulated mRNA expression of several TLR. Specifically in human CD34+-derived human mast cells (HuMC), LTC4 inhibited expression of TLR1, 2, 4, 5, 6 and 7 while LTD4 inhibited expression of TLR1-7. Montelukast blocked LTC4-mediated downregulation of all TLR, suggesting that these effects were mediated by activation of the CysLT1 receptor (CysLT1R). Flow cytometry analysis confirmed that LTC4 downregulated surface expression of TLR2 which was blocked by montelukast. These data show that CysLT can modulate human mast cell expression of TLR and that montelukast may be beneficial for innate immune responses mediated by mast cells.
Abstract Mast cells are key effectors of allergic inflammation. IgE-mediated mast cell activation induces degranulation and inflammatory mediator release. Omalizumab (Xolair; Genentech Inc.) is a recombinant humanized monoclonal anti-IgE antibody that prevents IgE binding to its receptor, FcϵRI. Objective: We investigated the effects of omalizumab on IgE pre-sensitized human LAD2 mast cells. Methods: LAD2 degranulation was determined by β-hexosaminidase assay. Chemokine expression and prostaglandin synthesis was measured by quantitative PCR analysis and ELISA, respectively. IgE binding and FcϵRI expression was determined by flow cytometry. Results: Omalizumab pretreatment inhibited IgE binding to LAD2 cells and entirely prevented IgE-dependent upregulation of FcϵRI expression. In addition, omalizumab removed FcϵRI-prebound IgE as early as 24 hrs after treatment. After 5 days, bound IgE was reduced by 92%. Furthermore, omalizumab concomitantly reversed IgE-dependent FcϵRI upregulation by 49% 48 hrs post treatment and by 93% 5 days post treatment. Consequently, omalizumab attenuated ongoing IgE-mediated responses, reducing degranulation by 34%, chemokine expression up to 79% and prostaglandin synthesis by 34% after 7 days of omalizumab treatment. Conclusions: Omalizumab is able to remove pre-bound IgE from sensitized mast cells thereby reducing ongoing response to FcϵRI-dependent signals. This data suggests that omalizumab is an effective inhibitor of sensitized human mast cells.
BackgroundIgE binding via the high affinity FceRI receptor modu-lates FceRI expression and cytokine production in mastcells. Antigen crosslinking of bound IgE further activatesmast cells, inducing degranulation and inflammatorymediator release. Omalizumab (Xolair; Genentech Inc)is a recombinant human monoclonal anti-IgE antibodythat prevents IgE binding to FceRI.ObjectiveWe investigated the effects of omalizumab on IgE-mediated responses in human mast cells.MethodsLAD2 and CD34
.Resveratrol and tranilast blocked cytokine formation,reducing substance P-induced TNF production (65%;P=0.04 and 46%; P=0.09, respectively), but not MCP-1production. Furthermore, resveratrol inhibited Fcepsi-lonRI mediated production of cysLT by 31% compared tocontrol, whereas tranilast had no effect. The effects ofresveratrol on degranulation and release of cysLT weremore marked in human primary mast cells (HuMC)(64% and 90% inhibition, respectively; P<0.05), and thepolyphenol was found to be significantly more efficaciousthan tranilast in these cells.ConclusionsResveratrol inhibited mast cell function at the level ofdegranulation, and cytokine and cysLT production, andwas comparable, and in some cases, more potent thanthe anti-allergy drug tranilast. Thus resveratrol may bean effective therapeutic agent for the treatment of aller-gic disease.
Isoprostanes were first recognized as convenient markers of oxidative stress, but their powerful effects on a variety of cell functions are now also being increasingly appreciated. This is particularly true of the lung, which is comprised of a wide variety of different cell types (smooth muscle, innervation, epithelium, lymphatics, etc.), all of which have been shown to respond to exogenously applied isoprostanes. In this review, we summarize these biological responses in the lung, and also consider the roles that isoprostanes might play in a range of pulmonary clinical disorders.
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