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Pathways internship usa jobs near me freecell. Cysteinyl leukotrienes: multi-functional mediators in allergic rhinitis
Systemic aspects of allergic disease: the role of the bone marrow. Low serum vitamin D-status, air pollution and obesity: a dangerous liaison. Labonte et al. Pharmacol Res. Tissue eosinophilia is a function of both the influx of eosinophils into the nasal mucosa as well as their half-life survival. Moreover, maternal circulating 25 OH D levels affect the gut microbiota and can therefore indirectly modulate immune responses in the lung via the gut-lung-axis Notably, three studies were retrieved on POMC methylation in relation to alcohol craving Muschler et al.
Further effects of 1,25 OH 2 D on local innate and adaptive immune responses in the epithelial mucosa are mediated through its actions on immune and structural cells and have been reviewed by Heulens et al. Taken together, these findings suggest that on the one hand 1,25 OH 2 D protects against infections by enhancing epithelial barrier function and production of AMPs, and on the other hand 1,25 OH 2 D induces tolerance and dampens proinflammatory responses in various cell types of the airway mucosa.
Thereby, 1,25 OH 2 D may prevent exaggerated inflammatory responses and further damage to the mucosal tissue, qualities that are very relevant in the context of chronic inflammatory lung diseases Figure 2. COPD is considered to be a disease of accelerated aging lungs, underscored by markers of aging being increased in these patients partly as a result of oxidative stress Evidence that 1,25 OH 2 D may protect epithelial cells from oxidative stress was provided by Pfeffer et al. Furthermore, 1,25 OH 2 D increased the ratio of reduced to oxidized glutathione and decreased the formation of 8-isoprostane after exposure to PM Expression of klotho is impaired in the airways of smokers and further decreased in the airways of COPD patients and in cultures of the bronchial epithelial cell line 16HBE after CSE exposure These studies suggest that 1,25 OH 2 D may protect against aging via inhibition of oxidative stress and possibly via its ability to restore klotho expression Figure 2.
However, direct evidence showing that 1,25 OH 2 D indeed increases expression of klotho in airway epithelial cells is currently lacking.
In addition to providing protection against oxidative stress and aging, data from studies using intestinal epithelial cells suggest that 1,25 OH 2 D may also promote cellular survival via the induction of autophagy and reduction of apoptosis , In chronic inflammatory lung diseases, aberrant activation of autophagy plays a role in disease pathogenesis A recent study showed that club cells and autophagy-related proteins were both decreased in COPD patients and that these proteins were important for club cell structure and function in airways However, the effects of 1,25 OH 2 D on autophagy in the airway mucosa of chronic inflammatory lung diseases are still unclear and need to be further evaluated Clearly vitamin D has pivotal actions in host defense that are relevant in the context of chronic inflammatory lung diseases, in which vitamin D deficiency may be prevalent.
Strategies to promote local levels of 1,25 OH 2 D or use it as a treatment itself could be therefore of interest. Here, we will discuss the latest clinical evidence accompanied with functional in vitro and animal studies that may explain the effects of vitamin D supplementation on typical hallmarks of chronic airway diseases.
Currently, inhaled corticosteroid ICS -use with or without long acting bronchodilators is the most frequently used treatment for COPD and asthma patients 1. However, the response to corticosteroids is not always effective in many COPD patients and in patients with steroid resistant SR -asthma There are several complex mechanisms that underlie the resistance to corticosteroids in both COPD and SR-asthma that include but are not limited to genetic background, impaired glucocorticoid receptor binding, T helper type 17 cell Th17 -inflammation and oxidative stress e.
A further potential treatment role of 1,25 OH 2 D was elegantly illustrated by studies that showed that vitamin D deficiency is associated with decreased steroid responsiveness in asthmatics and by the fact that several potential underlying mechanisms of SR such as oxidative stress and Thmediated inflammatory responses could be reversed by vitamin D treatment 59 , — Interestingly, the corticosteroid dexamethasone was shown to increase expression of the 25 OH D and 1,25 OH 2 D degrading enzyme CYP24A1 in renal cells and osteoblasts , which suggests a bidirectional interaction between corticosteroids and 1,25 OH 2 D and could further limit 1,25 OH 2 D levels for patients.
Additional research is needed to determine if vitamin D may also improve corticosteroid responsiveness in COPD. Exacerbations are a major burden for COPD patients, they accelerate decline in lung function and frequently result into hospital admissions , COPD patients generally have lower serum 25 OH D levels than age- and smoking-matched controls, which is associated with more and more severe exacerbations 8 , Several in vivo and in vitro studies have provided evidence that explain the protective effects of vitamin D on exacerbations in COPD patients and this will be discussed accordingly.
First of all, Pfeffer et al. In line with this, Bolcas et al. Vitamin D could therefore exert a protective role in air pollution-triggered exacerbations. Infections with respiratory viruses such as HRV, coronaviruses and to a lesser extend respiratory syncytial virus RSV and para influenza virus are present during exacerbations and may predispose the host toward secondary bacterial infections that can eventually lead to uncontrolled bacterial outgrowth, more severe exacerbations and neutrophilic inflammation , Two recent in vitro studies showed that acute exposure to relatively high doses — nM of 1,25 OH 2 D reduced HRV-infection in undifferentiated cultures of airway epithelial cells 58 , In fully differentiated airway epithelial cells, treatment with lower concentrations of 1,25 OH 2 D 10 nM during epithelial differentiation had no effect on acute HRV infection As for other viruses than HRV, both Hansdottir et al.
In addition, two other studies reported in influenza H9N2 and H1N1 -infected A cells comparable findings , Moreover, inhibitory effects of 1,25 OH 2 D on poly I:C -induced inflammatory responses were furthermore confirmed in primary airway epithelial cells Hansdottir et al.
Up to now, the afore mentioned studies suggest that higher doses of 1,25 OH 2 D might be protective against HRV-infections in undifferentiated airway epithelial cells only, whereas for other respiratory viral infections 1,25 OH 2 D mainly reduces inflammatory responses without affecting viral clearance.
However, more studies are needed, especially in differentiated airway epithelial cells using multiple HRV-serotypes that use different receptors for infection to verify if 1,25 OH 2 D indeed is capable of promoting HRV-clearance. There is more consensus about 1,25 OH 2 D reducing virus-induced inflammatory responses and this may certainly help to alleviate the burden of exacerbations in COPD 38 , Due to improved study design and sampling techniques from the lower airways using bronchoscopy in recent decades, the causative role of bacteria in COPD-related exacerbations has become clear This was additionally supported by Sethi et al.
Recent developments in assessing the airway microbiota using 16S rRNA sequencing techniques further demonstrated that during exacerbations, the relative abundance of Haemophilus, Pseudomonas, and Moraxella was increased and the microbial composition was shifted toward the Proteobacteria phylum The ability of 1,25 OH 2 D to promote antibacterial activity was recently demonstrated in cultures of airway epithelial cells.
In addition, Yim et al. These observed antibacterial effects of 1,25 OH 2 D on airway epithelium in vitro were recently confirmed in vivo by Vargas Buonfiglio et al.
Indeed, Niederstrasser et al. However, in a recently developed mouse model by Lowry et al. There are also multiple other murine studies that demonstrate protective effects of vitamin D on bacterial infections in the gut, indicating that 1,25 OH 2 D -mediated antibacterial effects are additional modulated by other mechanisms such as via enhancement of epithelial barrier integrity 67 , In conclusion, these observations show that 1,25 OH 2 D promotes protection against pollutants and enhances clearance of viral— and bacterial infections both Gram-positive and negative bacteria in combination with a dampening effect on exaggerated immune responses and these features might explain why vitamin D deficiency is linked to COPD exacerbations.
Evidence for a role of AMPs in regulating the composition of the microbiota in the gut came from a variety of studies, including those showing that Paneth cell-derived defensins may modulate the composition of the microbiome Alterations in the gut microbiota have been linked to many diseases of the gut such as IBD but also with diseases affecting the lungs such as COPD and asthma, implicating an important role for the so-called gut—lung axis , The mechanisms that explain how gut microbiota affect lung health and disease are complex and include the production of short chain fatty acids SCFAs.
SCFA have a wide range of effects on both immune and structural cells, and the effect of SCFA produced in the intestine on lung immunity may in part be explained by modulation of myeloid cells in the bone marrow, which subsequently migrate to the airways and modulate local immune responses Microbiota that are diverse, rich and contain a higher abundance of SCFA-producing species within these populations are considered to be associated with health However, due to the limited number of RCTs and small sample sizes, the precise effects on the microbiota and the mechanisms involved in this are still unclear Alterations in the lung microbiota are also observed in COPD and asthma patients and are likely the result of environmental exposures, airway remodeling, infections and treatments such as the use of antibiotics.
This may contribute to disease pathogenesis through altered epithelial innate and adaptive immune responses that damages the airway epithelial barrier and provokes further changes in the lung microbiome that accumulates with increasing disease severity , To date only 2 studies describe a possible influence of vitamin D on composition of the microbiota in the airways , Toivonen et al. The above described protective and therapeutic possibilities of vitamin D, together with observations that many COPD patients are vitamin D deficient, suggest that COPD patients might benefit from vitamin D supplementation.
As discussed elsewhere in this review, the link between circulating 25 OH D levels and the number of exacerbations has been extensively studied 8. However, in a post-hoc analysis, selecting those patients that were vitamin D deficient, exacerbations were indeed reduced after vitamin D supplementation. Jolliffe et al. These important findings suggest that exacerbations in this specific subset of COPD patients are connected to vitamin D deficiency and this part can be resolved with supplementation.
In summary, the protective effects of vitamin D in patients suffering from COPD are most prominent in those with vitamin D deficiency and this would indicate that serum levels 25 OH D in these patients should always be determined before considering using vitamin D supplementation. Currently, a multicenter RCT is being conducted by Rafiq et al. In addition to the effects of vitamin D supplementation in COPD patients, the effects of vitamin D supplementation has also been extensively investigated in other lung diseases which have associations with vitamin D deficiency such as asthma, cystic fibrosis, upper respiratory tract infections.
CF patients with vitamin D deficiency had a higher rate of exacerbations as compared to patients with sufficient 25 OH D levels However, only one recent multicenter RCT was conducted and indicated that vitamin D supplementation did not affect the number of exacerbations in CF patients with serum 25 OH D concentrations between 25 and In summary, the protective effects of vitamin D supplementation in patients suffering from COPD, asthma or ARTIs are most prominent in those with vitamin D deficiency and this would indicate the importance of establishing serum levels 25 OH D in these patients as supplementation could reduce unnecessary aggravated disease pathology as a result of this deficiency.
Many drivers of COPD pathogenesis such as chronic exposure to noxious particles and gases, which are present in CS and air pollution, proteolytic enzymes, cytokines and chemokines that are released by infiltrating inflammatory cells, are known to harm the epithelial barrier and cause aberrant remodeling of the airway epithelium with important functional consequences for e. A dysfunctional epithelial barrier increases the susceptibility toward bacterial and viral infections, which are important triggers of COPD exacerbations and these exacerbations contribute importantly to disease progression.
Sufficient local levels of 1,25 OH 2 D may provide partial protection against these effects by reducing the effects of oxidative stress induced by exposure to inhaled oxidants or those derived from recruited inflammatory cells. Protection against the detrimental effects of both bacterial and viral infections is provided by the ability of 1,25 OH 2 D to promote of antiviral responses, induce expression of AMPs and modulate of inflammatory responses.
Taken together, these activities suggest that 1,25 OH 2 D may provide protection against development and progression of COPD, and against disease exacerbations. In addition, the local inflammatory milieu as well as the chronic exposure to noxious particles and gases, which are present in CS and air pollution, may negatively affect synthesis and signaling of 1,25 OH 2 D.
Here we discussed recent in vitro studies that demonstrated that disease-associated factors such as inflammation and exposure to CS and air pollution could interfere with 1,25 OH 2 D signaling and its degradation and activation by affecting expression of VDR, CYP24A1 and CYP27B1, respectively.
This suggests that even in patients with sufficient 25 OH D serum levels the local activity of 1,25 OH 2 D in the lungs can be improved. We have to start generating more information on both systemic and local 1,25 OH 2 D levels and gene expression signatures related to 25 OH D and 1,25 OH 2 D metabolism or responses in COPD and other chronic inflammatory diseases that are related to vitamin D deficiency , both at baseline and after vitamin D supplementation. This information could lead to improved treatment strategies that enhance local efficacy of 1,25 OH 2 D, using e.
When considering such strategies, it should be noted that these may enhance the calcemic side effects and lead to unwanted inhibition of the immune system.
We therefore need to carefully analyze the preclinical in vivo and in vitro studies and balance the pros and cons of the different strategies.
In conclusion, future studies in COPD and but also in other chronic inflammatory diseases that are related to vitamin D deficiency, should be designed with more focus on assessing and improving local levels of 1,25 OH 2 D.
These new insights may lead to the development of new treatment strategies, such as those targeting CYP24A1 to enhance local 1,25 OH 2 D resulting in improved homeostasis and protection of the airway mucosa in patients with chronic inflammatory lung diseases.
JS: Analyzing literature and drafting the manuscript. AD and PH: Revision of the manuscript. All authors: reviewed the manuscript and agree with its submission. This study was supported by a grant from the Lung Foundation Netherlands grant 5. 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. Vitamin D and human health: lessons from vitamin D receptor null mice.
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J Invest Dermatol. J Steroid Biochem Mol Biol. J Cell Biochem. Nagata et al. These data suggest a positive feedback mechanism that increases the production of CysLTs at the site of eosinophil adhesion. Transendothelial migration of leucocytes across the vessel wall into the tissue follows cellular adhesion. CysLTs are direct chemoattractants for eosinophils and have been shown to enhance eosinophil migration in vivo [ — ] and in vitro [ 92 , , , ].
Eotaxin is a selective chemoattractant for eosinophils. The role of CysLTs in eosinophil recruitment is further implicated by the observation that LTC 4 increases eotaxin release from endothelial cells [ , ] and from ILprimed fibroblasts [ ], which is blocked by montelukast and pranlukast. Finally, montelukast treatment has been shown to reduce eosinophils in nasal mucosa of adults [ 46 ] and children [ 61 ] with AR.
Tissue eosinophilia is a function of both the influx of eosinophils into the nasal mucosa as well as their half-life survival.
CysLTs increase eosinophil survival time [ ], and this effect is inhibited by leukotriene receptor antagonists [ , ]. Once in the nasal tissue, CysLTs also promote inflammation by enhancing the activity of inflammatory cells. This section focuses on eosinophil activation, but the ability of CysLTs to affect the function of other inflammatory cells, including monocytes, basophils, mast cells, and T lymphocytes, is also described.
Activated eosinophils release a variety of inflammatory mediators and probably play a significant role in allergic disease. For example, eosinophilic cationic protein ECP is toxic to epithelial tissue; a consequence of such toxicity may be exposure of sensory nerve fibres to environmental irritants.
Major basic protein MBP , on the other hand, can inhibit the ability of acetylcholine to prevent further acetylcholine release from peripheral parasympathetic nerves by deactivating the M2 receptor [ ]. Elevated ECP in the nasal fluid of patients with AR [ ] correlates with an increase in LTC 4 [ ], and treatment with montelukast decreases ECP levels in the serum of adults [ ] and in nasal washes from pediatric patients [ ].
A significant correlation between CysLTs and eosinophilic protein X, a marker of eosinophilic activity, has also been demonstrated [ 27 ].
Superoxide radicals mediate inflammation through oxidative damage in cells, and LTD 4 was shown to increase superoxide radical levels in eosinophils in vitro [ ]. Eosinophil-derived neurotoxin EDN is another cytotoxic mediator. In clinical studies, the leukotriene receptor antagonist montelukast reduced peripheral blood eosinophil numbers in adults [ 53 — 56 ] and children [ 61 , ] with AR. Taken together, the effects of CysLTs on eosinophil differentiation, maturation, proliferation, adhesion molecule expression, migration, survival, and activation described above are consistent with a role of these mediators in local and systemic allergic inflammation.
A complex network of interactions exists between CysLTs and a variety of inflammatory mediators Fig. Interactions between cysteinyl leukotrienes CysLTs and inflammatory mediators. In patients with established allergic inflammation, immune responses to allergens are TH 2 polarized, resulting in a preponderance of TH 2 relative to the TH 1 cytokines [ , ]. In patients with perennial AR, 4 weeks of treatment with pranlukast suppressed nasal mucosal production of IL-4 and IL-5 [ 46 ].
A 2-week treatment with montelukast decreased IL-4 and IL levels in nasal lavage secretions from children with AR [ ]. Also, serum IL-5 levels were reduced in children with asthma after 6 weeks of treatment with montelukast [ ].
The level and activity of a variety of other mediators have been shown to be modulated by CysLTs. CysLTs have also been shown to affect mediators of inflammatory tissue growth and repair.
For example, the proliferative effects of epidermal growth factor EGF on smooth muscle cells in culture were potentiated by LTD 4 [ ]. The proliferative effects of insulin-like growth factor IGF on smooth muscle cells in culture were also potentiated by LTD 4 induction of matrix metalloproteinases MMP-1 [ ]. Plasminogen activator inhibitor type-1 PAI-1 promotion of abnormal tissue repair plays a role in airway remodeling; LTD 4 increased, and montelukast decreased, production of PAI-1 by mast cells [ ].
There is evidence for an interaction between CysLTs and histamine, another pivotal mediator of allergic reactions. LTD 4 enhanced histamine-induced elevation of cytosolic calcium levels in cultured embryonic carcinoma cells [ ] and prostaglandin E 2 PGE 2 production from human monocytes and smooth muscle cells, as well as mouse macrophages [ ]. The LTD 4 -enhanced histamine-induced PGE 2 production was coincident with the appearance of additional histamine receptors [ ].
These in vitro observations are in concordance with the in vivo effects of CysLT 1 antagonism on nasal responsiveness to histamine described earlier [ 67 ]. The modulation of endothelin by CysLTs has also been demonstrated [ ]. Exhaled nitric oxide NO is a marker of airway inflammation. Montelukast has been shown to reduce levels of exhaled NO in clinical trials with asthmatic adults [ , ] and children [ , ], but no studies have evaluated whether nasal NO is also affected.
In vitro , LTC 4 increased NO release from polymorphonuclear leucocytes [ ] and from macrophages [ ]. Ethacrynic acid, an inhibitor of LTC 4 production, has been shown to inhibit NO production by mouse peritoneal macrophages [ ]. Ovalbumin OVA challenge in OVA-sensitized rats increased lung-inducible nitric oxide synthase iNOS expression, which was decreased by treatment with montelukast [ ]. Taken together, these data suggest a mechanism for the reduction in eNO observed clinically with montelukast.
Superoxide radical levels in eosinophils have also been shown to be increased by LTD 4 [ ] and blocked by pranlukast [ ]. In addition to the effects of CysLTs on other inflammatory mediators, the converse is also true, in that various inflammatory mediators can exert regulatory effects on CysLTs. The full range of interaction between TH 2 cytokines and leukotrienes was illustrated in an in vitro study, which demonstrated that IL increased CysLT 1 receptor expression on lung-derived fibroblasts, subsequently enabling the cells to respond to LTC 4 stimulation by releasing functionally active eotaxin, which subsequently promoted eosinophil chemotaxis and migration [ ].
However, CysLT 1 receptors have not been observed on nasal polyp-derived fibroblasts [ ]. IL is increased in nasal mucosa of patients with AR during seasonal allergy exposure [ ] and is a chemoattractant for eosinophils. A substantial body of research reviewed in this article indicates that CysLTs satisfy Koch’s postulates as mediators of AR, as i they are overproduced in the nasal mucosa of patients with the disease; ii they reproduce many clinical features of AR; and iii pharmacologic agents that block their synthesis or receptor-mediated actions attenuate the manifestations of AR.
Recent studies have also elucidated a variety of mechanisms, other than direct symptom production, by which CysLTs promote AR. They have revealed that these lipid mediators participate in the genesis of systemic immune responses to antigen and in leucocyte accumulation, survival, and activation in affected tissues.
One particularly compelling, but underappreciated, aspect of the involvement of CysLTs in allergic disease is the bidirectional interplay between CysLTs and other inflammatory mediators, such as cytokines, chemokines, growth factors, histamine, and reactive oxygen and nitrogen species. In this regard, leukotrienes can modulate the generation of a variety of mediators, and other mediators can modulate leukotriene actions by influencing both their synthesis and the expression of their receptors.
Although a role for CysLTs in the pathogenesis of asthma was recognized first — involving many of these same mechanisms — the subsequent recognition of their role in AR supports the concept of a unified airway response to common triggering events. It should be clearly stated that CysLTs represent only one of the participants of the allergic response.
Other biologic products, including histamine or PGD 2 , play important roles. For example, histamine, acting through its H 1 receptors, not only generates acute nasal symptoms, but it also has several properties that are not identifiable on the basis of its acute action on the nasal mucosa, including immunomodulatory activities and interactions with other mediators [ , ].
CysLT 1 receptor antagonists, like H 1 receptor antagonists, have well-established clinical effects in AR. In fact, their overall clinical effectiveness appears to be of similar magnitude [ ].
These antagonists are less effective compared with nasal glucocorticosteroids because the latter agents have a wider target spectrum. It should be kept in mind, however, that the systemic nature of treatment that CysLT 1 receptor antagonists and antihistamines provide may have additional benefits that are not identifiable by the short-term studies that target the symptoms of AR [ ].
This concept requires exploration. The authors thank Carolyn Hustad, PhD, for editing and formatting the manuscript and Denise Stek and Jennifer Pawlowski for help with creating the reference list. Clinical and Experimental Allergy. Clin Exp Allergy. Author information Article notes Copyright and License information Disclaimer. E-mail: ude. Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.
Journal compilation Blackwell Publishing Ltd. Abstract Cysteinyl leukotrienes CysLTs are a family of inflammatory lipid mediators synthesized from arachidonic acid by a variety of cells, including mast cells, eosinophils, basophils, and macrophages.
Keywords: allergic rhinitis, cysteinyl leukotrienes, CysLT 1 receptor, eosinophils, inflammation, leukotriene C4 synthase, 5-lipoxygenase. Open in a separate window. Receptors for cysteinyl leukotrienes are found in tissue and on cells that are involved in allergic rhinitis inflammation and symptoms Using in situ hybridization and immunohistochemical techniques, the CysLT 1 receptor has been localized to nasal mucosal interstitial cells, glandular epithelium, and a variety of inflammatory cells Table 1.
Cysteinyl leukotrienes are found in patients with allergic rhinitis Several studies have demonstrated that CysLT levels in nasal fluids are increased in patients with AR Table 2. Table 2 Cysteinyl leukotrienes CysLTs are elevated in patients with allergic rhinitis and conjunctivitis. Cysteinyl leukotrienes may be participating in the process of allergic sensitization An allergic response requires processing of the allergen by an antigen-presenting cell.
Cysteinyl leukotrienes can produce symptoms of allergic rhinitis Experimental exposure of the nasal mucosa to allergens in sensitized individuals with AR initiates a dual-phase immune response [ 49 ]. Table 3 Allergen-induced rhinitis and clinical rhinitis outcomes affected by cysteinyl leukotrienes CysLTs.
LTRA, leukotriene receptor antagonist. Cysteinyl leukotrienes and cellular inflammation in allergic rhinitis In the course of natural exposure to aeroallergens, as well as with experimental allergen challenge, various inflammatory cells, including eosinophils, basophils, monocytes, and TH 2 lymphocytes, are elevated in nasal tissue and nasal secretions [ 76 , 77 ] and correlate with symptoms in patients with AR [ 78 , 81 ].
Step 1: haematopoiesis The role of eosinophil and basophil progenitors in allergic inflammation and their fluctuation with seasonal exposure has been reviewed [ 85 — 87 ]. Step 3: adhesion to post-capillary venules Leucocyte adhesion to the vascular wall is the first step in recruitment and migration into nasal tissue. Steps 4 and 5: migration and chemoattraction Transendothelial migration of leucocytes across the vessel wall into the tissue follows cellular adhesion.
Step 6: cell survival Tissue eosinophilia is a function of both the influx of eosinophils into the nasal mucosa as well as their half-life survival. Step 7: cellular activation Once in the nasal tissue, CysLTs also promote inflammation by enhancing the activity of inflammatory cells. Bidirectional modulation between cysteinyl leukotrienes and other inflammatory mediators A complex network of interactions exists between CysLTs and a variety of inflammatory mediators Fig.
Cysteinyl leukotrienes enhance the production and activity of inflammatory mediators In patients with established allergic inflammation, immune responses to allergens are TH 2 polarized, resulting in a preponderance of TH 2 relative to the TH 1 cytokines [ , ]. Inflammatory mediators enhance the production and activity of cysteinyl leukotrienes In addition to the effects of CysLTs on other inflammatory mediators, the converse is also true, in that various inflammatory mediators can exert regulatory effects on CysLTs.
Acknowledgments The authors thank Carolyn Hustad, PhD, for editing and formatting the manuscript and Denise Stek and Jennifer Pawlowski for help with creating the reference list. References 1.
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