首页 | 本学科首页   官方微博 | 高级检索  
相似文献
 共查询到20条相似文献,搜索用时 15 毫秒
1.
The LTB4 pathway is an attractive target for therapeutic drug development. Two broad classes of drugs have been pursued: antagonists of the primary LTB4 receptors (BLT1 and BLT2) and inhibitors of LTA4 Hydrolase (LTA4H), the rate limiting enzyme in the production of LTB4. An initial wave of effort culminated in the 1990s. Over the past 15 years, a second wave of more selective drug candidates, including at least 5 BLT antagonists and 6 LTA4H inhibitors, have reached Phase 2 clinical trials. Despite the extensive efforts to discover and develop LTB4 pathway targeting drugs, only one has reached the market to date. Recently discovered complexities in the pathway and challenges in matching pathway intervention with therapeutic effect could explain the limited clinical success of LTB4 pathway drugs, even though there is a large body of scientific evidence linking LTB4 to human diseases and demonstrating efficacy of these compounds in a wide array of preclinical models. Herein, we describe the clinical programs for the most prominent recent examples from each broad class and discuss the clinical outcomes and their implications for future development of LTB4 pathway drugs.  相似文献   

2.
The high affinity leukotriene B4 receptor, BLT1 mediates chemotaxis of diverse leukocyte subsets to the sites of infection or inflammation. Whereas the pathological functions of LTB4/BLT1 axis in allergy, autoimmunity and cardiovascular disorders are well established; its role in cancer is only beginning to emerge. In this review, we summarize recent findings on LTB4/BLT1 axis enabling distinct outcomes toward tumor progression. In a mouse lung tumor model promoted by silicosis-induced inflammation, genetic deletion of BLT1 attenuated neutrophilic inflammation and tumor promotion. In contrast, in a spontaneous model of intestinal tumorigenesis, absence of BLT1 led to defective mucosal host response, altered microbiota and bacteria dependent colon tumor progression. Furthermore, BLT1 mediated CD8+ T cell recruitment was shown to be essential for initiating anti-tumor immunity in number of xenograft models and is critical for effective PD1 based immunotherapy. BLT2 mediated chemotherapy resistance, tumor promotion and metastasis are also discussed. This new information points to a paradigm shift in our understanding of the LTB4 pathways in cancer.  相似文献   

3.
4.
5.
Vaccination with allergen-encoding DNA has been proposed as having potential for allergen-specific immunotherapy. In this study, we examine the therapeutic effect of allergen-encoding DNA vaccination directly to dendritic cells (DCs) on allergen-induced allergic airway inflammation in a mouse model and explore potential mechanism. Ovalbumin (OVA)-sensitized and challenged mice were immunized with DNA vaccine and received bronchoalveolar lavage (BAL) 1 day after the last challenge, to measure BAL levels of interleukin (IL)-4, IL-5, interferon (IFN)-gamma and differential cell count. Pulmonary DCs and Spleen DCs were purified and sorted according to the expression of CD(11c) (+)CD(80) (+) and CD(11c) (+)CD(86) (+) co-stimulatory molecules. Our data demonstrated that DNA vaccine therapy with OVA-Fc-pcDNA(3.1) significantly prevented OVA-increased levels of IL-4, IL-5 and the percentage of eosinophils and OVA-decreased level of IFN-gamma. OVA-Fc-pcDNA(3.1)-treated mice had less severity of airway inflammation, and lower expression of CD(11c) (+)CD(80) (+) and CD(11c) (+)CD(86) (+) on pulmonary DCs, as compared with animals with OVA-pcDNA(3.1,) pcDNA(3.1) and OVA respectively. DNA vaccine encoding both Fc and OVA was shown to be more effective than DNA vaccine encoding OVA alone. Our data indicate that Fc-antigen combination-encoding DNA vaccination has better preventive effects on antigen-induced airway inflammation by regulating DCs, and may be a new alternative therapy for asthma.  相似文献   

6.
7.
Leukotriene A4 (LTA4), a reactive electrophilic intermediate formed during the biosynthesis of inflammation‐related lipid mediators, has been found to bind covalently to DNA. The major DNA adducts formed by LTA4 in vitro and human cells have been identified by mass spectrometry on the nucleoside level. Here we investigated whether the thin‐layer chromatography (TLC) 32P‐postlabeling method is suitable for the detection of LTA4‐DNA adducts. The reaction of individual deoxynucleoside 3′‐monophosphates with LTA4 in aqueous basic solution yielded numerous adduct spots when analyzed by the two enrichment procedures of the 32P‐postlabeling method—nuclease P1 digestion and butanol extraction. Highest LTA4‐adduct levels were found with deoxyguanosine 3′‐phosphate (around one adduct per 104 normal nucleotides). Under similar reaction conditions LTA4 (25–320 μM) was incubated with calf thymus DNA, then DNA adduct patterns and levels were determined with the TLC 32P‐postlabeling method using both enrichment versions. The same DNA adduct pattern consisting of up to seven spots was observed with both enrichment versions. DNA adduct formation by LTA4 was concentration‐dependent with major adducts being derived from deoxyguanosine. When a human monocytic cell line (Mono Mac 6) was stimulated with arachidonic acid and calcium ionophore LTA4‐DNA adducts were detected by 32P‐postlabeling. However, the level of these endogenously formed DNA adducts was close to the detection limit (3 ± 2 adducts per 108 normal nucleotides). In summary, the TLC 32P‐postlabeling method is suitable for studying DNA adduct formation by LTA4 and can be used for further investigations on the link between inflammation and cancer. Environ. Mol. Mutagen. 2010. © 2010 Wiley‐Liss, Inc.  相似文献   

8.
9.
Trafficking and recruitment of immune cells to the site of inflammation with spatial and temporal synchronization is crucial for the development of allergic airway inflammation. Particularly, chemokines are known to be key players in these processes. Previous studies revealed that the CXCL12/CXCR4 axis plays an important role in regulating allergic airway inflammation. However, the role of CXCR7, a recently discovered second receptor for CXCL12, in regulating airway inflammation has not been explored. Initially, CXCR7 was considered as a decoy receptor; however, numerous subsequent studies revealed that engagement of CXCR7 triggered its own signalling or modulated CXCR4‐mediated signalling. In the present study, we detected the expression of CXCR7 in airway epithelial cells. Use of a lentiviral delivery system to knock down the expression of CXCR7 in the lung of sensitized mice abrogated the cardinal features of asthma, indicating that CXCR7 plays a role in regulating allergic airway inflammation. The activation of mitogen‐activated protein kinase and Akt signalling in response to CXCL12 in the mouse epithelial cell line MLE‐12 was reduced when CXCR7 expression was knocked down. However, either knockdown or overexpression of CXCR7 in MLE‐12 did not affect CXCL12‐mediated calcium influx, indicating that CXCR7 does not modulate CXCR4‐mediated signalling, and that it functions as a signalling receptor rather than a decoy receptor. Finally, we found that the expression of chemokine CCL2 is regulated by CXCR7/CXCL12‐mediated signalling through β‐arrestin in airway epithelial cells. Hence, regulating the expression of CCL2 in airway epithelial cells may be one mechanism by which CXCR7 participates in regulating allergic airway inflammation.  相似文献   

10.
BACKGROUND: Acetylcholine (ACh) plays an important role in smooth muscle contraction and in the development of airway narrowing; preliminary evidences led us to hypothesize that ACh might also play a role in the development of airways inflammation in chronic obstructive pulmonary disease (COPD). METHODS: We evaluated the concentrations of leukotriene B4 (LTB4) in induced sputum, and the expression of Ach M1, M2, and M3 receptors in sputum cells (SC) obtained from 16 patients with COPD, 11 smokers, and 14 control subjects. The SC were also treated with ACh and the production of LTB4 assessed in the presence or absence of a muscarinic antagonist (oxitropium). In blood monocytes, we evaluated LTB4 release and activation of the extracellular signal-regulated kinases (ERK) pathway after treatment with Ach. RESULTS: The LTB4 concentrations were higher in COPD than in controls (P < 0.01) and correlated with the number of neutrophil (P < 0.01). The M3 receptors expression was increased in COPD subjects when compared to smokers and control (P < 0.05 and 0.0001, respectively), while M2 expression resulted decreased (P < 0.05 and 0.01). The ACh-induced LTB(4) production was observed in peripheral blood monocytes, and was sensitive to ERK inhibition. Similarly, ACh significantly increased neutrophil chemotactic activity and LTB4 released from SC of COPD patients only, and these effects were blocked by pretreatment with the inhibitor of ERK pathway PD98059. CONCLUSIONS: The results obtained show that muscarinic receptors may be involved in airway inflammation in COPD subjects through ACh-induced, ERK1/2-dependent LTB4 release. Muscarinic antagonism may contribute to reduce neutrophil infiltration and activation in COPD.  相似文献   

11.
12.
13.
Background Plasmacytoid dendritic cells (pDCs) are involved in a variety of immune functions. However, the expression of cytotoxic granule proteins like granzymes and perforin in human pDCs is still poorly understood. Objective The aim of this study was to systematically analyse the expression and regulation of cytotoxic granule proteins in human pDCs. Methods The expression of cytotoxic proteins was analysed by RT‐PCR, flow cytometry, and fluorescence microscopy. The functional expression of these proteins was confirmed in a flow‐cytometry‐based cytotoxicity assay using K562 cells as targets. In order to analyse the regulation of pDC‐derived cytotoxic proteins in infectious and allergic diseases, human pDCs were analysed after stimulation with toll‐like receptor (TLR)7/9 ligands and in the human asthma model of segmental allergen challenge. Results Granzyme B (GrB), but not the granzymes A, H, K, M or perforin, was specifically expressed by human pDCs and this GrB expression was up‐regulated by IL‐3 stimulation. In addition, IL‐3‐stimulated pDCs were found to kill K562 cells in a GrB‐ and caspase‐dependent manner. TLR7/9 ligands significantly suppressed GrB expression in pDCs. In contrast, there was an up‐regulation of GrB in endobronchial pDCs 24 h after allergen challenge, and this was accompanied by enhanced GrB concentrations in bronchoalveolar lavage fluid. Conclusion We report the selective expression of GrB in human pDCs and show for the first time pDC‐mediated GrB‐ and caspase‐dependent cytotoxicity against target cells. In addition, the regulation of GrB expression was investigated in vitro and in vivo providing an evidence for a specific role of pDC‐derived GrB in allergic inflammation. Cite this as: K. Bratke, J. Nielsen, F. Manig, C. Klein, M. Kuepper, S. Geyer, P. Julius, M. Lommatzsch and J. C. Virchow, Clinical & Experimental Allergy, 2010 (40) 1015–1024.  相似文献   

14.
15.
We have investigated the expression and function of the VLA-4 heterodimer α4β1, a member of the β1 integrin subfamily, on human thymic epithelial cells (TEC) derived from cortical epithelium. The expression of the α4 integrin chain was studied in four different cloned TEC lines derived from either fetal or post-natal human thymus by both flow cytometry and immunoprecipitation techniques with anti-α4 MoAbs. All different cell lines assayed expressed significant levels of α4, as revealed by their reactivity with MoAbs specific for distinct α4 epitopes. The α4 subunit expressed by TEC was associated to β1 but not to β7 chain, and displayed the characteristic 80/70 kD pattern of proteolytic cleavage. The VLA-4 integrin in these cells was constitutively active in terms of adhesiveness to both fibronectin and vascular cell adhesion molecule-1 (VCAM-1). In addition, this heterodimer localized to punctate regions of the cell in the area of contact with the substratum, named point contacts assessed by staining with the anti-β1 activation epitope 15/7 MoAb. According to the cortical origin of the TEC lines expressing VLA-4, human thymus sections stained with different anti-α4 antibodies revealed the presence of cortical, and in smaller numbers medullary epithelial cells bearing α4 integrin. The expression of α4 in the thymus was also found in both adult and fetal rats, in which epithelial cells were also specifically stained. Altogether, our data show that VLA-4 is an additional component of the integrin repertoire of TEC, and suggest that it could have an important role in thymus epithelial cell–thymocyte interactions.  相似文献   

16.
BACKGROUND: Invariant T-cell receptor-positive natural killer (iNKT) cells have been shown to be essential for the development of allergen-induced airway hyperreactivity (AHR). OBJECTIVE: We examined the role of iNKT cells in allergic skin inflammation using a murine model of atopic dermatitis (AD) elicited by epicutaneous sensitization with ovalbumin (OVA). METHODS: Wild-type (WT) and natural killer T-cell-deficient CD1d-/- mice were epicutaneously sensitized with OVA or normal saline and challenged with aerosolized OVA. iNKT cells in skin and bronchoalveolar lavage fluid were analyzed by fluorescence-activated cell sorting, and cytokine mRNA levels were measured by quantitative RT-PCR. AHR to methacholine was measured after OVA inhalation. RESULTS: Skin infiltration by eosinophils and CD4+ cells and expression of mRNA encoding IL-4 and IL-13 in OVA-sensitized skin were similar in WT and CD1d-/- mice. No significant increase in iNKT cells was detectable in epicutaneously sensitized skin. In contrast, iNKT cells were found in the bronchoalveolar lavage fluid from OVA-challenged epicutaneously sensitized WT mice, but not CD1d-/- mice. Epicutaneously sensitized CD1d-/- mice had an impaired expression of IL-4, IL-5, and IL-13 mRNA in the lung and failed to develop AHR in response to airway challenge with OVA. CONCLUSION: These results demonstrate that iNKT cells are not required for allergic skin inflammation in a murine model of AD, in contrast with airway inflammation, in which iNKT cells are essential. CLINICAL IMPLICATIONS: Understanding the potential role of iNKT cells in AD will allow us to have a more specific target for therapeutic use.  相似文献   

17.
A critical role for leukotriene B(4) (LTB(4)) and/or platelet-activating factor (PAF) in regulating polymorphonuclear cell (PMN) trafficking to inflammatory sites has been reported in a number of experimental inflammatory models. In vitro, newly synthesized LTB(4) and PAF were shown to act in an autocrine/paracrine or intracrine fashion to enhance intracellular arachidonic acid availability and leukotriene biosynthesis. This suggested potentially cooperative effects of these lipid mediators in regulating PMN extravasation. The present study aimed to elucidate whether endogenous LTB(4) and PAF may both act to regulate plasma extravasation and PMN trafficking to inflammatory sites in experimental inflammation. With this aim, we have used selective and potent PAF and LTB(4) receptor antagonist pretreatments in dermal and pulmonary inflammation models in rats. Our results show additive inhibitory effects of dual LTB(4) and PAF receptor blockade in either PAF- or LTB(4)-elicited cutaneous PMN accumulation compared to single-drug administration. Furthermore, the combined administration of the drugs inhibited the PMN accumulation induced by the chemically unrelated soluble agonists tumour necrosis factor-alpha and C5a. Finally, in a model of pulmonary inflammation induced by the intravenous injection of Sephadex beads, lung neutrophilia was reduced by 63% following the administration of LTB(4) and PAF antagonists, in contrast with the lack of effect of single drug administration. Our results strongly support a role of both endogenous LTB(4) and PAF in regulating PMN trafficking to inflammatory sites in various experimental conditions.  相似文献   

18.
Background An induction of reactive oxygen species (ROS) is characteristic for inflammation but the exact pathways have not been identified for allergic airway diseases so far. Objective The aim of this study was to characterize the role of the tachykinin NK‐1 receptor on ROS production during allergen challenge and subsequent inflammation and remodelling. Methods Precision‐cut lung slices of ovalbumin (OVA)‐sensitized mice were cultivated and ROS‐generation in response to OVA challenge (10 μg/mL) was examined by the 2′,7′‐dichloroflourescein‐diacetate method. Long‐term ROS effects on epithelial proliferation were investigated by 5‐bromo‐2′‐deoxyuridine incorporation (72 h). In vivo, the results were validated in OVA‐sensitized animals which were treated intra‐nasally with either placebo, the tachykinin neurokinin 1 (NK‐1) receptor antagonist SR 140333 or the anti‐oxidant N‐acetylcystein (NAC) before allergen challenge. Inflammatory infiltration and remodelling were assessed 48 h after allergen challenge. Results ROS generation was increased by 3.7‐fold, which was inhibited by SR 140333. [Sar9,Met11(O2)]‐Substance P (5 nm ) caused a tachykinin NK‐1 receptor‐dependent fourfold increase in ROS generation. Epithelial proliferation was decreased by 68% by incubation with [Sar9,Met11(O2)]‐SP over 72 h. In‐vivo, treatment with SR 140333 and NAC reduced epithelial damage (91.4% and 76.8% vs. placebo, respectively, P<0.01) and goblet cell hyperplasia (67.4% and 50.1% vs. placebo, respectively, P<0.05), and decreased inflammatory cell influx (65.3% and 45.3% vs. placebo, respectively, P<0.01). Conclusion Allergen challenge induces ROS in a tachykinin NK‐1 receptor‐dependent manner. Inhibition of the tachykinin NK‐1 receptor reduces epithelial damage and subsequent remodelling in vivo. Therefore, patients may possibly benefit from treatment regime that includes radical scavengers or tachykinin NK‐1 receptor antagonists.  相似文献   

19.
20.
We have investigated the expression and function of the VLA-4 heterodimer α4β1, a member of the β1 integrin subfamily, on human thymic epithelial cells (TEC) derived from cortical epithelium. The expression of the α4 integrin chain was studied in four different cloned TEC lines derived from either fetal or post-natal human thymus by both flow cytometry and immunoprecipitation techniques with anti-α4 MoAbs. All different cell lines assayed expressed significant levels of α4, as revealed by their reactivity with MoAbs specific for distinct α4epitopes. The α4 subunit expressed by TEC was associated to β1 but not to β7 chain, and displayed the characteristic 80/70 kD pattern of proteolytic cleavage. The VLA-4 integrin in these cells was constitutively active in terms of adhesiveness to both fibronectin and vascular cell adhesion molecule-1 (VCAM-1). In addition, this heterodimer localized to punctate regions of the cell in the area of contact with the substratum, named point contacts assessed by staining with the anti-β1 activation epitope 15/7 MoAb. According to the cortical origin of the TEC lines expressing VLA-4, human thymus sections stained with different anti-α4 antibodies revealed the presence of cortical, and in smaller numbers medullary epithelial cells bearing α4 integrin. The expression of α4 in the thymus was also found in both adult and fetal rats, in which epithelial cells were also specifically stained. Altogether, our data show that VLA-4 is an additional component of the integrin repertoire of TEC, and suggest that it could have an important role in thymus epithelial cell–thymocyte interactions.  相似文献   

设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号