UNASSIGNED: Chronic obstructive pulmonary disease (COPD) is associated with tobacco smoking and biomass-burning smoke exposure. Toll-like receptor 4 (TLR4) single-nucleotide polymorphisms (SNPs) may contribute to its pathogenesis. The study aimed to assess the association of rs4986790 and rs4986791 in the TLR4 gene in a Mexican mestizo population with COPD secondary to tobacco smoking (COPD-TS) and biomass-burning smoke (COPD-BBS) and to evaluate whether the genotypes of risk affect cytokine serum levels.
UNASSIGNED: We enrolled 2,092 participants and divided them into two comparisons according to their environmental exposure. SNPs were genotyped using TaqMan probes. Serum cytokine levels (IL-4, IL-5, IL-6, IL-10, and INF-γ) were quantified by ELISA.
UNASSIGNED: The rs4986790 AA genotype in COPD-TS was associated with a higher COPD risk (OR = 3.53). Haplotype analysis confirmed this association, identifying a block containing the rs4986790 allele (A-C, OR = 3.11). COPD-TS exhibited elevated IL-6, IL-4, and IL-5 levels compared with smokers without COPD (SWOC), whereas COPD-BBS displayed higher IFN-γ, IL-6, and IL-10 levels. The AA carriers in the COPD-TS group had elevated IL-4, IL-5, and IFN-γ compared with carriers of AG or GG.
UNASSIGNED: The rs4986790 common allele and the A-C haplotype (rs4986790-rs4986791) were associated with a higher COPD risk in smokers; COPD patients carrying the AA genotype showed increased pro-inflammatory cytokines.

Objective:The purpose of this study is to explore the expression of prostacyclin receptor（IP） in patients with chronic rhinosinusitis（CRS） and its possible association with type 2 inflammation. Methods:HE staining was used to observe the morphological changes of nasal mucosa, qRT-PCR was used to detect the expression of IP in polyps and nasal mucosa, and IHC was used to detect the expression of IP, IL-4, IL-5 and IL-13 in polyps and nasal mucosa. Results:Compared with the control group, the nasal mucosa of patients with various types of CRS was obviously thickened, accompanied by inflammatory cell infiltration and gland hyperplasia. The statistical results of IHC showed that the expression levels of IL-4, IL-5 and IL-13 in CRS group were significantly higher than those in control group（P<0.05）, and the IP expression in control group was significantly higher than that in ECRS group and non-ECRS group（P<0.05）. The IP expression in ECRS group was negatively correlated with IL-4, IL-5 and IL-13. The results of qRT-PCR showed that the expression of IP mRNA in control group was significantly higher than that in ECRS group and non-ECRS group（P<0.05）. Conclusion:IL-4, IL-5 and IL-13 are highly expressed in the nasal mucosa of CRS patients, while IP is poorly expressed in the nasal mucosa of CRS patients, and IP is negatively correlated with IL-4, IL-5 and IL-13, suggesting that IP is related to the occurrence and development of type 2 inflammation and may be a potential therapeutic target for CRS patients.
目的：本研究旨在探索慢性鼻窦炎（CRS）患者前列环素受体（IP）的表达及其与2型炎症之间可能存在的关联。 方法：采用苏木精-伊红染色对鼻黏膜组织形态改变进行观察，qRT-PCR用于检测息肉与鼻黏膜组织IP表达，免疫组织化学染色用于检测息肉与鼻黏膜组织IP、IL-4、IL-5和IL-13表达情况。以取自鼻中隔偏曲、垂体瘤、脑脊液鼻漏且无CRS患者的中鼻甲黏膜为对照组。 结果：与对照组比较，各型CRS患者鼻黏膜组织明显增厚，并伴随着炎症细胞浸润及腺体增生。免疫组织化学染色的统计结果显示，ECRS组和non-ECRS组的IL-4、IL-5和IL-13表达水平均明显高于对照组（P<0.05），对照组IP表达量均显著高于ECRS组和non-ECRS组（P<0.05），ECRS组中IP表达量与IL-4、IL-5和IL-13呈负相关。qRT-PCR结果显示，对照组IP mRNA表达量均明显高于ECRS组和non-ECRS组（P<0.05）。 结论：IL-4、IL-5和IL-13在CRS患者鼻黏膜中高表达，IP在CRS患者鼻黏膜中呈低表达，且IP与IL-4、IL-5和IL-13具有负相关性，提示IP与2型炎症的发生发展有关，可能是CRS患者潜在的治疗靶点。.

Objective: To identify potential therapeutic targets of chronic sinusitis with nasal polyps (CRSwNP) through proteomics screening of and verify its effectiveness experimentally. Methods: The nasal tissue samples were collected from patients undergoing surgical treatment in the Department of Otorhinolaryngology, Head and Neck Surgery in Yuhuangding Hospital of Yantai from June 2010 to December 2021, including 69 patients with CRSwNP and 39 patients in the control group. Tissue samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in data-independent acquisition (DIA) mode to find differentially expressed proteins. Bioinformatics tools were employed to analyze the functions of differentially expressed proteins. The expression of hematopoietic cell kinase (HCK) in nasal tissues of patients with CRSwNP was further confirmed by qPCR and western blot. The mouse model of CRSwNP was established and treated with HCK inhibitor. The levels of inflammatory factors IgE, IL-4 and IL-5 in serum of CRSwNP mice, both treated and untreated with HCK inhibitors, were detected by enzyme-linked immunosorbent assay (ELISA) across different experimental groups. The experimental data were analyzed by Graphpad Prism 9 software. Results: DIA analysis identified 1 850 differential proteins, including 760 up-regulated proteins and 1 090 down-regulated proteins. Weighted correlation network analysis (WGCNA) correlation analysis of phenotypic data such as cell count and CT score with the results of genomics indemnified 575 proteins of MEBrown module which intersected with 35 kinases further screened from 1 850 differential proteins, yielding eight protein kinases: HCK, SYK, PDK2, FGR, PRKCB, ROR1, CAMK1 and GRK6. qPCR showed that the expression of HCK in CRSwNP was significantly higher than that in the control group (P<0.05). Further experiments in mice confirmed that the secretion of IgE, IL-4 and IL-5 in the serum of CRSwNP group was significantly higher than the control group (all P<0.05), indicating successful model establishment. The intervention of HCK significantly decreased the secretion of IgE, IL-4 and IL-5 in serum of mice (all P<0.05). Conclusion: The HCK inhibitor can reduce the inflammatory index of mice with CRSwNP, and HCK is a potential therapeutic target of CRSwNP.
目的： 通过蛋白质组学方法筛选慢性鼻窦炎伴鼻息肉（CRSwNP）的潜在治疗靶点，并通过实验验证其有效性。 方法： 收集自2020年6月至2021年12月于烟台毓璜顶医院耳鼻咽喉头颈外科行手术治疗的患者的鼻黏膜组织样本，其中CRSwNP患者69例，对照组（行上颌窦囊肿切除或视神经减压术）患者39例。通过液相色谱-串联质谱法（liquid chromatography-tandem mass spectrometry，LC-MS/MS）以数据独立采集（data-independent acquisition，DIA）模式分析组织样本，寻找差异表达蛋白，结合生物信息学工具对差异蛋白功能进行分析。并通过实时荧光定量聚合酶链反应（qPCR）及蛋白免疫印迹（WB）技术明确CRSwNP患者鼻组织造血细胞激酶（hematopoietic cell kinase，HCK）表达情况。同时构建CRSwNP小鼠模型并给予HCK抑制剂干预治疗，酶联免疫吸附实验（ELISA）检测不同实验组小鼠血清中炎性因子免疫球蛋白E（IgE）、白细胞介素（IL）-4及IL-5的分泌情况。 结果： 与对照组相比，CRSwNP组鼻黏膜组织筛选出差异蛋白1 850个，其中上调蛋白760个，下调蛋白1 090个。将细胞计数、CT评分等表型数据与组学结果进行加权基因共表达网络分析（weighted correlation network analysis，WGCNA）关联分析，选取MEBrown模块的575个蛋白，与通过蛋白质组学得到的1 850个差异蛋白中进一步筛选出的35个激酶取交集，获得8个蛋白激酶，分别是HCK、SYK、PDK2、FGR、PRKCB、ROR1、CAMK1及GRK6。对差异表达倍数最高的HCK进行实验验证，qPCR及WB结果表明，CRSwNP鼻组织中HCK的表达明显高于对照组（P<0.05）。在动物实验中发现，CRSwNP组小鼠血清中IgE、IL-4及IL-5分泌量较对照组显著升高（P<0.05），而经HCK抑制剂干预后，小鼠血清中IgE、IL-4及IL-5分泌量显著降低（P<0.05）。 结论： HCK抑制剂能够降低CRSwNP小鼠的炎性指标，HCK有望成为CRSwNP的潜在治疗靶点。.

The immunological pathogenesis of atopic dermatitis (AD) and chronic spontaneous urticaria (CSU) has not been fully elucidated yet. The aim of our research was to assess the serum concentration of interleukin-5 receptor (IL-5R) in relation to the disease activity and pruritus intensity in adult patients with AD and CSU. This pilot study included 45 participants (15 patients with AD, 15 patients with CSU, and 15 healthy controls). Blood samples were taken to examine the serum levels of IL-5R using the enzyme-linked immunosorbent assay (ELISA) test. The Scoring Atopic Dermatitis (SCORAD) index, the Urticaria Activity Score (UAS7), and the Visual Analogue Scale (VAS) were used to assess the disease activity and the pruritus intensity, respectively. Obtained results revealed that the IL-5R concentration was significantly higher in patients with CSU than in patients with AD and in the controls (p = 0.038). There was a positive correlation between the IL-5R level and the SCORAD index in patients with AD (r = -0.9, p = 0.047), which was not found for the CSU activity by UAS7 and with the pruritus severity by VAS in both examined groups of patients. Our findings underscore higher serum levels of IL-5R among CSU and AD patients, which may highlight its functional role in the pathogenesis of these diseases. In contrast, IL-5R might not be fully useful in reflecting the severity of symptoms. Although our results are promising, this study should be conducted on a larger cohort of patients.

Interleukin-5 functions as a B-cell differentiation factor, but more importantly, in the context of this review, it plays a variety of roles in eosinophil biology, including eosinophil differentiation and maturation in the bone marrow, and facilitates eosinophil migration to tissue sites, usually in the context of an allergic reaction. Given the availability of selective anti-IL-5 drugs such as mepolizumab and reslizumab, as well as the IL-5 receptor antagonist benralizumab, it is worth investigating whether they could be used in some cases of allergic disease. Asthma has a well-documented involvement of IL-5 in its pathophysiology and has clear benefits in the case of anti-IL-5 therapy; therefore, current knowledge is presented to provide a reference point for the study of less-described diseases such as atopic dermatitis, chronic rhinosinusitis, chronic spontaneous urticaria, and its association with both IL-5 and anti-IL-5 treatment options. We then review the current literature on these diseases, explain where appropriate potential reasons why anti-IL-5 treatments are ineffective, and then point out possible future directions for further research.

β-Lactoglobulin (βLG) is a major allergen in bovine milk protein. This study was designed to investigate changes in βLG structure, digestibility, and allergenicity induced by covalent binding modification with different contents of (-)-epigallocatechin 3-gallate (EGCG). The reaction of EGCG conjugation with βLG reached saturation at a molar ratio of 1:60 βLG:EGCG. Conjugation with EGCG altered the βLG structure, decreased IgE-binding capacity, and increased digestibility in a dose-dependent manner. In vivo studies showed that covalent conjugation with EGCG can reduce βLG-induced allergic symptoms with reducing levels of IgE, histamine, and mast cell protease-1 (mMCP-1) and the percentage of sensitized mast cells. Allergenicity was reduced more effectively in saturated βLG-EGCG conjugates compared to semisaturated conjugates. Observed changes in IFN-γ, IL-4, IL-5, IL-10, and TGF-β levels suggested that βLG-EGCG conjugates were able to promote Th1/Th2 immune balance. These findings further our understanding of the relationship between the degree of polyphenol conjugation and the allergenicity of food allergens.

UNASSIGNED: Chronic rhinosinusitis (CRS) endotypes have demonstrated clinical value in guiding treatment decisions. Bacterial lysates are immunomodulators that have shown beneficial effects in various respiratory inflammatory diseases. This study aimed to evaluate the effect of postoperative bacterial lysate therapy on different CRS endotypes.
UNASSIGNED: Patients diagnosed with CRS who underwent endoscopic sinus surgery were recruited. Bacterial lysates were administered postoperatively for 10 days per month for 3 months to the experimental group comprising patients with a history of frequent upper respiratory infections without adverse reactions. The remaining participants were allocated to the control group. The results of the postoperative 3-, 6-, and 12-month assessments, including the modified Lund-Kennedy (mLK) endoscopic and Sinonasal Outcome Test (SNOT) 22 scores, for the groups were compared. The tissue samples obtained from the participants were evaluated to detect the presence of relevant inflammatory mediators.
UNASSIGNED: Among the 92 participants, 47 started bacterial lysate therapy 2 weeks after the surgery. The tissue cytokine profiles and clinical parameters, such as the disease severity and blood eosinophil percentage, of the bacterial lysate and control groups were comparable before treatment. The mLK endoscopic and SNOT-22 scores did not differ after 3, 6, and 12 months of follow-up. The subgroup analysis revealed that the bacterial lysate group had significantly lower mLK endoscopic scores than the control group for CRS without nasal polyps, while there was a tendency toward significance for the interleukin (IL)-5 negative group after 6 months.
UNASSIGNED: Postoperative bacterial lysate therapy has some beneficial effects on the endoscopic findings of patients with CRS without nasal polyps or those who are negative for IL-5.

BACKGROUND: Gene expression can provide distinct information compared to clinical biomarkers in the context of longitudinal clinical outcomes in asthma patients.
OBJECTIVE: This study examined the association between the gene expression levels of upstream (IL-25, IL-33, and TSLP) and downstream cytokines (IL-5, IL-4, and IL-13) in the T2 inflammatory pathway with a 12-month follow-up of exacerbation, lung function, and steroid use.
METHODS: Transcriptomic sequencing analysis was performed on peripheral blood mononuclear cells from 279 adult asthmatics. Survival analysis and linear mixed-effect models were used to investigate potential differences between the high-level and low-level gene expression groups and the clinical outcomes. Analysis was performed separately for the upstream, downstream, and all 6 cytokines.
RESULTS: In general, T2 inflammatory cytokine gene expression showed a weak correlation with blood eosinophil counts (all r < 0.1) and clinical outcomes. Among moderate-to-severe eosinophilic asthma (MSEA) patients, individuals with elevated levels of downstream cytokines were at increased risk of time-to-first exacerbation (p = 0.044) and a greater increase of inhaled corticosteroid use over time (p = 0.002) compared to those with lower gene expression. There was no association between baseline T2 inflammatory cytokine gene expression and the longitudinal changes in lung function over time among MSEA patients.
CONCLUSIONS: These findings suggest that, among MSEA patients, the gene expression levels of downstream cytokines in the T2 inflammatory pathway may serve as indicators for endotyping asthma.

Dupilumab is a monoclonal antibody approved for the treatment of atopic dermatitis (AD); however, its effects on molecular, cellular, and immunological levels remain to be elucidated. In this study, blood and dermal interstitial fluid (ISF) from nonlesional (NL) and lesional (L) skin were collected from eight patients with moderate to severe AD, before (visit 2-v2) and at the end of a 16-week treatment with dupilumab (visit 10-v10). Clinical treatment effect was demonstrated by significantly decreased AD severity scores at the end of treatment. At v10 versus v2, the percentages of CD4+ interleukin-producing cells showed a decreasing trend in ISF L and NL, unbound IL-4 levels in plasma were increased, IL-5 levels in ISF L reduced, and levels of factors involved in anti-inflammatory pathways and re-epithelization increased. At v2, ISF L showed that AD lesions might have altered amino acid pathways and lipid signaling compared to ISF NL. At v10, ISF L exhibited raised levels of long- and very-long-chain fatty acids and lipids compared to v2. Furthermore, dupilumab administration caused reduced expression of miR-155-5p and miR-378a-3p in ISF L. In conclusion, results from the present study provided novel knowledge by linking local immune and metabolic alterations to AD pathogenesis and treatment response.

Interleukin-5 (IL-5) has been reported to be involved in cardiovascular diseases, such as atherosclerosis and cardiac injury. This study aimed to investigate the effects of IL-5 on cardiac remodelling. Mice were infused with angiotensin II (Ang II), and the expression and source of cardiac IL-5 were analysed. The results showed that cardiac IL-5 expression was time- and dose-dependently decreased after Ang II infusion, and was mainly derived from cardiac macrophages. Additionally, IL-5-knockout (IL-5-/-) mice were used to observe the effects of IL-5 knockout on Ang II-induced cardiac remodelling. We found knockout of IL-5 significantly increased the expression of cardiac hypertrophy markers, elevated myocardial cell cross-sectional areas and worsened cardiac dysfunction in Ang II-infused mice. IL-5 deletion also promoted M2 macrophage differentiation and exacerbated cardiac fibrosis. Furthermore, the effects of IL-5 deletion on cardiac remodelling was detected after the STAT3 pathway was inhibited by S31-201. The effects of IL-5 on cardiac remodelling and M2 macrophage differentiation were reversed by S31-201. Finally, the effects of IL-5 on macrophage differentiation and macrophage-related cardiac hypertrophy and fibrosis were analysed in vitro. IL-5 knockout significantly increased the Ang II-induced mRNA expression of cardiac hypertrophy markers in myocardial cells that were co-cultured with macrophages, and this effect was reversed by S31-201. Similar trends in the mRNA levels of fibrosis markers were observed when cardiac fibroblasts and macrophages were co-cultured. In conclusions, IL-5 deficiency promote the differentiation of M2 macrophages by activating the STAT3 pathway, thereby exacerbating cardiac remodelling in Ang II-infused mice. IL-5 may be a potential target for the clinical prevention of cardiac remodelling.