Role of epithelial interleukin-8 (IL-8) and neutrophil IL-8 receptor A in Escherichia coli-induced transuroepithelial neutrophil migration.

Escherichia coli stimulates neutrophil migration across human uroepithelial cell layers. This study investigated the role of the neutrophil chemokine interleukin-8 (IL-8) in this process. E. coli and IL-1alpha stimulated urinary tract epithelial layers to secrete IL-8 and induced transepithelial neutrophil migration. Anti-IL-8 antibody reduced neutrophil migration across epithelial cell layers, indicating a central role for this chemokine in the migration process. Furthermore, addition of recombinant IL-8 to unstimulated cell layers was sufficient to induce migration. The IL-8 dependence of neutrophil migration was maintained after removal of soluble IL-8 by washing of the cell layers. Flow cytometry analysis with fluorescein isothiocyanate-labelled IL-8 confirmed IL-8's ability to bind to the epithelial cell surface. Indirect immunofluorescence with confocal laser scanning microscopy showed that IL-8 associated with the epithelial cell layers. Prior incubation of neutrophils with antibodies to IL-8 receptor A (IL-8RA) reduced neutrophil migration. Anti-IL-8 RB antibody had no effect on neutrophil migration. These results demonstrate that IL-8 plays a key role in E. coli- or IL-1alpha-induced transuroepithelial migration and suggest that epithelial cell-produced IL-8 interacts with IL-8RA on the neutrophil surface.     

Th17细胞及白细胞介素17A在慢性气道炎症性疾病中的作用

长期以来,人们对于T淋巴细胞的研究集中在辅助性T细胞1型、2型(Th1、Th2)、调节性T细胞(Treg)以及细胞毒性T细胞(Tc)等亚群上。传统理论认为,Th1细胞介导细胞免疫,在抗胞内菌感染的过程中发挥作用;而Th2细胞介导体液免疫,与过敏性疾病以及抗寄生虫感染的过程紧密相关。Th1/Th2失衡被认为是许多疾病产生和发展的重要因素。     

Role of the upper airways in patients with chronic cough

PURPOSE OF THE REVIEW: Chronic cough can be caused by a number of factors, including infections, rhinosinusitis, asthma and environmental stimuli. This paper reviews recent findings and opinions regarding the role played by the upper airways in chronic cough. RECENT FINDINGS: Chronic cough has a significant impact on quality of life, which is more pronounced in women. In Western countries, the reported occurrence of rhinosinusitis in patient groups with chronic cough ranges from 8% to 81%. Allergic rhinitis is a risk factor for later development of asthma. In children, bronchiectasis is combined with upper airway abnormalities in the majority of cases. Increased expression of the capsaicin receptor subtype named 'transient receptor potential vanilloid-1', which correlates with capsaicin cough response, has been identified in patients with chronic cough. Patients with airway chemical sensitivity and chronic cough as one symptom have augmented capsaicin cough sensitivity that is related to changed levels of nerve growth factor in nasal lavage. SUMMARY: Involvement of the upper airways in chronic cough has been confirmed in several studies. However, there are considerable differences between different health centres in the occurrence of rhinosinusitis as a cause of chronic cough. In patients with chronic cough of various causes, a neurochemical alteration in both the upper and the lower airways appears to have taken place, followed by increased cough sensitivity.     

血清IL-6、IL-8在急性心肌梗死缺血-再灌注过程中的动态变化及其临床意义

目的 :探讨血清IL 6、IL 8在急性心肌梗死 (AMI)早期及溶栓治疗过程中的动态变化及其意义。方法 :采用放射免疫分析法对 30例AMI患者入院当时、溶栓前及溶栓后不同时间点的血清IL 6、IL 8进行检测 ,分析其与心肌缺血 再灌注间的关系。结果 :与健康对照组相比 ,所有AMI患者的IL 6、IL 8水平于入院时即已开始升高 ,溶栓治疗后继续升高 ,其中IL 6高峰期在溶栓后 12～ 2 4小时 ,IL 8在 4～ 8小时 ;溶栓再通组升高更明显 (P <0 0 5 ) ;伴有心源性休克 ,急性心力衰竭及严重心律失常并发症的AMI患者较无并发症者增高明显 (P <0 0 5 )。结论 :观察细胞因子IL 6、IL 8动态变化规律有助于判定AMI病情及估价溶栓治疗效果。     

Urinary 8-hydroxy-2'-deoxyguanosin (8-OHdG) in patients with chronic liver diseases

Urinary 8-hydroxy-2'-deoxyguanosin(8-OHdG) has been reported as sensitive biomarker of oxidative DNA damage and also of oxidative stress. We measured the urinary 8-OHdG in patients with chronic liver diseases by competitive ELISA, and analyzed the relationship with clinical characteristics. Fifty patients (male/female: 22/28) with chronic liver disease were enrolled this study. The mean concentration of urinary 8-OHdG in healthy control and patients with liver cirrhosis, chronic hepatitis C, chronic hepatitis B, and autoimmune hepatitis were 10.40+/-3.14, 10.14+/-4.19, 11.79+/-5.58, 14.99+/-4.46, and 13.64+/-3.84 microg/gCr, respectively. There were no significant differences among the five group. The mean concentration of urinary 8-OHdG in inveterate drinker was significantly higher than that in non-drinker (16.67+/-4.29 vs. 11.19+/-4.80 microg/gCr, p<0.05). The smoking enhanced the elevation of urinary 8-OHdG in drinkers. In clinical characteristics, serum y-GTP, a marker of alcoholic liver disease, had significant positive correlation with urinary 8-OHdG on the drinker with chronic hepatitis. In addition, there was a positive correlation between serum ferritin levels and urinary 8-OHdG levels. Iron in the liver suggested oxidative damage of hepatocytes through the fenton reaction in patients with chronic liver disease. In conclusion, drinking and smoking induced liver damage by oxidative stress, and urinary 8-OHdG may be reliable marker of oxidative stress in patients with chronic liver disease.     

An immunohistochemical study of interleukin-8 (IL-8) in breast cancer

The use of prognostic markers for breast cancer is important for routine diagnosis and research. Interleukin-8 is a chemotactic cytokine produced by several cell types in response to inflammation, however, its expression, regulation and function are poorly understood. Recent studies have associated angiogenesis and inflammatory processes with tumor malignancy. The present study investigated the correlation between interleukin-8 expression and breast cancer prognosis. Interleukin-8 expression was assessed in 72 women with mammary neoplasia by immunohistochemistry and the results were statistically correlated with clinical-pathological findings. There was an inverse correlation between interleukin-8 expression and metastasis (p = 0.03) and/or local recurrence (p = 0.02). In the patient group that received post-surgery chemotherapy and radiotherapy, a lower interleukin-8 expression was found in those women that showed local recurrence (p = 0.01). Multivariate logistic regression showed estrogen receptor negativity, progesterone positivity and metastasis with increased risk of death (p < 0.05). The data reflect the complexity of the role of interleukin-8 in tumor microenvironment and support its classification as a possible prognostic marker, although more studies are necessary for its inclusion in clinical practice.     

Influence of cetirizine and loratadine on granulocyte-macrophage colony-stimulating factor and interleukin-8 release in A549 human airway epithelial cells stimulated with interleukin-1beta.

BACKGROUND AND PURPOSE: In addition to being antagonists of histamine receptors, some antihistamines modulate the pathogenesis of allergic inflammation by reducing mediator release, adhesion molecule expression and, consequently, recruitment of inflammatory cells. The aim of this study was to explore the effects of 2 second-generation antihistamines, cetirizine and loratadine, on granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-8 (IL-8) secretions in human airway epithelial cells. METHODS: A549 cells were pre-incubated with cetirizine (1, 5, 10 microM) or loratadine (1 microM) individually for 16 h followed by stimulation with IL-1beta for 8 h. The levels of GM-CSF and IL-8 were measured by an enzyme-linked immunosorbant assay. RESULTS: Cetirizine (10 microM) and loratadine significantly reduced the release of GM-CSF, by 37% and 40%, respectively (p<0.05). Cetirizine (5, 10 microM) inhibited the production of IL-8 by 19% (p<0.05). However, cetirizine (1 microM) and loratadine (1 microM) did not appreciably inhibit IL-8 release. CONCLUSIONS: These observations indicate that these 2 second-generation antihistamines inhibit the release of GM-CSF and IL-8 beyond their antagonistic histamine H1 receptor activity and may thus exert clinically relevant anti-inflammatory effects in inflammatory airway disorders.     

Vibration enhances interleukin-8 release in a cell model of snoring-induced airway inflammation

STUDY OBJECTIVES: To test a cell model of snoring-induced airway inflammation and to assess whether a vibration stimulus simulating the one experienced by airway tissues in snoring patients induces inflammation in airway epithelial cells. DESIGN: Prospective controlled study in cell culture. SETTING: University laboratory. PATIENTS OR PARTICIPANTS: Human bronchial epithelial cells (BEAS-2B cell line). INTERVENTIONS: Cell cultures were subjected to vibration (60 Hz, +/- 0.3 mm) for time periods of 6 hours, 12 hours, and 24 hours. The vibratory stimulus was applied with and without treatment with inhibitors of the 3 main pathways of mitogen-activated protein kinases (MAPK): p38, MEK1/2, and JNK. MEASUREMENTS AND RESULTS: The effect of vibration was assessed by comparing cell proliferation and release of interleukin-8 (IL-8; measured by enzyme-linked immunosorbent assay) in cells subjected to the vibratory stimulus (both when treated and untreated with MAPK inhibitors) and in controls. Application of vibration up to 24 hours did not significantly modify cell proliferation. By contrast, the concentration of IL-8 in the supernatant was significantly increased after 12 hours and 24 hours of vibration. The inhibition of the p38, MEK1/2, and JNK MAPK pathways significantly reduced the overexpression of IL-8 resulting from the vibration stimulus. CONCLUSIONS: A mechanical vibration simulating snoring triggered an inflammatory cascade, as reflected by the increase in IL-8 release mediated by MAPK pathways. The novel model developed is potentially applicable to studying the effects of the vibration due to snoring in the different cell types (epithelial, endothelial, muscular, neuronal) involved in airway pathophysiology during respiratory sleep disturbances.     

Dissociation of cell-associated interleukin-1 (IL-1) and IL-1 release induced by lipopolysaccharide and lipid A.

The capacities of lipopolysaccharide (LPS) and lipid A to trigger mouse BALB/c peritoneal macrophages and to induce the production of cell-associated interleukin-1 (IL-1) and membrane-associated IL-1 and IL-1 release have been compared. Bordetella pertussis lipid A was 1,000 to 10,000 times less efficient than the native LPS to induce IL-1 release by freshly isolated elicited macrophages. When resident macrophages were studied, lipid A, at high concentrations (greater than 2 micrograms/ml), induced significant levels of cell-associated IL-1 but little or no IL-1 release. With synthetic lipid A built up with the Escherichia coli lipid A structure (compound 506), IL-1 activity was present in the supernatants of elicited peritoneal macrophages and to a lesser extent in those of resident macrophages. However, the release of IL-1 induced by synthetic lipid A 506 remained much lower than those induced by rough LPS. Membrane-associated IL-1 could be induced on BALB/c macrophages with LPS and natural or synthetic lipid A, the LPS being the most active. In C3H/HeJ mice, neither natural nor synthetic lipid A could induce detectable cell-associated IL-1, whereas LPS could induce cell-associated and membrane IL-1 activity but no IL-1 release. Our results indicate that fragments of endotoxins may induce the production of IL-1 but the entire structure of the LPS molecule is the most effective to induce intracellular IL-1 production, expression of membrane IL-1, and release of IL-1.     

Role of PAF in zymosan-induced IL-8 release from human neutrophils

Stimulation of human neutrophils with zymosan particles resulted in a dose-response release of IL-8 in the 24 h culture supernatant, measured using a specific radioimmunoassay. IL-8 was detected after 8 h (0.11±0.08 nM) and peaked at 24 h (2.81±0.85 nM). Two distinct PAF receptor antagonists, WEB 2086 and UK 74505 produced a dose-dependent inhibition of zymosan-induced IL-8 release. This inhibitory action was maximal (68% 10⁻⁶ M WEB 2086; 71% 10⁻⁸ M UK 74505) when the drug was co-administered with zymosan, becoming progressively less effective when administered at increasing intervals after addition of zymosan. In contrast, a specific LTB₄ antagonist, LY 255283, an IL-1 receptor antagonist and an anti-human TNFα antibody were unable to modulate the response indicating that these mediators are not involved. This study provides the first direct evidence of a central role for the phospholipid mediator PAF in the pathway of IL-8 release, following neutrophil activation by a particulate stimulusin vitro.

     

Role of interleukin-18 (IL-18) in mycobacterial infection in IL-18-gene-disrupted mice

Immunity to mycobacterial infection is closely linked to the emergence of T cells that secrete cytokines, gamma interferon (IFN-gamma), interleukin-12 (IL-12), and tumor necrosis factor alpha (TNF-alpha), resulting in macrophage activation and recruitment of circulating monocytes to initiate chronic granuloma formation. The cytokine that mediates macrophage activation is IFN-gamma, and, like IL-12, IL-18 was shown to activate Th1 cells and induce IFN-gamma production by these cells. In order to investigate the role of IL-18 in mycobacterial infection, IL-18-deficient mice were infected with Mycobacterium tuberculosis and Mycobacterium bovis BCG Pasteur, and their capacities to control bacterial growth, granuloma formation, cytokine secretion, and NO production were examined. These mice developed marked granulomatous, but not necrotic, lesions in their lungs and spleens. Compared with the levels in wild-type mice, the splenic IFN-gamma levels were low but the IL-12 levels were normal in IL-18-deficient mice. The reduced IFN-gamma production was not secondary to reduced induction of IL-12 production. The levels of NO production by peritoneal macrophages of IL-18-deficient and wild-type mice did not differ significantly. Granulomatous lesion development by IL-18-deficient mice was inhibited significantly by treatment with exogenous recombinant IL-18. Therefore, IL-18 is important for the generation of protective immunity to mycobacteria, and its main function is the induction of IFN-gamma expression.     

Ethnic differences in plasma levels of interleukin-8 (IL-8) and granulocyte colony stimulating factor (G-CSF)

Ethnic neutropenia is common in people of African descent. As interleukin-8 (IL-8) and granulocyte colony stimulating factor (G-CSF) bind to receptors on neutrophils, ethnic differences in neutrophil counts are hypothesized to result in different plasma levels of these cytokines. A prospective study was conducted in 72 healthy young volunteers. Neutrophil counts were 60% higher in Caucasians (P<0.00001). Average IL-8 and G-CSF levels were about 50% and 70% higher in African volunteers compared with Caucasian volunteers (P=0.0008 and P=0.00005, respectively). Additionally, oxidative burst capacity in stimulated neutrophils was significantly lower in volunteers of African descent (P=0.03 between both groups). In sum, lower neutrophil counts are associated with higher levels of IL-8 and G-CSF in Africans.     

Simulation of the effect of airway disease on respiratory airways

Airway disease such as tumours and asthma lead to lung injuries. Therefore, a better understanding of airway mechanics parameters is very important to avoid lung injuries in patients undergoing mechanical ventilation for treatment of respiratory problems in intensive-care medicine as well as pulmonary medicine. The objective of this study was to investigate the role of airway diseases such as asthma and tumours on airway mechanics parameters using coupled fluid–solid computational analysis. The results obtained indicate that both tumours and asthma greatly affect the airway mechanics parameters (airflow velocity increased by about 15% and the strains increased by about 40%). Strain results of this study highlight significant changes in levels of airway parameters, which may translate into higher health risk associated with airway tumours and the asthmatic airways. These results combined with optimization suggest that it is possible to develop mechanical ventilation protocols to avoid lung injuries in patients.     

Simulation of the effect of airway disease on respiratory airways

Airway disease such as tumours and asthma lead to lung injuries. Therefore, a better understanding of airway mechanics parameters is very important to avoid lung injuries in patients undergoing mechanical ventilation for treatment of respiratory problems in intensive-care medicine as well as pulmonary medicine. The objective of this study was to investigate the role of airway diseases such as asthma and tumours on airway mechanics parameters using coupled fluid-solid computational analysis. The results obtained indicate that both tumours and asthma greatly affect the airway mechanics parameters (airflow velocity increased by about 15% and the strains increased by about 40%). Strain results of this study highlight significant changes in levels of airway parameters, which may translate into higher health risk associated with airway tumours and the asthmatic airways. These results combined with optimization suggest that it is possible to develop mechanical ventilation protocols to avoid lung injuries in patients.     

Downmodulation of CXCL8/IL-8 receptors on neutrophils after recruitment in the airways

BACKGROUND: CXCL8/IL-8 is the most significant chemokine for neutrophils, and CXC chemokine receptor (CXCR) 1 and 2 are its 2 receptors, which are downmodulated by CXCL8/IL-8 and endotoxin on activated neutrophils. OBJECTIVE: We sought to evaluate the expression of the CXCL8/IL-8 receptors and the activation marker CD11b on neutrophils in peripheral blood and in the site of airway inflammation. METHODS: The flow cytometric expression of CXCR1, CXCR2, and CD11b was evaluated on peripheral blood and induced sputum neutrophils in patients with nonsevere asthma with greater than 60% sputum neutrophils, in patients with chronic obstructive pulmonary disease (COPD), and in healthy control subjects. RESULTS: Asthmatic patients and patients with COPD had comparable expressions of CXCR1, CXCR2, and CD11b on peripheral blood and sputum neutrophils. Compared with control subjects, the peripheral neutrophil expression of CXCR2 was lower in patients with COPD ( P = .03) and that of CD11b was higher in asthmatic patients and patients with COPD ( P < .02 and P < .002). The expression of the CXCL8/IL-8 receptors on sputum neutrophils was markedly lower than on peripheral blood neutrophils ( P < .0001). The downmodulation of CXCL8/IL-8 receptors was also present in healthy control subjects but less than that seen in asthmatic patients. The difference between peripheral blood and sputum expression of CXCL8/IL-8 receptors correlated with serum CXCL8/IL-8 levels. In asthmatic patients the expression of CXCR1 and CXCR2 on sputum neutrophils negatively correlated with sputum neutrophils. CONCLUSION: In neutrophilic asthma the expression of CXCL8/IL-8 receptors on peripheral and sputum neutrophils is similar to COPD and negatively correlated with the inflammatory infiltrate in the airways. The downmodulation of CXCL8/IL-8 receptors detected in the airways should be taken into account for an eventual therapeutic inhibition of these receptors.     

Particle-epithelial interaction: effect of priming and bystander neutrophils on interleukin-8 release

Exposure to ambient air pollution particles causes greater health effects in individuals with preexisting inflammatory lung diseases. To model inflammatory priming in vitro, HTB54 lung epithelial cells were pretreated with tumor necrosis factor-alpha (TNF-alpha) and then exposed to a panel of environmental particles, including concentrated ambient particles (CAPs). TNF-alpha priming significantly enhanced interleukin (IL)-8 secretion in response to CAPs and other urban air particles in HTB54 cells. Enhancement was seen with whole CAP suspensions as well as with its separate water-soluble and -insoluble components. Treating CAP suspensions with 20 microM deferoxamine or 2 mM dimethylthiourea attenuated the enhancement, indicating that transition metals and oxidative stress participate in the CAPs-dependent IL-8 response of primed cells. Because activated neutrophils are also present in diseased lungs and are sources of additional oxidative stress on epithelial cells, primed HTB54 cells were cocultured with activated neutrophils. Wild-type neutrophils markedly enhanced IL-8 release to CAPs in primed HTB54 cells, an effect substantially diminished when neutrophils from NADPH knockout mice were used. Cytokine priming and interactions with activated neutrophils can amplify lung epithelial inflammatory responses to ambient air particles.