interleukin-8 and Bronchiolitis

Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in young infants. However, it is also a significant pathogen in older adults. Validated biomarkers of RSV disease severity would benefit diagnostics, treatment decisions, and prophylactic interventions. This review summarizes knowledge of biomarkers for RSV disease in adults.. A literature review was performed using Ovid Medline, Embase, Global health, Scopus, and Web of Science for articles published 1946-October 2016. Nine articles were identified plus 9 from other sources.. From observational studies of natural infection and challenge studies in volunteers, biomarkers of RSV susceptibility or disease severity in adults were: (1) lower anti-RSV neutralizing antibodies, where neutralizing antibody (and local IgA) may be a correlate of susceptibility/severity; (2) RSV-specific CD8+ T cells in bronchoalveolar lavage fluid preinfection (subjects with higher levels had less severe illness); and (3) elevated interleukin-6 (IL-6), IL-8, and myeloperoxidase levels in the airway are indicative of severe infection.. Factors determining susceptibility to and severity of RSV disease in adults have not been well defined. Respiratory mucosal antibodies and CD8+ T cells appear to contribute to preventing infection and modulation of disease severity. Studies of RSV pathogenesis in at-risk populations are needed.

Topics: Antibodies, Neutralizing; Biomarkers; Bronchiolitis; CD8-Positive T-Lymphocytes; Humans; Immunity, Cellular; Inflammation; Interleukin-6; Interleukin-8; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human; Severity of Illness Index; Viral Load

Infants with the respiratory syncytial virus (RSV) and human rhinovirus respiratory infection (HRV) produce inflammatory interleukins (ILs) in the respiratory epithelium. The aim of this study was to evaluate the levels of interleukin-8 in RSV negative and RSV positive patients. This study search was conducted without a time limit until 2020 through the databases of PubMed, Wiley, Springer, ScienceDirect and Google Scholar search engines, by two researchers independently. The random-effects model was used to compare of interleukin-8 in RSV negative vs. RSV positive patients, using Revman software version 5 meta-analysis software. Totally, 921 patients were evaluated (207 RSV-negative and 714 RSV-positive). The mean concentration of IL8 in RSV positive patients was 15.02 pg/ml (95% CI: 13.68- 16.35%).  According to the meta-analysis results, the standardized mean difference (SMD) of IL8 concentration between RSV-positive and negative patients was 6.31 pg/ml) (95% confidence interval: 2.50- 10.13%). subtotal analysis of the IL8 laboratory assessment method revealed that there was no significant SMD deference in the studies that have used chemiluminescence (P=0.21). while IL8 concentrations were significantly higher in RSV positives in ELISA and Magnetic bead-based assays (P<0.05).  It appears that RSV positive patients may have greater levels of IL8 than RSV negative ones; whereas the synthesis of IL8 tends to be more secreted into the nasopharyngeal space; whereas the evaluation approach can also affect the results.

Topics: Bronchiolitis; Databases, Factual; Enzyme-Linked Immunosorbent Assay; Humans; Interleukin-8; Luminescent Measurements; Nasopharynx; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human

Macrolides may attenuate airway inflammation of bronchiolitis with anti-inflammatory and antiviral effects. However, the potential mechanisms of action underlying the efficiency of macrolides in treating bronchiolitis are limited. Therefore, we performed a meta-analysis to assess the effects of macrolides on airway microbiome and cytokine of children with bronchiolitis. PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched until May 2018. The reference lists of included studies and pertinent reviews were investigated for supplementing our search. Randomized controlled trials (RCTs) that compared macrolides with placebo assessing the change of microbiome in airway and cytokine were included. A total of four RCTs were included in this review. Data analysis showed no significant reduction of viruses at 48 hr after azithromycin treatment (p = 0.41). There were significant reductions in Streptococcus pneumoniae (risk ratio [RR] 0.28, 95% confidence interval (CI) 0.14 to 0.6, p < 0.01), Haemophilus influenza (RR 0.35, 95% CI 0.2 to 0.62, p < 0.01), and Moraxella catarrhalis (RR 0.29, 95% CI 0.17 to 0.5, p < 0.01), but no significant reduction of Staphylococcus aureus (p = 0.28) following treatment with macrolides. There was a significant decrease in the serum interleukin-8(IL-8), interleukin-4(IL-4), and eotaxin levels following 3 weeks of clarithromycin therapy. There was no significant difference in the serum IL-8 level at Day 15 after the intervention between the azithromycin and control groups; however, a significant reduction of nasal lavage IL-8 level was found. The macrolides may reduce the IL-8 levels in the airway and plasma, but failed to demonstrate an antiviral effect in children with bronchiolitis.

Topics: Anti-Bacterial Agents; Azithromycin; Bronchiolitis; Cytokines; Databases, Factual; Haemophilus influenzae; Humans; Infant; Interleukin-4; Interleukin-8; Macrolides; Microbiota; Moraxella; Respiratory System; Staphylococcus aureus; Streptococcus pneumoniae

Topics: Anti-Bacterial Agents; Bronchiolitis; Cell Division; Erythromycin; Humans; Interleukin-8; Lymphocytes; Macrophage Activation; Neutrophils; Prognosis

We aimed to use serum metabolomics to discriminate infants with severe respiratory syncytial virus (RSV) bronchiolitis who later developed subsequent recurrent wheezing from those who did not and to investigate the relationship between serum metabolome and host immune responses with regard to the subsequent development of recurrent wheezing. Fifty-one infants who were hospitalized during an initial episode of severe RSV bronchiolitis at 6 months of age or less were included and followed for up to the age of 3 years. Of them, 24 developed subsequent recurrent wheezing and 27 did not. Untargeted serum metabolomics was performed by ultraperformance liquid chromatography coupled with high-resolution mass spectrometry (UPLC-MS/MS). Cytokines were measured by multiplex immunoassay. Difference in serum metabolomic profiles was observed between infants who developed recurrent wheezing and those who did not. L-lactic acid level was significantly higher in infants with recurrent wheezing than those without. Pyrimidine metabolism, glycerophospholipid metabolism, and arginine biosynthesis were identified as the most significant changed pathways between the two groups. Moreover, L-lactic acid level was positively associated with serum CXCL8 level. This exploratory study showed that differential serum metabolic signatures during severe RSV bronchiolitis in early infancy were associated with the development of subsequent recurrent wheezing in later childhood.

Topics: Bronchiolitis; Child, Preschool; Chromatography, High Pressure Liquid; Cytokines; Female; Follow-Up Studies; Humans; Infant; Interleukin-8; Lactic Acid; Male; Metabolomics; Pyrimidines; Respiratory Sounds; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Serum; Tandem Mass Spectrometry

Early interactions between respiratory viruses and microbiota might modulate host immune responses and subsequently contribute to later development of recurrent wheezing and asthma in childhood. We aimed to study the possible association between respiratory microbiome, host immune response, and the development of recurrent wheezing in infants with severe respiratory syncytial virus (RSV) bronchiolitis.. Seventy-four infants who were hospitalized at Beijing Children's Hospital during an initial episode of severe RSV bronchiolitis at 6 months of age or less were included and followed up until the age of 3 years. Sputum samples were collected, and their microbiota profiles, LPS, and cytokines were analyzed by 16S rRNA-based sequencing, ELISA, and multiplex immunoassay, respectively.. Twenty-six (35.1%) infants developed recurrent wheezing by the age of 3 years, and 48 (64.9%) did not. The relative abundance of Haemophilus, Moraxella, and Klebsiella was higher in infants who later developed recurrent wheezing than in those who did not (LDA score >3.5). Airway levels of LPS (P = .003), CXCL8 (P = .004), CCL5 (P = .029), IL-6 (P = .004), and IL-13 (P < .001) were significantly higher in infants who later developed recurrent wheezing than in those who did not. Moreover, high airway abundance of Haemophilus was associated with CXCL8 (r = 0.246, P = .037) level, and that of Moraxella was associated with IL-6 level (r = 0.236, P = .046) and IL-10 level (r = 0.266, P = .024).. Our study suggests that higher abundance of Haemophilus and Moraxella in airway microbiome might modulate airway inflammation during severe RSV bronchiolitis in infancy, potentially contributing to the development of subsequent recurrent wheezing in later childhood.

Topics: Asthma; Beijing; Bronchiolitis; Child, Preschool; Female; Humans; Immunity; Infant; Interleukin-10; Interleukin-13; Interleukin-8; Male; Microbiota; Prospective Studies; Recurrence; Respiratory Sounds; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Respiratory System; RNA, Ribosomal, 16S; Sputum

Hospitalization with bronchiolitis is linked to the development of early childhood chronic wheeze and asthma. Viral etiology and severity of inflammation are potential contributing factors. Previously we observed reduced airway neutrophil infiltration in breastfed bronchiolitic infants, with a corresponding reduction in disease severity. This study aimed to examine whether respiratory viral etiology and co-infection alters the pattern of neutrophil influx, and the inflammatory mediator profile, resulting in epithelial damage in bronchiolitis.. Nasopharyngeal aspirates (NPAs) collected from hospitalized infants were assessed for viruses, soluble protein, cellular infiltrate, interleukin (IL)-6, -8, and myeloperoxidase (MPO).. NPAs were collected from 228 bronchiolitic and 14 non-bronchiolitic infants. In the bronchiolitic cohort, human rhinovirus was most prevalent (38%), followed by respiratory syncytial virus (36%), adenovirus (10%), and human metapneumovirus (6%), with 25% positive for viral co-infections and 25% negative for all screened viruses. Viral-induced bronchiolitis was associated with increased cellular infiltrate and protein, above control, and virus-negative infants (P < 0.05). Cellular infiltrate correlated to IL-6, -8, and MPO (r = 0.331, 0.669, and 0.661; P < 0.01). Protein, IL-6, -8, and MPO differed significantly between viral groups; however, the majority of marker values for all groups fall within an overlapping, indistinguishable range, precluding their use as biomarkers of viral etiology. No significant difference was found between single and viral co-infections for any parameter.. Bronchiolitic infants presenting with a detectable respiratory virus during hospitalization demonstrated elevated markers of airway tissue inflammation and injury. In this cohort, viral etiology did not discernibly modulate chemokine-mediated neutrophil infiltration and activation. Pediatr Pulmonol. 2017;52:238-246. © 2016 Wiley Periodicals, Inc.

Topics: Adenoviridae; Adenoviridae Infections; Breast Feeding; Bronchiolitis; Bronchiolitis, Viral; Coinfection; Female; Humans; Immunoassay; Infant; Inflammation; Interleukin-6; Interleukin-8; Male; Metapneumovirus; Nasopharynx; Neutrophil Infiltration; Neutrophils; Paramyxoviridae Infections; Peroxidase; Picornaviridae Infections; Polymerase Chain Reaction; Respiratory Sounds; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Rhinovirus; Severity of Illness Index

Primary respiratory syncytial virus (RSV) infections are characterized by high levels of IL-8 and an intense neutrophilia. Little is known about the cytokine responses in secondary infections. Preschool children experiencing RSV secondary infections were recruited from the siblings of infants admitted to hospital with RSV acute bronchiolitis.. Fifty-one infants with acute bronchiolitis (39 RSV positive, 12 RSV negative) and 20 age-matched control infants were recruited. In addition, seven older siblings of infants from the RSV-positive cohort and confirmed RSV infection were recruited. Samples of nasal secretions were obtained using a flocked swab, and secretions extracted using centrifugation. Cytokine bead array was used to obtain levels of interleukin (IL)-17A, IL-8, IL-6, IL-21, and tumor necrosis factor-α.. Levels of IL-8 and IL-6 were significantly lower in the RSV-positive siblings compared with the RSV-positive infants. There were no significant differences between levels of the other cytokines in the primary and secondary infections.. The very high levels of IL-8 and IL-6 response characteristic of the primary RSV infection was not observed in secondary RSV-positive infections and this did not appear to be due to a global reduction in cytokine production.

Topics: Bronchiolitis; Case-Control Studies; Cohort Studies; Cytokines; Epidemics; Female; Humans; Infant; Infant, Newborn; Interleukin-6; Interleukin-8; Male; Neutrophils; Patient Admission; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Seasons; Siblings

The tobacco smoking habit interferes with the innate host defence system against infections. Recurrent infections accelerated the functional respiratory decline. The present study assessed the effects of ceftaroline on TLR2 and TLR4 and on pro-inflammatory responses in airway epithelial cells (16HBE cell line and primary bronchial epithelial cells) with or without cigarette smoke extracts (CSE 10%). TLR2, TLR4, LPS binding and human beta defensin 2 (HBD2) were assessed by flow cytometry, NFkB nuclear translocation by western blot analysis, IL-8 and HBD2 mRNA by Real Time PCR; the localization of NFkB on the HBD2 and IL-8 promoters by ChiP Assay. CSE increased TLR4, TLR2 expression, LPS binding and IL-8 mRNA; CSE decreased HBD2 (protein and mRNA), activated NFkB and promoted the localization of NFkB on IL-8 promoter and not on HBD2 promoter. Ceftaroline counteracted the CSE effect on TLR2 expression, on LPS binding, on IL-8 mRNA, HBD2 and NFkB in 16HBE. The effects of ceftaroline on HBD2 protein and on IL-8 mRNA were confirmed in primary bronchial epithelial cells. In conclusion, ceftaroline is able to counteract the effects of CSE on the innate immunity and pro-inflammatory responses modulating TLR2, LPS binding, NFkB activation and activity, HBD2 and IL-8 expression in bronchial epithelial cells.

Topics: Active Transport, Cell Nucleus; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; beta-Defensins; Bronchioles; Bronchiolitis; Ceftaroline; Cell Line; Cell Line, Transformed; Cells, Cultured; Cephalosporins; Gene Expression Regulation; Humans; Immunity, Innate; Interleukin-8; Lipopolysaccharides; NF-kappa B; Prodrugs; Promoter Regions, Genetic; Respiratory Mucosa; Tobacco Smoke Pollution; Toll-Like Receptor 2; Toll-Like Receptor 4

To assess whether cumulative dust exposure in foundry work is associated with airway inflammation measured by the analysis of fractionated exhaled nitric oxide (NO) concentration, or by inflammatory markers in exhaled breath condensate or serum.. We examined 476 dust-exposed and nonexposed foundry workers, and assessed the individual cumulative exposure to dusts and respirable quartz. Bronchial and alveolar NO production and inflammatory markers in exhaled breath condensate and in serum samples were also analyzed.. After adjusting for pack-years of smoking, increased levels of alveolar NO, serum C-reactive protein, and interleukin-8 were associated with a higher level of cumulative exposure to dust. The referents had higher serum myeloperoxidase levels, bronchial NO output, and 8-isoprostane levels in exhaled breath condensate than in the dust-exposed groups.. Dust exposure in foundry work may induce both systemic and alveolar inflammation.

Topics: Adult; Biomarkers; Breath Tests; Bronchiolitis; C-Reactive Protein; Cross-Sectional Studies; Dust; Humans; Interleukin-8; Lung Diseases, Interstitial; Male; Metallurgy; Middle Aged; Nitric Oxide; Occupational Exposure

Breastfeeding during the first 12 months of life confers demonstrable immunologic benefit against infective pathogens, including those of the respiratory tract. However, the mechanism by which the ingestion of human milk modifies immunologic defense against such pathogens remains elusive. Bronchiolitis, caused predominantly by respiratory syncytial virus, is the most common clinical presentation of severe upper respiratory illness requiring hospitalization in infants and remains one of the developed world's leading causes of infant mortality and morbidity over both the short and long term. The mechanism by which an early, severe case of bronchiolitis can result in the development of recurrent childhood wheeze or asthma is unclear; however, mucosal inflammation and pulmonary neutrophilia are believed to play a significant role. The aim of this study was to examine the immune response of breastfed infants hospitalized with severe bronchiolitis, compared with formula-fed controls. Nasopharyngeal aspirates (NPA) were collected from 18 infants (aged

Topics: Acute Disease; Breast Feeding; Bronchiolitis; Cell Degranulation; Chemokine CCL2; Disease Progression; Female; Humans; Immunity, Maternally-Acquired; Infant; Infant, Newborn; Interleukin-8; Male; Neutrophils; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Risk Factors; Sputum

alpha-Defensins, antimicrobial peptides produced mainly by neutrophils, have been reported to be associated with a wide variety of lung diseases, including idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF), and diffuse panbronchiolitis (DPB). In each disease, alpha-defensins are located in different areas, such as around the alveolar septa in IPF and around the airways in CF and DPB, suggesting that alpha-defensins play different roles. Meanwhile, growth factors are known to contribute to IPF, CF, and DPB. alpha-Defensins are known to induce interleukin (IL)-8 in airway epithelial cells, but the effects of alpha-defensins on the release of growth factors from various components in the lung have not been sufficiently investigated. In the present study, the in vitro effects of human neutrophil peptide (HNP)-1 (a subtype of alpha-defensin) on the expressions of IL-8 and growth factors in lung fibroblasts, bronchial epithelial cells, and alveolar epithelial cells were examined. HNP-1 mainly enhanced the expression of IL-8 in epithelial cells, whereas it enhanced transforming growth factor-beta and vascular endothelial growth factor expressions in lung fibroblasts. These results suggest that alpha-defensins play different roles in the pathogenesis of IPF, CF, and DPB according to the location in the lung where the alpha-defensins are mainly produced.

Topics: alpha-Defensins; Bronchiolitis; Cells, Cultured; Cystic Fibrosis; Epithelial Cells; Fibroblasts; Haemophilus Infections; Humans; Idiopathic Pulmonary Fibrosis; Interleukin-8; Lung; Transforming Growth Factor beta; Vascular Endothelial Growth Factors

Cigarette smoking causes inflammatory responses in the airways. However, not all smokers exhibit the development of airflow limitation. This study was designed to determine the implications of small airways inflammation in the development of airflow limitation in smokers by our newly explored method. Twenty-eight smokers (15 smokers without airflow limitation and 13 with airflow limitation) were included in this study. Levels of interleukin-8 (IL-8) and 8-isoprostane were measured in epithelial lining fluid (ELF) from central and peripheral airways separately collected using a bronchoscopic microsampling technique. 8-isoprostane levels in ELF from central or peripheral airways did not significantly differ between the two groups. However, these levels were markedly higher in peripheral than in central airways. Similarly, IL-8 levels in ELF from central airways did not significantly differ between the two groups. In smokers without airflow limitation, IL-8 levels were not higher in peripheral than in central airways. In contrast, in smokers with airflow limitation, IL-8 levels were significantly higher in peripheral airways. Moreover, in smokers with airflow limitation, 8-isoprostane levels in central or peripheral airways were not significantly correlated with FEV(1). However, IL-8 levels in peripheral airways were inversely correlated with FEV(1), though those levels in central airways were not. Thus our technique provides a novel method for ELF sampling from central or peripheral airways separately, and the preliminary evidence that support differences in oxidative stress and neutrophil chemotactic stimulus in these two locations.

Topics: Aged; Biomarkers; Bronchi; Bronchioles; Bronchiolitis; Bronchitis; Bronchoscopy; Dinoprost; Extracellular Fluid; Female; Humans; Interleukin-8; Male; Middle Aged; Prospective Studies; Respiratory Mucosa; Smoking; Statistics, Nonparametric

Respiratory syncytial virus (RSV) infects nearly all children under two years of age. It is not understood why some develop serious bronchiolitis. Whether there is a genetic component is not known. The nature of the association between RSV bronchiolitis and subsequent wheezing remains unknown. interleukin-8 (IL-8) is a potent neutrophil chemokine and activator, which plays a role in virus-induced wheezing diseases. The purpose of this study was to assess the genetic association between the IL-8 gene promoter -251A/T polymorphism and RSV bronchiolitis and post-bronchiolitis wheezing in children.. Totally 320 children who were hospitalized for bronchiolitis together with positive immunofluorescence for RSV were recruited in this study from Jan. 2002 to Jan. 2004. A group of 272 healthy children were enrolled as controls. The age of these children ranged from 1 to 12 months. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to identify the polymorphism at position-251 of the IL-8 promoter in RSV bronchiolitis and control groups. The total IL-8 and IgE concentrations in serum samples were measured by enzyme-linked immunosorbent assay (ELISA). The patients with RSV bronchiolitis were followed up in order to analyze the occurrence of wheezing post-bronchiolitis.. (1) Both A allele and T allele were detected at -251 of the IL-8 promoter; the prevalence of the A allele in RSV bronchiolitis group was 45.6%, as compared with 37.7% in normal group. The prevalence of IL-8-251A allele was significantly different between the two groups (P < 0.05). (2) For genotypes T/T, A/T, A/A in RSV bronchiolitis, level of serum IL-8 were (17 +/- 6) ng/L, (21 +/- 7) ng/L, (24 +/- 9) ng/L, respectively, the difference was significant among the three genotypes (P < 0.01). (3) The prevalence of the A allele in the group who wheezed after the episode of RSV bronchiolitis was 54.6%, as compared with 35.8% in the group who had bronchiolitis but did not go on to wheeze. The prevalence of IL-8-251A allele was significantly different between the two groups (P < 0.05).. Polymorphism of IL-8 promoter-251A/T was associated with susceptibility to RSV bronchiolitis in children. The association of IL-8-251A with severe RSV bronchiolitis is most marked in the children who go on to wheeze.

Topics: Adolescent; Alleles; Bronchiolitis; Child; Child, Preschool; Chromosome Mapping; Enzyme-Linked Immunosorbent Assay; Female; Genetic Predisposition to Disease; Genotype; Humans; Infant; Interleukin-8; Male; Polymorphism, Genetic; Respiratory Sounds; Respiratory Syncytial Virus Infections

In this study, we measured the levels of eosinophil cationic protein (ECP) and interleukin (IL)-8 in bronchoalveolar lavage (BAL) fluid from patients with acute asthma and acute bronchiolitis, to determine any similarities or dissimilarities in the profiles of these biochemical markers in the two diseases.. BAL fluids were obtained from children with acute asthma (n=16), infants with acute bronchiolitis caused by respiratory syncytial virus (n=18), and control subjects (n=14). Children with asthma were selected to be free of viral infection. BAL cell counts and differentials were determined, and ECP and IL-8 levels were measured by radioimmunoassay and ELISA, respectively.. ECP levels in BAL fluids were significantly higher in the asthma group than in the bronchiolitis (P<0.01) or control (P<0.0001) groups. However, IL-8 levels were significantly higher in the bronchiolitis group than in the asthma (P<0.01) or control (P<0.001) groups. IL-8 levels in the asthma group and ECP levels in the bronchiolitis group were similar to those of the control group.. This difference in profiles of ECP and IL-8 in acute asthma and acute bronchiolitis, together with a different inflammatory cell pattern, suggests that the nature of the inflammatory process within the lower respiratory tract may be distinctive in these two diseases.

Topics: Acute Disease; Asthma; Bronchiolitis; Bronchoalveolar Lavage Fluid; Bronchoscopy; Child, Preschool; Eosinophil Cationic Protein; Eosinophils; Female; Humans; Interleukin-8; Macrophages; Male; Neutrophils

Long-term macrolide therapy has been proven to improve survival in patients with diffuse panbronchiolitis. Although its mechanisms remain unknown, previous studies have suggested the effects of macrolide might be anti-inflammatory rather than antibacterial. To elucidate the molecular mechanisms of its action, we studied here the effects of erythromycin (EM) and its new derivative, EM703, which shows no antibacterial action, on the activation of the transcription factor nuclear factor-kappaB (NF-kappaB) in human bronchial epithelial cells. Western blotting analysis showed that EM did not inhibit the degradation of IkappaBalpha, suggesting the molecular target for EM was not the dissociation of NF-kappaB from IkappaB. An electrophoretic mobility shift assay showed that EM did not interrupt the NF-kappaB DNA-binding activity in the nucleus under the conditions tested. Moreover, not only EM but also EM703 suppressed the activation of NF-kappaB and the production of interleukin-8, demonstrating that the anti-inflammatory action of the macrolide is independent of its antibacterial activity. Taken together, these data suggest EM has an anti-inflammatory action, presumably via an interaction with the NF-kappaB signaling pathway in the downstream of the dissociation from IkappaB, resulting in the inhibition of NF-kappaB.

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Blotting, Western; Bronchiolitis; Cells, Cultured; Cytokines; DNA; Electrophoretic Mobility Shift Assay; Epithelial Cells; Erythromycin; Humans; Interleukin-8; NF-kappa B; Phosphorylation; Signal Transduction; Transcription Factor AP-1; Tumor Necrosis Factor-alpha

Human T lymphotrophic virus type-I (HTLV-I), a human retrovirus, infects CD4(+) lymphocytes and is thought to modify their function and a possible association with pulmonary diseases has also been suggested. However, little is known about the influence of HTLV-I on diffuse pan-bronchiolitis (DPB), a chronic inflammatory lung disease with infiltration of lymphocytes and hyperplasia of the bronchus-associated lymphoid tissue. In this study, 35 DPB patients with and without HTLV-I infection were examined. HTLV-I positive DPB patients were likely to have a larger affected area with lower FEV(1). The CD3(+)/CD25(+) lymphocyte percentage was significantly higher in the BALF of HTLV-I positive patients than in negative patients. MIP-1 alpha, IP-10 and levels in BALF were also significantly higher in HTLV-I positive patients than in negative patients. The levels of MCP-1 and IL-8 were not significantly different. In HTLV-I positive patients, the MIP-1 alpha and IP-10 levels showed a significant positive correlation with the percentage of CD3(+)/CD25 lymphocytes. BALF cells of all HTLV-I positive DPB patients showed expression of p40(tax) mRNA. We suggest that HTLV-I infection may modify DPB pathogenesis via activation of T cells. We also found that the frequency of ATL development in HTLV-I positive DPB patients was significantly higher than in all HTLV-I positive patients (OR = 8.22, 95% CI = 2.61-25.9, P < 0.01). The levels of TGF-beta in patients who developed ATL were significantly lower than in patients who did not develop ATL. Sensitivity and specificity were 80% and 85.7%, respectively (cut-off = 20 pg/ml). We also propose that these features should be taken into consideration in the treatment of DPB in HTLV-I infected individuals.

Topics: Adult; Aged; Bronchiolitis; Bronchoalveolar Lavage Fluid; CD4-Positive T-Lymphocytes; Chemokine CCL2; Chemokine CCL4; Chemokine CXCL10; Chi-Square Distribution; Chronic Disease; Female; HTLV-I Infections; Human T-lymphotropic virus 1; Humans; Interleukin-8; Lymphocyte Activation; Macrophage Inflammatory Proteins; Male; Middle Aged; Prevalence; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Statistics, Nonparametric; Transforming Growth Factor beta

The host inflammatory response and innate immunity play a complex role in respiratory diseases.. We evaluated the levels of inflammatory mediators and antibacterial proteins in children who required bronchoscopy and bronchoalveolar lavage fluid (BALF) for clinical indications such as chronic tracheostomy (n=15) and chronic suppurative lung disease (n=8).. Our results suggested the presence of interleukin-1beta (IL-1beta) and IL-8 as major inflammatory mediators in BALF samples. The level of the antibacterial protein sIgA was higher than lactoferrin and lysozyme. BALF IL-8 levels significantly correlated with the presence of IL-1beta, IL-6, IL-10, IL-16, sIgA and lysozyme. BALF IL-8 levels did not correlate with the levels of immunomodulatory and anti-inflammatory clara cell 10 kDa protein (CC10) or lactoferrin.. This study suggests that patients with high levels of BALF IL-8 could potentially have high levels of IL-6, IL-10, IL-16, lysozyme and sIgA. Evaluating the inflammatory mediators (IL-8) in relation to other BALF protein components provides insight into understanding the role of inflammatory mediators in the regulation of host defense and the response to lung inflammation and injury.

Topics: Biomarkers; Bronchiolitis; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Bronchoscopy; Child; Humans; Immunity, Innate; Inflammation; Interleukin-1; Interleukin-8; Lactoferrin; Respiration Disorders; Uteroglobin

Human beta-defensin (HBD)-1 and -2 are antimicrobial peptides present in the respiratory tract. Recent reports have indicated reduced activity of beta-defensins in cystic fibrosis, suggesting that beta-defensins may play an important role in the pathological process of chronic respiratory tract infection. Diffuse panbronchiolitis (DPB) is a progressive disease characterised by frequent episodes of superimposed infection, typically caused by Pseudomonas aeruginosa. The aim of this study was to elucidate the role of these antimicrobial peptides in this disease.. The concentrations of HBD-1 and HBD-2 in plasma and bronchoalveolar lavage (BAL) fluid from 33 patients with DPB and 30 normal adults were measured by radioimmunoassay. Localisation of HBD-2 was investigated immunohistochemically in an open lung biopsy specimen obtained from a patient with DPB.. High concentrations of HBD-1 and HBD-2 were noted in BAL fluid from DPB patients. Increased plasma concentrations of HBD-2, but not HBD-1, were found in patients with DPB compared with control subjects. In patients with DPB the HBD-2 concentration in BAL fluid correlated significantly with the numbers of cells recovered from the BAL fluid (total cells, neutrophils, and lymphocytes) and with the BAL fluid concentration of IL-1beta. Synthetic HBD-2, but not HBD-1, had dose dependent bactericidal activity against P aeruginosa. Treatment of 14 patients with macrolides significantly reduced BAL fluid concentrations of HBD-2 but not HBD-1 or plasma concentrations of HBD-1 and HBD-2. Immunohistochemistry of lung tissue showed localisation of HBD-2 in the epithelia of the distal bronchioles.. These results indicate that beta-defensins, particularly HBD-2, participate in antimicrobial defence in the respiratory tract in DPB, and that the BAL fluid concentration of HBD-2 may be a useful marker of airway inflammation in patients with DPB.

Topics: Adult; Anti-Bacterial Agents; beta-Defensins; Bronchiolitis; Bronchoalveolar Lavage Fluid; Female; Humans; Immunohistochemistry; Interleukin-1; Interleukin-8; Macrolides; Male; Pseudomonas aeruginosa; Pseudomonas Infections

In infants with respiratory syncytial virus (RSV) bronchiolitis, we investigated whether disease severity is associated with the genotype of the infecting virus, or with the infant's immunological response to the infection, as determined by measurement of interleukin-8 mRNA in the nasopharyngeal aspirate. This was a cross-sectional observational study, performed in the Accident and Emergency Department, wards, and Intensive Care Unit of a large pediatric hospital. Participants included 276 infants with respiratory syncytial virus infection. Outcome variables included: disease severity (infants requiring oxygen or ventilation were classified as having severe disease); RSV virus genotype (determined according to typing scheme based on the nucleoprotein and G glycoprotein genes); and amount of interleukin-8 mRNA in the nasopharyngeal aspirate, as measured by a semiquantitative polymerase chain reaction assay. This was corrected for the amount of cellular material in the sample by expressing it relative to mRNA for a constitutively expressed gene, HGPRT. We found a highly significant association between the ratio of interleukin-8 mRNA/HGPRT mRNA in the nasopharyngeal aspirate and the occurrence of severe disease. Odds ratio per unit increase of interleukin-8 mRNA/HGPRT mRNA was 1.15 (95% CI, 1.06, 1.24), P = 0.0004. There was no association between virus genotype and either disease severity or amount of interleukin-8 mRNA/HGPRT mRNA. In conclusion, there is a strong, dose-related association between interleukin-8 mRNA produced locally in the airways and disease severity, and a lack of association with virus genotype. This suggests that clinical manifestations of respiratory syncytial virus bronchiolitis are determined by local immunological responses to infection, rather than by characteristics of the infecting virus.

Topics: Bronchiolitis; Cross-Sectional Studies; Genotype; Humans; Infant; Interleukin-8; Respiratory Syncytial Virus Infections; Severity of Illness Index

Respiratory syncytial virus (RSV) infects nearly all children by the end of their second winter. Why some develop bronchiolitis is poorly understood; it is not known whether there is a genetic component. The pathological features include neutrophil infiltration and high levels of interleukin 8 (IL-8), a potent neutrophil chemoattractant.. Common genetic variants of the promoter region of the IL-8 gene were identified by sequencing DNA from 36 healthy individuals. Genetic correlates of IL-8 production were assessed using whole blood from 50 healthy subjects. To investigate genetic correlates of disease severity 117 nuclear families were recruited in which a child had required hospital admission for RSV bronchiolitis.. A common single nucleotide polymorphism (allele frequency 0.44) was identified 251 bp upstream of the IL-8 transcription start site. The IL8-251A allele tended to be associated with increased IL-8 production by lipopolysaccharide stimulated whole blood (p=0.07). Using the transmission disequilibrium test, the frequency of this allele was significantly increased in infants with bronchiolitis (transmission = 62% (95% confidence interval (CI) 53 to 71), p=0.014) and particularly in those without known risk factors (transmission = 78% (95% CI 62 to 93), p=0.004).. Disease severity following RSV infection appears to be determined by a genetic factor close to the IL-8 gene. Further analysis of this effect may elucidate causal processes in the pathogenesis of RSV bronchiolitis.

Topics: Alleles; Bronchiolitis; Cell Culture Techniques; Female; Genetic Predisposition to Disease; Genotype; Humans; Infant; Infant, Newborn; Interleukin-8; Male; Polymorphism, Genetic; Promoter Regions, Genetic; Respiratory Syncytial Virus Infections

Diffuse panbronchiolitis (DPB) is a distinctive chronic inflammatory lung disease predominantly found in Asian populations. Although its etiology is unknown, DPB is considered to be a multifactorial disease of whose susceptibility is determined by genetic predisposition unique to Asians. We and others have previously reported that the B*5401 allele of the human leukocyte antigen (HLA)-B gene or a closely linked gene in the HLA region on 6p21.3 is one of the major genetic factors in susceptibility to this disease. However, the association with B*5401 is not absolute and the contribution of other genetic or environmental factors should also be considered. Here, four candidate genes that are postulated to play a role in the pathophysiology of DPB, namely, RON-kinase, CYP3A4, motilin, and interleukin (IL)-8, were chosen, and association studies between microsatellite markers at these loci and DPB were conducted. We demonstrated the presence of a specific allele at the IL-8 locus was associated with the disease (c2 = 9.13; P = 0.0025; corrected P [Pc] < 0.05). Although further studies are needed to examine whether neutrophil accumulation in the airways of patients with DPB is controlled by a possible genetic variation of IL-8 or other chemokine genes located in the region 4q12-q13, our data suggest that genes other than those of the HLA system may also contribute to a genetic predisposition to DPB.

Topics: Asian People; Bronchiolitis; Chromosomes, Human, Pair 6; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Gene Frequency; Genetic Linkage; Genetic Markers; Genetic Predisposition to Disease; Humans; Interleukin-8; Japan; Microsatellite Repeats; Mixed Function Oxygenases; Motilin; Multifactorial Inheritance; Polymorphism, Genetic; Receptor Protein-Tyrosine Kinases; Receptors, Cell Surface

The clinical and immunoregulatory effects of long-term macrolide antibiotic therapy for patients with chronic lower respiratory tract infections (CLRTI) were investigated. Clinical parameters and neutrophil chemotactic mediators in the epithelial lining fluid (ELF) of CLRTI patients (n = 10) were examined before and after 3 months oral administration of roxithromycin (RXM). The in vitro effects of RXM were also examined on the release of these mediators from alveolar macrophages (AM) and neutrophils. Arterial oxygen tension (p<0.05), vital capacity (VC) (p<0.001), %VC (p<0.05) and forced expiratory volume in one second (p<0.01) were improved after RXM treatment, but airway bacteria were not eradicated. Among the mediators, the levels of interleukin (IL)-8, neutrophil elastase (NE) and leukotriene B4 (LTB4) were higher in ELF than in plasma of CLRTI patients and they decreased after RXM treatment (n = 7, p<0.05 for each). RXM concentrations were significantly increased in the bronchoalveolar lavage cells of the treated patients. In in vitro experiments, RXM showed inhibitory effects on IL-8 release from AM and neutrophils. In conclusion, interleukin-8, neutrophil elastase and leukotriene B4 contribute to the neutrophilic inflammation in the airways of chronic lower respiratory tract infection patients and the clinical effects of roxithromycin may, in part, be attributable to the suppression of excess release of the chemotactic mediators from inflammatory cells.

Topics: Anti-Bacterial Agents; Bronchiectasis; Bronchiolitis; Bronchoalveolar Lavage Fluid; Chemotactic Factors; Chronic Disease; Forced Expiratory Volume; Humans; In Vitro Techniques; Interleukin-8; Leukocyte Elastase; Leukotriene B4; Macrophages, Alveolar; Middle Aged; Neutrophils; Oxygen; Respiratory Tract Infections; Roxithromycin; Vital Capacity

We measured the levels of interleukin (IL) 1 beta, tumor necrosis factor alpha, and IL-8 in bronchoalveolar lavage fluid (BALF) and sera of patients with diffuse panbronchiolitis (DPB) before and after administration of erythromycin or roxithromycin. The pretreatment levels of IL-1 beta and IL-8 were significantly higher in the BALF of patients with DPB than in the BALF of patients with sarcoidosis and controls. The tumor necrosis factor alpha level was also higher than in controls, but not statistically significant. There was a significant correlation between percentage of neutrophils and IL-8 level in the BALF of DPB patients (r = 0.509; p < 0.05) on the one hand and between IL-1 beta and IL-8 on the other (r = 0.476; p < 0.04). Treatment for 1-24 months significantly reduced BALF levels of IL-1 beta and IL-8 of DPB patients in parallel with a reduction in BALF neutrophils. The serum level of IL-8 of DPB patients was higher, albeit insignificant, than that of controls and significantly lower than that in the BALF of the same patients (p = 0.0088). Serum IL-1 beta was below the detection limit. In addition, the concentration of IL-8 in alveolar macrophages obtained from 2 volunteers before and after oral erythromycin administration also decreased ex vivo. Our results indicate that IL-8 induces the migration of neutrophils to inflammatory sites. It is possible that the macrolides impair production and/or secretion of these cytokines, ultimately reducing neutrophil accumulation in the airway.

Topics: Adult; Bronchiolitis; Bronchoalveolar Lavage Fluid; Female; Humans; Interleukin-1; Interleukin-8; Macrolides; Macrophages, Alveolar; Male; Middle Aged; Tumor Necrosis Factor-alpha

Since 1973, the occurrence of respiratory tract infections due to P. aeruginosa has increased associated with the development of broad-spectrum penicillins. A clinical entity, diffuse panbronchiolitis (DPB) is a representative disease of chronic P. aeruginosa infections in Japan. In this paper, recent advances of research on pathogenesis and treatments of chronic P. aeruginosa lower respiratory tract infections in our department are reported. We examined sputum from patients with chronic P. aeruginosa infections under the electron microscope. Mucoid type of microcolonies were observed with fibrous matrix of exopolysaccharide. Neutrophils were found to be partially surrounding the microcolony in an attempt to defense. Debris was formed mainly by the destruction of the neutrophils. Most neutrophils were found full of phagocytized debris. These data support that instead of phagocytizing bacteria, neutrophils phagocytized debris and bacteria were not completely eradicated. This might be a factor in the pathogenesis of persistent colonization of P. aeruginosa. In the airways of patients with chronic airway diseases (CAD), neutrophils enhance the recruitment of more neutrophils through the production of neutrophil chemotactic factors such as interleukin-8 (IL-8) and LTB4, perpetuating a cycle of inflammation in the lung. We demonstrated increased levels of IL-8, a chemotactic cytokine, in bronchoalveolar lavage (BAL) fluid from patients with CAD associated with P. aeruginosa infections. We also documented a significant correlation between neutrophil numbers and IL-8 levels or IL-1 beta levels or neutrophil elastase levels in BAL fluids from patients with CAD. By immunohistochemical studies and in vitro data, three major sources of IL-8 in the airways of CAD patients were found to be alveolar macrophages, bronchial epithelial cells, and migrated neutrophils. In Japan, the clinical effectiveness of oral erythromycin (EM) for CAD, including DPB seems to be established, but its pharmacological mechanism remains unclear. In addition, we found a marked decrease of IL-8 levels in BAL fluid from two patients with CAD after treatment with EM. Therefore, we postulated that EM inhibited IL-8 production by stimulated respiratory cells. EM and Roxythromycin, suppressed IL-8 production in Pseudomonas-stimulated neutrophils in a dose-dependent manner. 1 alpha, 25-dihydroxy vitamin D3 also inhibited neutrophil-derived IL-8. Our data encourage the development of new anti-IL-8 a

Topics: Anti-Bacterial Agents; Bronchiolitis; Bronchoalveolar Lavage Fluid; Chronic Disease; Cytokines; Erythromycin; Humans; Interleukin-8; Pseudomonas aeruginosa; Pseudomonas Infections; Radiography; Respiratory Tract Infections

To study the role of T cells in diffuse panbronchiolitis (DPB), we investigated T-cell subsets in bronchoalveolar lavage fluid (BALF) or 33 patients with DPB, nine patients with bronchiectasis, and 20 healthy volunteers. BALF from DPB patients contained a higher percentage of neutrophils than that from patients with bronchiectasis or healthy volunteers, whereas the percentage of lymphocytes was similar in the three groups. DPB patients, however, had a higher number of lymphocytes and a reduced CD4/CD8 ratio compared with the other subjects. A two-color analysis of T-cell subsets in peripheral blood and BALF revealed a significant increase in the percentage and number of CD8+HLA-DR+ cells and in the number of CD4+HLA-DR+ cells in BALF of DPB patients. The expression of the adhesion molecules CD 11a and CD18 on lung CD3+ cells was enhanced over that on blood CD3+ cells in DPB patients. However, there was no significant difference in the expression of these antigens in peripheral blood or BALF among the groups. There was no significant relationship between BALF interleukin (IL)-8 and lymphocyte accumulation in the lungs of the DPB patients, whereas a significant correlation between the percentage of neutrophils and IL-8 levels in BALF of DPB patients was observed. After treatment with macrolide antibiotics, a significant reduction in the number of lymphocytes and activated CD8+ cells and an elevation in the CD4/CD8 ratio in BALF of DPB patients was observed. Our findings suggest an activation of CD8+ cells in the airway lumen of DPB patients, supporting the hypothesis that lymphocytes are important cellular components of bronchial inflammation in DPB.

Topics: Anti-Bacterial Agents; Bronchi; Bronchiectasis; Bronchiolitis; Bronchoalveolar Lavage Fluid; Case-Control Studies; CD18 Antigens; CD4-CD8 Ratio; CD8-Positive T-Lymphocytes; Female; HLA-DR Antigens; Humans; Interleukin-8; Leukocyte Count; Lymphocyte Activation; Lymphocyte Count; Lymphocyte Function-Associated Antigen-1; Macrolides; Male; Neutrophils; T-Lymphocyte Subsets; T-Lymphocytes, Helper-Inducer

Recently, "low-dose and long-term" erythromycin (EM) has been reported to be effective in treatment of diffuse panbronchiolitis (DPB), but its mechanism is still obscure. We studied the effect of EM on cytokine mRNA expression by using LPS-stimulated human whole blood as an experimental vivo model. IL-8 mRNA was expressed in biphasic fashion with peak expression at 6 hours and 20 hours from the start of LPS stimulation. When whole blood was pretreated with EM (2 micrograms/ml) for 1 hours. IL-8 mRNA expression was depressed at 20 hours (p < 0.025) from the start of LPS (1 microgram/ml) stimulation. However, when pretreated for 12 hours, it was not depressed. EM (2 micrograms/ml) also depressed IL-1 beta (p < 0.025) and TNF alpha (p < 0.05) mRNA expressions at 6 hours from the start of LPS stimulation. From the above results, it was suggested that the direct inhibition of IL-1 beta and TNF alpha production by EM resulted in subsequent depression of production of IL-8 that is a potent chemotactic factor for neutrophil, and consequently, EM acts to protect the bronchiole tissues of DPB patients from destruction by proteolytic enzymes released from neutrophils. This assumption seems to be supported by our previous observation that when patients with DPB were treated with EM a marked decrease in number of neutrophil in bronchoalveolar lavage fluid (BALF) was accompanied by clinical and radiographic improvement.

Topics: Adult; Base Sequence; Bronchiolitis; Cytokines; Erythromycin; Humans; Interleukin-1; Interleukin-8; Male; Molecular Sequence Data; RNA, Messenger; Tumor Necrosis Factor-alpha

Diffuse panbronchiolitis (DPB) is a chronic airway disorder exclusively seen in Japan, characterized by chronic inflammation of the respiratory bronchioles leading to air flow obstruction. Although the pathogenesis of the disorder is unknown, current studies based on bronchoalveolar lavage (BAL) have implied an important role of neutrophil-mediated inflammation as a characteristic pathological feature of the disease. Interleukin 8 (IL-8), a cytokine with potent chemotactic activity for neutrophils, has been proven to have close association with many inflammatory disorders. In this study, neutrophil chemotactic activity (NCA) and IL-8 were measured in the BAL fluid in eight patients with DPB to examine the roles of IL-8 in the neutrophil recruitment to the lower respiratory tract in DPB. Significantly higher levels of NCA and IL-8 were demonstrated in the BAL fluid of DPB patients (71.6 +/- 3.6%, 491.9 +/- 48.0 pg/ml, respectively) compared with that of chronic bronchitis (CB) patients (24.8 +/- 2.8%, 54.1 +/- 13.9 pg/ml, p < 0.001) and of healthy control subjects (7.0 +/- 0.9%, 14.2 +/- 3.9 pg/ml, p < 0.001). The IL-8 values were positively correlated with the NCA in the BAL fluid of DPB patients. Treatment with anti-IL-8 could significantly inhibited the NCA. These results suggest that IL-8 plays an important role in the recruitment of neutrophils to the lower respiratory tract in DPB.

Topics: Adult; Bronchiolitis; Bronchoalveolar Lavage Fluid; Chemotaxis, Leukocyte; Female; Humans; Interleukin-8; Male; Middle Aged; Neutrophils

It is well known that erythromycin (EM) therapy is effective on chronic lower respiratory tract disease, including diffuse panbronchiolitis (DPB). In this study we investigated the relationship between clinical findings and neutrophil chemotactic activity (NCA) in bronchoalveolar lavage fluid (BALF) in patients with DPB receiving orally EM therapy. The NCA in post-EM therapy BALF was significantly reduced (p less than 0.001) compared with that in BALF before EM therapy (30.17 +/- 7.84% vs 53.05 +/- 10.65%). On the respiratory function before and after EM therapy, DPB patients (20 cases) showed significant improvement of %VC, FEV1.0, RV/TLC (p less than 0.001, each) and V25 (p less than 0.05). And on the post-EM therapy blood gas, PaO2 and AaDO2 level were confirmed to be significantly improved (p less than 0.001). In addition, we examined the correlation between the improvement ratio of clinical finding and the reduction of NCA in BALF after EM therapy in 10 patients with DPB. We found the significant correlation between the improvement ratio of PaO2 and the reduction NCA in BALF of those patients (p less than 0.05). There were no significant relationships between the improvement ratio in other parameters as stated above and the reduction of NCA in BALF. These findings indicate that EM restrains the NCA in BALF of patients with DPB and impairs the accumulation of neutrophils in respiratory tract, ultimately contributes to the improvement of clinical symptoms such as sputum and clinical findings such as PaO2 in patients with DPB.

Topics: Adult; Bronchiolitis; Bronchoalveolar Lavage Fluid; Erythromycin; Female; Humans; Interleukin-8; Male; Middle Aged