The heterogeneity of the biologic response of COPD exacerbations can be defined. Sputum IL-1β, serum CXCL10, and peripheral eosinophils are biomarkers of bacteria-, virus-, or eosinophil-associated exacerbations of COPD. Whether phenotype-specific biomarkers can be applied to direct therapy warrants further investigation.
Background: Asthma and chronic obstructive pulmonary disease (COPD) display features of overlap in airway physiology and airway inflammation. Whether inflammatory phenotypes in airway disease describe similar mediator expression is unknown. Objectives: To explore the relationship of airway inflammation and cytokine and chemokine expression in asthma and COPD. Methods: Subjects with asthma and COPD (n = 54 and n = 49) were studied. Clinical characteristics and sputum were collected at entry into the study. A 2-step sputum processing method was performed for supernatant and cytospin preparation. Meso Scale Discovery and Luminex platforms were used to measure cytokines, chemokines and matrix metalloproteinase levels. Results: Analytes sensitive to dithiothreitol (DTT) that had increased recovery in the 2-step sputum process were IL-1β, 4, 5, 10, 13, IFN-γ, TNFRI, GM-CSF, CCL2, 3, 4, 5, 13 and 17. There was a differential expression in IL-8, TNFRI and TNFRII between asthma and COPD [mean fold difference (95% CI): IL-8, 2.6 (1.3–5.4), p = 0.01; TNFRI, 2.1 (1.3–5.4), p = 0.03; TNFRII, 2.6 (1.2–5.6), p = 0.02]. In neutrophilic and eosinophilic airway inflammation, TNFα, TNFRI, TNFRII, IL-6, IL-8 and IL-5 could differentiate between these phenotypes. However, these phenotypes were unrelated to the diagnosis of asthma or COPD. Conclusion: Recovery of sputum mediators sensitive to DTT can be improved using the described sputum processing technique. Within airway inflammatory sub-phenotypes there is a differential pattern of mediator expression that is independent of disease. Whether these inflammatory phenotypes in asthma and COPD confer distinct pathogeneses, therapeutic responses and clinical phenotypes needs to be further evaluated.
Background:Antibiotic overuse in respiratory illness is common and is associated with drug resistance and hospital-acquired infection. Biomarkers that can identify bacterial infections may reduce antibiotic prescription. We aimed to compare the usefulness of the biomarkers procalcitonin and C-reactive protein (CRP) in patients with pneumonia or exacerbations of asthma or COPD.Methods:Patients with a diagnosis of community-acquired pneumonia or exacerbation of asthma or COPD were recruited during the winter months of 2006 to 2008. Demographics, clinical data, and blood samples were collected. Procalcitonin and CRP concentrations were measured from available sera.Results:Sixty-two patients with pneumonia, 96 with asthma, and 161 with COPD were studied. Serum procalcitonin and CRP concentrations were strongly correlated (Spearman rank correlation coefficient [rs] = 0.56, P < .001). Patients with pneumonia had increased procalcitonin and CRP levels (median [interquartile range] 1.27 ng/mL [2.36], 191 mg/L [159]) compared with those with asthma (0.03 ng/mL [0.04], 9 mg/L [21]) and COPD (0.05 ng/mL [0.06], 16 mg/L [34]). The area under the receiver operating characteristic curve (95% CI) for distinguishing between patients with pneumonia (antibiotics required) and exacerbations of asthma (antibiotics not required), for procalcitonin and CRP was 0.93 (0.88-0.98) and 0.96 (0.93-1.00). A CRP value > 48 mg/L had a sensitivity of 91% (95% CI, 80%-97%) and specificity of 93% (95% CI, 86%-98%) for identifying patients with pneumonia.Conclusions:Procalcitonin and CRP levels can both independently distinguish pneumonia from exacerbations of asthma. CRP levels could be used to guide antibiotic therapy and reduce antibiotic overuse in hospitalized patients with acute respiratory illness.
The gene encoding for the CMP-NeuNAc synthetase enzyme of Neisseria meningitidis group B was cloned by complementation of a mutant of Escherichia coli defective for this enzyme. The gene (neuA) was isolated on a 4.1-kb fragment of meningococcal chromosomal DNA. Determination of the nucleotide sequence of this fragment revealed the presence of three genes, termed neuA, neuB, and neuC, organized in a single operon. The presence of a truncated ctrA gene at one end of the cloned DNA and a truncated gene encoding for the meningococcal sialyltransferase at the other confirmed that the cloned DNA corresponded to region A and part of region C of the meningococcal capsule gene cluster. The predicted amino acid sequence of the meningococcal NeuA protein was 57% homologous to that of NeuA, the CMP-NeuNAc synthetase encoded by E. coli K1. The predicted molecular mass of meningococcal NeuA protein was 24.8 kDa, which was 6 kDa larger than that formerly predicted (U. Edwards and M. Frosch, FEMS Microbiol. Lett. 96:161-166, 1992). Purification of the recombinant meningococcal NeuA protein together with determination of the N-terminal amino acid sequence confirmed that this 24.8-kDa protein was indeed the meningococcal CMP-NeuNAc synthetase. The predicted amino acid sequences of the two other encoded proteins were homologous to those of the NeuC and NeuB proteins of E. coli K1, two proteins involved in the synthesis of NeuNAc. These results indicate that common steps exist in the biosynthesis of NeuNAc in these two microorganisms.
Background The K + channel KCa3.1 is expressed by several inflammatory and structural airway cells including mast cells and airway smooth muscle (ASM). We have proposed that this channel may play roles in the development of both airway inflammation and remodelling in asthma and COPD. The role of KCa3.1 channels in chemokine secretion by ASM is not known. Aims To investigate the expression of KCa3.1 in ASM in the airways of healthy and asthmatic subjects, and its function in ex vivo cultured primary human ASM cells. Methods Tissue was collected at bronchoscopy from subjects with asthma and healthy controls, and either processed into GMA for immunohistochemistry, or dissected for the culture of ASM. Further ASM samples were cultured from patients with COPD undergoing lung resection for carcinoma. To examine ASM chemokine production, we used our well-established cellular model of corticosteroid resistance (TNFa/IFNgamma-treated ASM cells). Results KCa3.1 immunostaining was evident in the ASM in healthy subjects and patients with asthma. There was no difference in the level of expression between healthy subjects (n¼7), and those with moderate (n¼5) and severe (n¼6) asthma. In cultured ASM cells exposed to TNFa/IFNgamma, both ELISA and RT-PCR demonstrated expression of CX3CL1 or CCL5 which were (1) synergistically produced at 24 h and (2) completely resistant to fluticasone pre-treatment (100 nM). We found that KCa3.1 block alone did not inhibit the secretion of CX3CL1 or CCL5. Interestingly, the failure of fluticasone to suppress CX3CL1 and CCL5 expression in response to TNFa/IFNgamma combination was reversed by TRAM-34, a selective inhibitor of KCa3.1 channels. The increased anti-inflammatory action induced by the TRAM-34-fluticasone combination was observed in cells derived from healthy (n¼3), asthmatic (n¼3) and COPD (n¼3) patients. In addition, restoration of corticosteroid sensitivity by KCa3.1 blockers was associated with an increased GR phosphorylation on serine 211 residues. Conclusions Together, these data suggest that targeting KCa3.1 channels could serve as a novel approach to enhancing/restoring steroid sensitivity in pulmonary disease.
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