Airway inflammation, cough and athlete quality of life in elite female cross-country skiers: A longitudinal study.

The aim of this study was to investigate the effect of a season of cross-country training and racing on airway inflammation, cough symptoms, and athlete quality of life in female skiers. Eighteen elite female skiers performed sputum induction and completed the Leicester Cough Questionnaire (LCQ) and the Recovery-Stress Questionnaire (REST-Q) at three time points (T1 - May/Jun, T2 - Oct/Nov, T3 - Jan-Mar) during the year. No changes were observed between T1 and T2. However, an increase in sputum eosinophils and lymphocytes (P < 0.05) and a significant change in all three domains of the LCQ were observed between T1 and T3 (P < 0.05). A significant association was found between the total yearly hours of training and the change in the total cell count (r(2) = 0.74; P = 0.006), and a number of other sputum cell counts between T1 and T3. No changes were observed for any domain of the REST-Q. The results of this study demonstrate that airway inflammation and cough symptoms are significantly increased in elite female cross-country skiers across a year of training and racing. The increase in airway inflammation is related to the total amount of training and is worse during the winter months when athletes are training and racing in cold, dry air.

Human rhinovirus-induced ISG15 selectively modulates epithelial antiviral immunity.

Human rhinovirus (HRV) infections trigger exacerbations of lower airway diseases. HRV infects human airway epithelial cells and induces proinflammatory and antiviral molecules that regulate the response to HRV infection. Interferon (IFN)-stimulated gene of 15 kDa (ISG15) has been shown to regulate other viruses. We now show that HRV-16 infection induces both intracellular epithelial ISG15 expression and ISG15 secretion in vitro. Moreover, ISG15 protein levels increased in nasal secretions of subjects with symptomatic HRV infections. HRV-16-induced ISG15 expression is transcriptionally regulated via an IFN regulatory factor pathway. ISG15 does not directly alter HRV replication but does modulate immune signaling via the viral sensor protein RIG-I to impact production of CXCL10, which has been linked to innate immunity to viruses. Extracellular ISG15 also alters CXCL10 production. We conclude that ISG15 has a complex role in host defense against HRV infection, and that additional studies are needed to clarify the role of this molecule.

Expression of muscarinic receptors by human macrophages.

Macrophages increase in number and are highly activated in chronic obstructive pulmonary disease (COPD). Muscarinic receptor antagonists inhibit acetylcholine-stimulated release of neutrophilic chemoattractants, suggesting that acetylcholine may regulate macrophage responses. Therefore, expression and function of components of the non-neuronal cholinergic system in monocyte-macrophage cells was investigated. RNA was isolated from monocytes, monocyte-derived macrophages (MDMs), lung and alveolar macrophages from nonsmokers, smokers and COPD patients, and expression of the high-affinity choline transporter, choline acetyltransferase, vesicular acetylcholine transporter and muscarinic receptors (M(1)-M(5)) ascertained using real-time PCR. M(2) and M(3) receptor expression was confirmed using immunocytochemistry. Release of interleukin (IL)-8, IL-6 and leukotriene (LT)B(4) were measured by ELISA or EIA. All monocyte-macrophage cells expressed mRNA for components of the non-neuronal cholinergic system. Lung macrophages expressed significantly more M(1) mRNA compared with monocytes, and both lung macrophages and alveolar macrophages expressed the highest levels of M(3) mRNA. Expression of M(2) and M(3) protein was confirmed in MDMs and lung macrophages. Carbachol stimulated release of LTB(4) from lung macrophages (buffer 222.3 ± 75.1 versus carbachol 1,118 ± 622.4 pg · mL(-1); n = 15, p<0.05) but not IL-6 or IL-8. LTB(4) release was attenuated by the M(3) antagonist, 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP; half maximal effective concentration 5.2 ± 2.2 nM; n = 9). Stimulation of macrophage M(3) receptors promotes release of LTB(4), suggesting that anti-muscarinic agents may be anti-inflammatory.

Cigarette smoke modulates rhinovirus-induced airway epithelial cell chemokine production.

Human rhinovirus (HRV) infections induce epithelial cell production of chemokines that may contribute to the pathogenesis of exacerbations of chronic obstructive pulmonary disease (COPD) and asthma. Cigarette smoking is the predominant risk factor for the development of COPD and also aggravates asthma symptoms. We examined whether cigarette smoke extract (CSE) modulates viral inflammation by altering the profile of HRV-induced epithelial chemokine production. Purified HRV-16, and CSE were used to examine the effects on CXC chemokine ligand (CXCL)8 and CXCL10 production from both primary human bronchial epithelial cells and the BEAS-2B epithelial cell line. Both CSE and HRV-16 induced CXCL8 production and, when used in combination, induced at least an additive production of CXCL8 compared with either stimulus alone. In contrast, CSE did not induce CXCL10 and markedly inhibited HRV-16-induced CXCL10 production. Inhibition of HRV-16-induced CXCL10 by CSE was mediated, at least in part, via transcriptional regulation. The increased CXCL8 production seen with the combination of CSE and HRV-16 was not due to transcriptional regulation but was associated with CXCL8 mRNA stabilisation. Thus, CSE differentially modulates HRV-16-induced chemokine production from human airway epithelial cells in a manner that might be expected to alter inflammatory cell profiles.

Sputum matrix metalloproteases: comparison between chronic obstructive pulmonary disease and asthma.

Asthma and chronic obstructive pulmonary disease (COPD) are different conditions with contrasting airway inflammation and parenchymal disease patterns. A number of matrix metalloproteases (MMPs) are implicated in the pathophysiology of COPD and asthma. Different profiles of airway MMPs may, therefore, be expected in asthma and COPD. The present study compared MMP profiles in the airways of non-smokers, non-symptomatic cigarette smokers, and patients with COPD or asthma (n = 15 subjects per group). Induced sputum was assessed for MMP-1, -2, -3, -8 and -9, and tissue inhibitor of metalloproteases (TIMP)-1 by ELISA. Gelatinase activity was determined by zymography. Sputum from COPD patients contained increased levels of MMP-1, -8 and -9 compared with the other groups (2-7-fold, depending upon group). MMP-9 activity was elevated in COPD sputum by 3-12-fold above the other groups. Sputum from COPD patients had 3-fold higher levels of TIMP-1 than samples from asthmatics or controls, but was not different to smokers. FEV1 correlated negatively with MMP-1, -8, -9, MMP-9 activity and TIMP-1, whereas percent neutrophils in sputum correlated positively with MMP-1, -8, -9, TIMP-1 and MMP-9 activity. The MMP profile in COPD differs to that in asthma and cigarette smokers. This may contribute to, or be a marker of, different pathophysiologies of asthma and COPD.

Increased levels of the chemokines GROalpha and MCP-1 in sputum samples from patients with COPD.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have increased numbers of neutrophils and macrophages in their lungs. Growth related oncogene-alpha (GROalpha) attracts neutrophils, whereas monocyte chemoattractant protein-1 (MCP-1) attracts monocytes that can differentiate into macrophages. The aim of this study was to determine the concentration of GROalpha and MCP-1 in bronchoalveolar lavage (BAL) fluid and sputum from non-smokers, healthy smokers and patients with COPD, and to see if there was a correlation between the concentrations of these chemokines, lung function, and numbers of inflammatory cells. METHODS: BAL fluid and sputum from non-smokers (n=32), healthy smokers (n=36), and patients with COPD (n=40) were analysed for the presence of GROalpha and MCP-1 using ELISA. Cells counts were performed on the samples and correlations between the concentrations of these chemokines, lung function, and inflammatory cells observed. RESULTS: Median (SE) GROalpha and MCP-1 levels were significantly increased in sputum from patients with COPD compared with non-smokers and healthy smokers (GROalpha: 31 (11) v 2 (2) v 3 (0.8) ng/ml; MCP-1: 0.8 (0.4) v 0.2 (0.1) v 0.1 (0.04) ng/ml, p<0.05), but not in BAL fluid. There were significant negative correlations between both GROalpha and MCP-1 levels in sputum and forced expiratory volume in 1 second (FEV(1)) % predicted (GROalpha: r=-0.5, p<0.001; MCP-1: r=-0.5, p<0.001), together with significant positive correlations between GROalpha and MCP-1 and neutrophil numbers in sputum (GROalpha: r=0.6, p<0.001; MCP-1: r=0.4, p<0.01). CONCLUSION: These results suggest that GROalpha and MCP-1 are involved in the migration of inflammatory cells, thus contributing to the inflammatory load associated with COPD.