Increased bronchoalveolar lavage fluid CD1c expressing dendritic cells in idiopathic pulmonary fibrosis.

BACKGROUND: Chronic inflammation is implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis and is associated with persistent activation of immune responses. These are largely controlled by dendritic cells (DCs). Although large numbers of DCs infiltrate the lungs of patients with IPF, there are no similar reports in bronchoalveolar lavage fluid (BALF). OBJECTIVES: We aimed to investigate DC populations in BALF of IPF patients. METHODS: CD1c(+) myeloid DCs, BDCA3(high) myeloid DCs, BDCA2(+) plasmacytoid DCs and CD83(+) mature DCs were identified by flow cytometry in the BALF of 10 IPF patients and 10 controls. DC numbers were expressed as percentages of total BALF leukocytes. RESULTS: CD1c(+) myeloid DCs were increased in IPF patients versus controls [median (ranges in parentheses) 1.16% (0.25-3.97) vs. 0.61% (0.19-1.10), p = 0.01]. There was also a trend towards increased BDCA3(high) myeloid DCs [0.57% (0.23-0.88) vs. 0.28% (0.07-0.96), p = 0.07]. No differences were reported in BDCA2(+) DCs and CD83(+) DCs between IPF patients and controls. CONCLUSIONS: IPF is associated with an increase in percentages of BALF myeloid DCs. Considering that such an increase was not observed in CD83(+) mature DCs, most of these DCs should be immature.

Effect of voluntary respiratory efforts on breath-holding time.

INTRODUCTION: Near the end of a maximal voluntary breath-hold, re-inhalation of the expired gas allows an additional period of breath-holding, indicating that the breaking point does not depend solely on chemical drive. We hypothesized that afferents from respiratory muscle and/or chest wall are significant in breath-holding. METHODS: Nineteen normal adults breathed room air through a mouthpiece connected to a pneumotachograph and were instructed to breath-hold with and without voluntary regular respiratory efforts against an occluded airway. RESULTS: Fifty one trials with and 53 without respiratory efforts were analyzed. The mean number of efforts per minute was 19+/-2.3 and the mean lowest airway pressure (P(aw)) -16.6+/-5.4 cmH(2)O. Breath-holding time (BHT) did not differ without (33.0+/-18.2 s) and with (29.3+/-12.3 s) efforts. In five patients arterial blood gasses were measured before and at the end of breath-holding and they did not differ between trials without and with efforts, indicating similar chemical drive. Our results suggest that afferents from respiratory muscle and/or chest wall are not the major determinants of BHT.

Induced sputum in the investigation of airway inflammation of COPD.

During the last decade, the method of sputum induction (SI) has offered the opportunity to study inflammation in patients with chronic obstructive pulmonary disease (COPD). This paper reviews methodological aspects of SI and summarizes its uses in the research of inflammation in COPD, including sputum cellularity and soluble markers. SI is a relatively safe, reliable, and reproducible technique, used to investigate different aspects of airway inflammation. Although various methods of induction and processing have been proved safe and highly reproducible, a generally accepted method is needed. Sputum analysis has given evidence for increased numbers of macrophages and neutrophils in COPD patients compared to normal subjects. In some studies, increased numbers of eosinophils have been also reported. Changes in various mediators have been found in sputum supernatant of COPD patients (IL-8, LTB-4 and TNF-a). The clinical usefulness of the method in the follow-up of the disease has not been explored extensively. A number of observations in patients with different clinical characteristics could be proven useful in identifying patterns of inflammation associated with different prognosis. Finally, SI could also guide treatment; such as, sputum eosinophilia in COPD could predict response to inhaled corticosteroids.

Mechanisms of altered cell immunity and cytotoxicity in COPD.

The lungs of smokers are exposed to the toxic substances of cigarette smoke, but only 10-20% of them will develop chronic obstructive pulmonary disease (COPD). For COPD to develop, cigarette smoke has to bypass or overwhelm the host front lines of defence, i.e. the respiratory tract mucosal epithelium, which serves as an effective physical barrier and the innate immune system, which provides an immediate, yet non-specific response. In this review, we will describe briefly how cigarette smoke succeeds in damaging the physical barrier of mucosal epithelium and the innate immune system, and how it induces effector mechanisms of the adaptive immune system, which are particularly cytotoxic to the host. We will also discuss the role of other stimuli with immunogenic potential, such of the role of pathogens which colonize or evade the lungs of COPD patients and of self tissue antigens, which may lead to autoimmune disease when there is chronic inflammation. Although the primary mechanism(s) of undesirable innate and adaptive immune responses in COPD are still a matter of debate, it is currently accepted that they are the root cause of COPD.

Differences in microsatellite DNA level between asthma and chronic obstructive pulmonary disease.

Previous studies have shown that microsatellite (MS) DNA instability (MSI) is detectable in sputum cells in chronic obstructive pulmonary disease (COPD) and asthma. The aim of the present study was to investigate whether asthma and COPD could be distinguished at the MS DNA level. DNA was extracted from sputum cells and white blood cells from 63 COPD patients, 60 non-COPD smokers, 36 asthmatics and 30 healthy nonsmokers. Ten MS markers located on chromosomes 2p, 5q, 6p, 10q, 13q, 14q and 17q were analysed. No MSI was detected in non-COPD smokers or healthy nonsmokers. A significantly higher proportion of COPD patients exhibited MSI (49.2%) compared to asthmatics (22.2%). MSI was detected even in the mild stages of COPD (33.3%) and asthma (22.2%). No relationship was found between MSI and COPD severity. The most frequently affected marker was D14S588 (17.5% in COPD and 2.7% in asthma). The markers D6S344, G29802 and D13S71 showed alterations only in COPD, and G29802 was associated with a significantly decreased forced expiratory volume in one second FEV1 (% predicted), whereas MSI in D6S344 was associated with a significantly higher FEV1 (% pred). The frequency of microsatellite instability was higher in chronic obstructive pulmonary disease than in asthma, and microsatellite instability in three workers showed chronic obstructive pulmonary disease specificity. However, further studies are needed to verify the differences between chronic obstructive pulmonary disease and asthma at the microsatellite level.

Inflammatory cell profiles and T-lymphocyte subsets in chronic obstructive pulmonary disease and severe persistent asthma.

BACKGROUND: Severe persistent asthma (SPA) and chronic obstructive pulmonary disease (COPD) are both associated with non-reversible airflow limitation and airway neutrophilia. OBJECTIVE: To compare inflammatory cell profiles and T lymphocyte subsets between SPA and COPD patients with similar severity of airflow limitation. METHODS: Sputum induction and lung function tests were performed in 15 COPD patients aged (mean+/-SD) 68+/-8 years, ex-smokers, mean forced expiratory volume in 1 s (FEV1) 45% of predicted (% pred) and 13 SPA aged 55+/-10 years, non-smokers, mean FEV(1) 49% pred. All patients were on inhaled steroid treatment. Eight asthmatics exhibited irreversible airflow limitation. Differential cell count, metachromatic cell count and double immunocytochemistry for the analysis of T lymphocyte subsets were performed on sputum slides. RESULTS: COPD patients had increased sputum neutrophils in comparison with SPA (P<0.03), but similar to SPA with fixed obstruction. In COPD sputum neutrophils negatively correlated with the lung transfer factor for carbon monoxide (KCO) (r=-0.462, P=0.04). SPA showed significantly increased eosinophils and metachromatic cells vs. COPD patients (P<0.04, P<0.007, respectively). Increased CD4/CD8 and decreased CD4-IFN-gamma/CD4-IL4+ cell ratio (P<0.001) were found in SPA vs. COPD. In SPA, CD4/CD8+ cell ratio correlated with sputum eosinophils (r=0.567, P=0.04). CONCLUSION: In spite of treatment with inhaled steroids, SPA and COPD exhibit distinct sputum inflammatory cell patterns, although SPA with fixed airflow limitation and COPD patients have similar numbers of neutrophils.

Effect of digoxin on global respiratory muscle strength after cholecystectomy: a double blind study.

BACKGROUND: Upper abdominal surgery has been shown to impair the function of the respiratory muscles. In addition, controversial results have been reported concerning the effect of digoxin on the diaphragm. The aim of this study was to investigate further the mechanism(s) of respiratory muscle dysfunction after cholecystectomy and the effect of digoxin on the impaired respiratory muscle function. METHODS: Twenty three patients (four men) were studied before and 48 hours after surgery. Eleven received digoxin and 12 placebo. Respiratory muscle strength was assessed 48 hours after surgery by measuring mouth pressure during maximum static inspiratory (PImax) and expiratory (PEmax) efforts before and after 90 minutes of intravenous administration of 0.25 mg digoxin in a double blind, placebo controlled fashion. In addition, spirometric and pain measurements were performed. RESULTS: Postoperatively (+48 h) PImax and PEmax decreased significantly (p<0.01) from their preoperative values in both groups by a similar degree. After administration of digoxin or placebo only the digoxin group showed a significant increase in both PImax (p<0.02) and PEmax (p<0.05) with a mean increase of 15% for PImax and 12.3% for PEmax. The mean difference in PImax (DeltaPImax) and PEmax (DeltaPEmax) between the digoxin and placebo groups was 1.01 (95% CI 0.28 to 2.2) and 1.05 (95% CI 0.04 to 2.4), respectively. Estimates of postoperative pain did not differ between the two groups. Spirometric indices showed a similar restrictive defect postoperatively in both groups but did not change after digoxin or placebo. CONCLUSION: Digoxin improves the impaired global strength of the inspiratory and expiratory muscles after cholecystectomy and this may be clinically relevant. Muscle contractility could play a part in this impairment.