Microbiota abnormalities in inflammatory airway diseases - Potential for therapy.

Increasingly the development of novel therapeutic strategies is taking into consideration the contribution of the intestinal microbiota to health and disease. Dysbiosis of the microbial communities colonizing the human intestinal tract has been described for a variety of chronic diseases, such as inflammatory bowel disease, obesity and asthma. In particular, reduction of several so-called probiotic species including Lactobacilli and Bifidobacteria that are generally considered to be beneficial, as well as an outgrowth of potentially pathogenic bacteria is often reported. Thus a tempting therapeutic approach is to shape the constituents of the microbiota in an attempt to restore the microbial balance towards the growth of 'health-promoting' bacterial species. A twist to this scenario is the recent discovery that the respiratory tract also harbors a microbiota under steady-state conditions. Investigators have shown that the microbial composition of the airway flora is different between healthy lungs and those with chronic lung diseases, such as asthma, chronic obstructive pulmonary disease as well as cystic fibrosis. This is an emerging field, and thus far there is very limited data showing a direct contribution of the airway microbiota to the onset and progression of disease. However, should future studies provide such evidence, the airway microbiota might soon join the intestinal microbiota as a target for therapeutic intervention. In this review, we highlight the major advances that have been made describing the microbiota in chronic lung disease and discuss current and future approaches concerning manipulation of the microbiota for the treatment and prevention of disease.

Lung transplantation for COPD - evidence-based?

Lung transplantation has now been performed for more than 30 years in patients with end-stage chronic obstructive pulmonary disease (COPD). This disease is the major indication for lung transplantation, involving more than one third of the procedures worldwide. Although lung transplantation in COPD patients has clearly shown a positive impact on lung function, exercise capacity and quality of life, the survival benefit remains difficult to ascertain. Several methodological difficulties, particularly the absence of classical randomised studies, make the analysis especially challenging. There is however indirect but convincing evidence that lung transplantation can, when appropriate selection criteria are applied, provide not only an active post-transplant lifestyle but also a survival benefit for patients with COPD.

Ventricular arrhythmia in coronary artery disease: limits of a risk stratification strategy based on the ejection fraction alone and impact of infarct localization.

AIMS: Estimates of the left ventricular ejection fraction (LVEF) in patients with life-threatening ventricular arrhythmias related to coronary artery disease (CAD) have rarely been reported despite it has become the basis for determining patient's eligibility for prophylactic defibrillator. We aimed to determine the extent and distribution of reduced LVEF in patients with sustained ventricular tachycardia or ventricular fibrillation. METHODS AND RESULTS: 252 patients admitted for ventricular arrhythmia related to CAD were included: 149 had acute myocardial infarction (MI) (Group I, 59%), 54 had significant chronic obstructive CAD suggestive of an ischaemic arrhythmic trigger (Group II, 21%) and 49 patients had an old MI without residual ischaemia (Group III, 19%). 34% of the patients with scar-related arrhythmias had an LVEF > or =40%. Based on pre-event LVEF evaluation, it can be estimated that less than one quarter of the whole study population had a known chronic MI with severely reduced LVEF. In Group III, the proportion of inferior MI was significantly higher than anterior MI (81 vs. 19%; absolute difference, -62; 95% confidence interval, -45 to -79; P < or = 0.0001), though median LVEF was higher in inferior MI (0.37 +/- 10 vs. 0.29 +/- 10; P = 0.0499). CONCLUSION: Patients included in defibrillator trials represent only a minority of the patients at risk of sudden cardiac death. By applying the current risk stratification strategy based on LVEF, more than one third of the patients with old MI would not have qualified for a prophylactic defibrillator. Our study also suggests that inferior scars may be more prone to ventricular arrhythmia compared to anterior scars.

Airway surface liquid volume regulation determines different airway phenotypes in liddle compared with betaENaC-overexpressing mice.

Studies in cystic fibrosis patients and mice overexpressing the epithelial Na(+) channel beta-subunit (betaENaC-Tg) suggest that raised airway Na(+) transport and airway surface liquid (ASL) depletion are central to the pathogenesis of cystic fibrosis lung disease. However, patients or mice with Liddle gain-of-function betaENaC mutations exhibit hypertension but no lung disease. To investigate this apparent paradox, we compared the airway phenotype (nasal versus tracheal) of Liddle with CFTR-null, betaENaC-Tg, and double mutant mice. In mouse nasal epithelium, the region that functionally mimics human airways, high levels of CFTR expression inhibited Liddle epithelial Nat channel (ENaC) hyperfunction. Conversely, in mouse trachea, low levels of CFTR failed to suppress Liddle ENaC hyperfunction. Indeed, Na(+) transport measured in Ussing chambers ("flooded" conditions) was raised in both Liddle and betaENaC-Tg mice. Because enhanced Na(+) transport did not correlate with lung disease in these mutant mice, measurements in tracheal cultures under physiologic "thin film" conditions and in vivo were performed. Regulation of ASL volume and ENaC-mediated Na(+) absorption were intact in Liddle but defective in betaENaC-Tg mice. We conclude that the capacity to regulate Na(+) transport and ASL volume, not absolute Na(+) transport rates in Ussing chambers, is the key physiologic function protecting airways from dehydration-induced lung disease.

Trazodone increases arousal threshold in obstructive sleep apnoea.

A low arousal threshold is believed to predispose to breathing instability during sleep. The present authors hypothesised that trazodone, a nonmyorelaxant sleep-promoting agent, would increase the effort-related arousal threshold in obstructive sleep apnoea (OSA) patients. In total, nine OSA patients, mean+/-sd age 49+/-9 yrs, apnoea/hypopnoea index 52+/-32 events.h(-1), were studied on 2 nights, one with trazodone at 100 mg and one with a placebo, in a double blind randomised fashion. While receiving continuous positive airway pressure (CPAP), repeated arousals were induced: 1) by increasing inspired CO(2) and 2) by stepwise decreases in CPAP level. Respiratory effort was measured with an oesophageal balloon. End-tidal CO(2 )tension (P(ET,CO(2))) was monitored with a nasal catheter. During trazodone nights, compared with placebo nights, the arousals occurred at a higher P(ET,CO(2)) level (mean+/-sd 7.30+/-0.57 versus 6.62+/-0.64 kPa (54.9+/-4.3 versus 49.8+/-4.8 mmHg), respectively). When arousals were triggered by increasing inspired CO(2) level, the maximal oesophageal pressure swing was greater (19.4+/-4.0 versus 13.1+/-4.9 cm H(2)O) and the oesophageal pressure nadir before the arousals was lower (-5.1+/-4.7 versus -0.38+/-4.2 cm H(2)O) with trazodone. When arousals were induced by stepwise CPAP drops, the maximal oesophageal pressure swings before the arousals did not differ. Trazodone at 100 mg increased the effort-related arousal threshold in response to hypercapnia in obstructive sleep apnoea patients and allowed them to tolerate higher CO(2) levels.