<i>Respirology</i> year‐in‐review 2008: Basic science

In this review, we present important findings in basic sciences from articles published in Respirology in 2008. Our aim is to provide a summary and interpretation of new data published in the journal in the basic translational sciences, which will lead to a better understanding of lung diseases, and lead to improved diagnosis, prevention and treatment. COPD is a chronic inflammatory disease of the lungs leading to airflow limitation, gas trapping, breathlessness, respiratory failure, exacerbations and death. Cigarette smoke exposure is the predominant cause of COPD, although there is variable susceptibility to the development of COPD, indicating the effects of gene–environment interaction. While direct cigarette smoke exposure is the predominant causative factor leading to COPD, environmental tobacco smoke exposure may also be important in the development of airway inflammation. The smoking of even a single cigarette releases particulate matter into the adjacent environment. In a granulometry study (the study of the size distribution of ‘grains’ or particles), an enclosed office space was used as the laboratory.1 In each experiment, a single cigarette was smoked, and the resulting suspended particle, dust and microbial load was measured within the room for 3 h afterwards. The concentration of suspended large and medium-sized particles reached a peak soon after smoking, whereas the concentration of small particles (< 0.7 µmol/L) remained elevated after the cigarette was smoked. Bacteria were detected and cultured in the basal conditions prior to the cigarette being smoked. The load of microorganisms sedimented by gravity increased in the first hour after the smoking of the cigarette, followed by a decrease in load. The authors suggested that cigarette smoke may aggregate with bacteria, and (although not specifically tested) that these sedimented aggregates may later be resuspended and inhaled as people move around a room after passive smoking, potentially leading to respiratory infections.1 Genetic risk factors are likely to interact with exposure to cigarette smoke and other environmental irritants, to play a role in the aetiology of COPD. Many studies have examined gene–environment interaction in COPD. The only confirmed genetic risk factor is homozygous ZZ α1-antitrypsin deficiency, although this contributes only a small fraction of COPD and emphysema. Numerous other candidate genes have been postulated;2 however, none has been definitively confirmed in genetic association studies, possibly due to small genetic effects, heterogeneity in study design and phenotyping of COPD, different populations and small sample sizes.3 Genome-wide association studies in COPD are awaited with interest, and will potentially confirm known candidates as well as identifying novel candidate genes. One of the main mechanisms implicated in emphysema is protease–antiprotease imbalance. Cathepsins are cysteine proteases, and cathepsin S is expressed by antigen-presenting cells. The cathepsin S gene (CTSS) was examined in a genetic association study of 204 smokers with COPD and 104 healthy non-smokers.4 Screening of the promoter region of the gene identified a number of polymorphisms, including single nucleotide polymorphisms, variable number of tandem repeats and an insertion/deletion polymorphism. The two main haplotypes (combinations of alleles) differed in promoter function, as determined by luciferase assay in a macrophage-like cell line stimulated by the inflammatory cytokine, interferon-γ. Finally, one of the haplotypes was more frequent in smokers with various severities of airflow limitation, compared with never smokers.4 The precise role of these polymorphisms in the cathepsin S gene in COPD pathogenesis remains to be worked out, particularly the alterations in protease function and immune modulation. Microsomal epoxide hydrolase (mEH) is an enzyme that potentially reduces oxidative stress by detoxifying epoxide compounds such as those found in cigarette smoke. Genotypes at two genetic loci within the mEH gene (EPHX1) appear to influence mEH activity. Of the coding region polymorphisms, the histidine (His) to arginine (Arg) polymorphism at residue 139 exists in exon 4 of EPHX1 (the Arg139 allele has fast enzyme activity), and the tyrosine (Tyr) to histidine (His) polymorphism at residue 113 occurs in exon 3 (the His113 allele has slow enzyme activity). The haplotypes with slow activity (i.e. reduced detoxification) have been associated with increased risk and severity of COPD, but not consistently in all studies. An updated meta-analysis of 16 studies of EPHX1 polymorphisms in COPD pooled results across studies totalling 1847 COPD subjects and 2455 controls.5 The His/His113 genotype was associated with increased risk of COPD (odds ratio 1.59, 95% confidence interval 1.14–2.21), compared with the Tyr/Tyr113 genotype; this association was stronger in Asian populations. Other genotypes altering enzyme activity were also associated with increased or decreased risk of developing COPD. The results of this meta-analysis suggest that polymorphisms in xenobiotic metabolism pathways may contribute to susceptibility to COPD, adding to the support for specific candidate genes such as EPHX1 in COPD. Once COPD has developed, further genetic factors may play a role in the progression of COPD and its phenotypes. The angiotensin-converting enzyme (ACE) gene has functions in the lung related to inflammation and respiratory drive, and has been hypothesized to regulate skeletal muscle function. In a study of 61 COPD patients and 57 controls, ventilator response to exercise was not altered by ACE genotype, whereas the ACE insertion/insertion genotype was associated with maximal work load and aerobic work efficiency.6 The mechanism for this association is not clear, although the authors speculated that changes in muscle fibre type could be an underlying mechanisms resulting from different ACE genotypes. Biomarkers of severity of COPD would be useful for monitoring patients, prognostication and developing therapeutic targets. Induced sputum is a potentially useful, non-invasive tool for studying biomarkers in COPD. In a study of 43 COPD patients, 12 smoking controls and 10 non-smokers, the levels of prostaglandin E2 (PGE2) and matrix metalloproteinase-2 (MMP-2) in induced sputum were higher in COPD patients, and inversely correlated with FEV1 % predicted.7 The cyclo-oxygenase pathway, from which PGE2 is a product, activates MMP-2, lending weight to the notion that these markers are implicated in COPD pathogenesis, through their involvement in inflammation and airway remodelling. Acute exacerbations of COPD contribute substantially to the cost and personal burden of COPD, and are associated with mortality and accelerated lung function decline. Viral and bacterial infections are the predominant cause of exacerbations. Colonization by bacteria, and possibly viruses, may lead to chronic mucus hypersecretion and frequent exacerbations. Innate and acquired immunity are both important in the host defence system of the lungs against microbial infection. There are concerns about impaired host defence with cigarette smoke exposure and COPD, particularly reduced mucociliary clearance. In a mouse model, mice were exposed to cigarettes for 6 months, and the mRNA gene expression of antimicrobial molecules in the lungs was compared with mice without cigarette smoke exposure.8 Cigarette smoke upregulated levels of surfactant protein-A, β-defensins 2 and 3, and secretory leucocyte protease inhibitor, whereas there was no change in lysozyme expression, and a decrease in β-defensin-1 expression. From these data, it can be concluded that, similar to the human airway transcriptome,9 antimicrobial and host defence molecules are in fact activated (rather than impaired) in the airways of mouse models of smoking and COPD. Therefore, other pathways in the immune response should be examined for defects that underpin impaired host defence and frequent exacerbations. Expression of other pattern recognition receptors, such as Toll-like receptors (TLR), has been shown to be altered in COPD. In an elastase-induced mouse model of emphysema, exposure to the bacteria Streptococcus pneumoniae induced expression of TLR2 and TLR4 in alveolar macrophages.10 Subsequently, the numbers of neutrophils increased in the BAL, as did the levels of inflammatory cytokines (tumour necrosis factor (TNF)-α, IL-1-β and IL-6). The reasons for the enhanced immune and inflammatory response in this model should be investigated to further understand differences in the response to bacterial infection in disease models, given that some previous studies have found impaired responses, depending on the model used. The relationship between the presence of bronchodilator reversibility and airway inflammation in COPD is unclear. Traditionally, COPD is characterized as being non-reversible or at least chronic airflow limitation that does not fully reverse with bronchodilator. Sputum eosinophilia is observed in some COPD patients, including in exacerbations, although the underlying mechanisms leading to this are not certain. Thirty-six subjects with mild or moderate COPD were investigated in a randomized controlled trial of inhaled fluticasone of 6 months' duration.11 Airway inflammatory markers, including eosinophilia at baseline did not correlate with the degree of bronchodilator reversibility. Inhaled fluticasone reduced counts of neutrophils and epithelial cells in BAL, whereas airway wall neutrophil counts increased with the inhaled steroid. Bronchodilator reversibility and airway inflammatory markers at baseline did not predict the changes in airway inflammation with fluticasone. Further work is required to predict future treatment response to inhaled steroids and long-acting bronchodilators.12 Pharmacogenomics has emerged as a discipline studying the effects of variation in the human genome on treatment responses, particularly pharmacological therapy. The use of such information may lead to individualized treatment (e.g. choice of bronchodilators) based on the patient's ‘personal genome’. It is recognized that cross-talk may occur between muscarinic acetylcholine receptors (which mediate the bronchodilatation of anticholinergic agents) and β2-adrenergic receptors (which mediate the bronchodilatation of β-agonists). In an 8-week study of 44 COPD patients receiving the long-acting anticholinergic bronchodilator, tiotropium, subjects with the Arg/Arg genotype at amino acid 16 of the β2-adrenergic receptor gene had greater FEV1 and quality of life improvements, compared with the other genotypes carrying the glycine (Gly) allele.13 Whether this effect is due to the desensitization of the Gly form of the β2-adrenergic receptor, and therefore reduced functional capacity for bronchodilatation, is yet to be explored. Given the differential expression of mediators in the airways and lungs in asthma, monitoring of biomarkers of airway inflammation,14 a key feature of asthma, is important. 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The effects of in exacerbations further While of steroids on gene expression to there is recognition of the effects of In an model, the effect of steroids on oxidative stress was of oxidative stress increased inhaled given reduced the degree of within as measured by capacity in and lung activity. novel findings the for more into the effects of steroids in asthma, which will provide into the mechanism and of of direct to treatment of exacerbations of of is being as an treatment for have of of the in moderate to further the mechanisms a mouse model has been used to measure airway effect of with reduced the number of neutrophils and in the and the and also reduced the of and mouse model is likely to be useful for further effects of including other pathways altered by and markers of response that would with treatment. of gene expression is an to understanding the development and severity of are including gene expression and of gene expression. 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