Optimal use of advanced technology

Abstract

The Asian Pacific Society of Respirology held its 13th Congress in Bangkok, Thailand, between 19 and 22 November 2008. It was attended by over 1500 delegates from around the world, particularly well represented by delegates from the Asia Pacific Rim. The congress was highlighted by an excellent scientific program, preceded by an educational course on pulmonary laboratory practices and several postgraduate courses. Office bearers representing the American Thoracic Society, European Respiratory Society and American College of Chest Physicians, among others, made significant contributions, further enhancing the high-quality faculty.

Genetics of asthma & role of environment

With the increasing recognition of genetic influences on asthma, much recent work has focused on the interaction of genes for asthma and atopy with the environment. Recent years have seen the identification of genes for atopy, IgE and asthma, such as the chromosome 5q interleukin cluster. Despite this, it has become apparent that the genetics of asthma and atopy are exceedingly complex and significant translation of research findings to the clinic has yet to occur. The concept of multilocus interactions (i.e., gene–gene, gene–environment and gene–gene–environment interactions) is becoming apparent. The issues of interpreting data about the relatively large number of distinct, yet overlapping, clinically important asthma phenotypes, and how these phenotypes are analyzed with respect to genetic variants continues to be highly debated.

Important phenotypes in asthma that are being actively investigated include diagnosis of asthma, doctor-diagnosed asthma, total IgE and specific IgE, skin tests, airway hyper-reactivity, lung function and decline in lung function, among others. The importance of sufficient sample sizes for sufficient power to identify small effect sizes requires the careful planning of studies of sufficiently large and international cohorts. The high costs of large-scale studies mandates careful deliberation regarding the use of existing cohorts, including the potential for pooling cohorts. Future important requirements in gene–environment interaction studies include the encouragement and facilitation of presentation of both positive and negative results, the refinement and validation of methods for whole-gene amplification and the development of user-friendly bioinformatics and statistical tools.

Environment & lung disease

The critical role of environmental agents and particles in the etiology of lung disease has long been known. With rapid technological advances in biomarker and molecular technology, there is emerging research on the modern use of biomarkers for occupational and environmental lung disease.

Examples of potential biomarkers include soluble mesothelin-related peptides (MRPs) and osteopontin for mesothelioma, exhaled condensates and volatile organic compounds, which include the inorganic gases nitric oxide and carbon monoxide as well as nonvolatile compounds, such as isoprostanes, ONOO (peroxynitirites) and cytokines. In addition to the use of a single or a few biomarkers, rapid genomic and proteomic advances are giving rise to the ability to test thousands of probes or elements on an unbiased basis. Examples include gene-expression signatures used to diagnose lung cancer [1], prognosticate lung cancer and assess chronic obstructive pulmonary disease (COPD) phenotypes [2].

Bhattacharya et al. performed RNA-expression profiling of lung tissue from 56 participants with varying degrees of COPD, using Affymetrix U133 Plus 2.0 arrays and applied different bioinformatic methods based on discrete and quantitative phenotypes [2]. They reported differentially expressed genes for discrete and quantitative measures of airflow obstruction, which were validated in an independent data set. Some of these candidate genes are known to have functions related to DNA binding and regulation of transcription. Modern genomic studies that exploit the increasing treasure trove of publicly available gene-expression array data (a prerequisite of many journals that publish these data) illustrate the potential for data mining. Such efforts will be able to exploit the increasing number of studies, generally of relatively modest sample sizes that are limited by cost.

The emerging field of biomarkers has led to a new paradigm, that of systems biology, which involves multivariate analysis, new theoretical models and the concept of emergence. An alternative paradigm invokes the notion that multiple exposures may implicate not only multiple biomarkers, but also multiple outcomes. The research challenge is to validate these candidate biomarkers in independent cohorts prospectively in a robust study design, preferably a randomized control setting, to allow for translation to daily practice.

Aging & the lung

Thanks to improved healthcare and modern treatments, people are living longer and longer, making the study and knowledge of age-related biological and physiological lung changes a major issue for the 21st Century.

With increasing age, structural changes occur in the connective tissue framework of the lung, with increases in type 3 collagen, decreases in elastin fibers, changes in cross linking and fiber orientation as well as changes in proteoglycans. There is also an alteration in alveolar number and dimensions, leading to a reduction of the surface-to-volume ratio. These changes lead to a reduction of lung elastic recoil and to an increase in lung distensibility. This is the major cause of age-related reduction in maximal expiratory flow. Accompanying these changes in elastic recoil of the lung is a reduction of compliance of the chest wall and reduction of respiratory muscle strength and these changes in the mechanical properties of the lung and chest wall largely determine the age-related changes in lung volume. Increased ventilation inhomogeneity and airway closure is observed with aging and this is responsible for both the increased dispersion of V/Q ratios and the increase in units with low V/Q. The age-related reduction in transfer factor is largely explained by a reduction in alveolar surface area, decreased density of alveolar capillaries and decreased pulmonary capillary blood volume [3]. There is a reduction with age in the perception of both internal and external resistive loads as well as impairment of ventilatory responses to isocapnic hypoxia and hypercapnia. The sensitivity of cough receptors also declines. Alveolar lavage studies have demonstrated increasing lung inflammation in the elderly, with increased neutrophil and IL-8 levels.

These changes need to be considered in the diagnosis, monitoring and assessment of responses to therapy in the elderly. Specifically, with increasing longevity, lung inflammation and oxidation may become important, with benefits from pleotropic anti-inflammatory agents. Decreased perception of mechanical loads may need to be considered when developing symptom-based treatment guidelines for the elderly.

MicroRNA & lung disease

Small noncoding RNA molecules are found widely in the genome of most cells and are encoded by up to approximately 1–5% of the predicted genes in plants, worms and vertebrates. They are generally localized in the introns of protein-coding genes or in the noncoding regions of the genome. One of these are the microRNAs (miRNAs); a highly conserved family of small noncoding RNAs able to negatively regulate gene expression via RNA interference mechanisms. It is believed that miRNAs may regulate up to a third of human genes and are associated with cancer and immune and inflammatory disease [4].

Evidence supporting a role for miRNAs in human malignancy came from a study by Calin et al. who identified two downregulated miRNAs (miR-15 and miR-16) within 13q14, a region frequently deleted in chronic lymphocytic leukemia [5]. Since then, altered miRNA expression has been reported in a wide spectrum of human malignancies, including lung and other cancers. In lung cancer, studies support a role for the tumour suppressing let-7 family and the oncogenic miR-17–92 cluster of miRNAs. The let-7 family of miRNAs has been consistently shown to have reduced expression in primary lung cancers and cell lines. Loss of expression abrogates let-7s control of RAS, allowing RAS overexpression and, thereby, contributes to lung carcinogenesis. Significant overexpression of the oncogenic miR-17-92 cluster of miRNAs occurs in lung cancer cell lines and primary tumors, where miR-17–92 miRNAs are upregulated by oncogenic c-Myc and act as part of a regulatory network, balancing cell death and proliferation with c-Myc and E2F1 [6–9].

It is also likely that miRNAs are implicated in complex lung diseases, such as asthma and COPD. For instance, miR-223 appears to act as a fine tuner of granulocyte production and the inflammatory response; mutant miR-223 mice show neutrophilic inflammatory lung pathology and increased tissue destruction after endotoxin challenge [10]. Expression profiling of miRNA is now possible and preliminary data suggest a role of selected miRNAs in asthma and COPD. It also appears that there is differential expression of miRNAs in the peripheral blood compartments of people with airway diseases. In addition, mouse models of asthma reveal the differential expression of miRNAs in the airway wall of these mice.

Thus, the study of miRNAs is likely to lead to a better understanding of disease pathogenesis and to the generation of novel diagnostic, prognostic biomarkers and potential therapeutic targets. Future therapeutic innovations may include antagomirs, locked nucleic acids or miRNA sponges, which can modulate endogenous miRNA function.

Infections & respiratory interventions

The recent outbreaks of SARS coronavirus and avian influenza have had major public health consequences, with implications on transmission to healthcare workers. While nosocomial spread of SARS is mainly due to infected droplets and fomites, as is the usual situation for viral pneumonia, there has been concern regarding potential viral spread by airborne transmission, such as from the use of oxygen masks. This is of major relevance given that during the SARS outbreak, respiratory failure was a major complication in week 2, with many patients requiring oxygen.

Modern investigative technology with human patient simulators using high-resolution video to identify laser light-sheet-detected intrapulmonary smoke leakage jet plumes is able to model various scenarios in the ward setting. One such model revealed a jet plume of air leaking through the side vents of a simple oxygen mask to lateral distances of 20, 22, 30 and 40 cm from the saggital plane during the delivery of oxygen at 4, 6, 8 and 10 l/min, respectively. The dispersion distance was found to be extended beyond 40 cm by coughing. These findings, therefore, have direct clinical implications for healthcare workers, who should take precautions when managing patients with community-acquired pneumonia of unknown etiology, which is complicated by respiratory failure and requires the use of supplementary oxygen via oxygen masks [11,12]. Thus, healthcare workers at risk of respiratory viruses, such as avian influenza, are recommended to apply strict standards, contact and droplet precautions when dealing with suspected cases, and undertake airborne precautions when performing aerosol-generating procedures [13].

Summary & conclusion

The theme of the 13th Congress of the Asian Pacific Society of Respiratory was the ‘Optimal Use of Advanced Technology’, and the high-level scientific and educational sessions exemplified this. Innovative technology is changing the face of modern lung research, ranging from bench research of the ‘omics’ type to modern physical and physiologic research. It is virtually certain that technology will continue to develop and impact on how scientists undertake lung research and how clinicians manage lung conditions in the future.

Financial & competing interests disclosure

The authors served as office bearers for the 2008 Asian Pacific Society of Respirology (APSR) Congress. KF is Chair of the APSR Central Program Committee, NB was serving president of the APSR, AN was Congress President of APSR 2008 and Chair of the Local Organizing Commiteee. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.