Year in review 2012: Acute lung injury, interstitial lung diseases, sleep and physiology

The incremental changes made in the definition of acute lung injury/adult respiratory distress syndrome (ARDS) over the last two decades represent a series of landmark events in the history of the condition. The first description of ARDS established the recognition of this syndrome;1 the 1994 America-European Consensus Conference definition set the standard for acute lung injury/ARDS clinical trials;2 while the new Berlin definition, which has revised the America-European Consensus Conference version, is based on 18 years clinical investigation and mechanism exploration, and as a result is a more precise and practical3 guide for clinical evaluation. The essential components of the new Berlin definition of ARDS are: removal of acute lung injury and division of ARDS into three successive stages (mild, moderate and severe) based on timing, chest imaging, partial pressure of oxygen in arterial blood (PaO2)/fraction of inspired oxygen (FiO2) ratio and level of positive end expiratory pressure applied, with, as previously, exclusion of heart failure or fluid overload. The new definition is based on two large-scale databases from seven medical centres and unifies the understanding of ARDS and establishes a new standard for future clinical trials. Being continuously open to the air makes the respiratory system particularly vulnerable to environmental changes and thus predisposes the lung to inflammation and injury. Of various aerosols and particles, diesel particulate matter and engineered nanoparticles are two major concerns when it comes to assessing the pulmonary risks posed by air pollution.4, 5 diesel particulate matter provokes oxidative stress through particle surface area, transition metal and constituent organics and stimulation of cytokine production which further induce inflammation.4 Air pollution including diesel particulate matter induces cellular epigenetic changes including DNA methylation and histone modification which may eventually lead to gene silencing or microRNA changes and which in some case ultimately lead to cell proliferation and cancer development.6 Understanding the mechanisms involved in cellular injury by air pollution using genome, epigenome, transcriptome and microRNAome assays may help to dissect the molecular pathways that might become potential prophylactic or therapeutic targets.6 Engineered nanoparticles arise as a consequence of modern nanomaterial production, and humans are exposed to engineered nanoparticles through daily life, working place or professional exposure. The toxicity of engineered nanoparticles depends on their size, shape, surface and corona. Engineered nanoparticles can enter into cell organelles and induce oxidative stress, inflammation and immune responses.5 Evaluation and understanding of the mechanisms by which air pollution affects human health not only provides approaches for potential intervention, but also helps to establish a legal framework for production, consumption and environmental protection.5 Another important environment hazard is radiation. Medical radiation therapy or accidental overexposure can initiate lung inflammation, injury and fibrosis.7 Captopril, an angiotensin-converting enzyme inhibitor, may mitigate lung injury and improve survival after radiation exposure, which is very promising even 1 week after radiation exposure. Angiotensin-converting enzyme inhibitors could be potential drug candidates for prophylaxis against radiation-induced lung injury, although the exact molecular mechanism by which they exert their effects is still under investigation. Tracheal transplant is a standard process in lung transplantation. A reproducible tracheal transplant animal model would be very useful for the study of epithelium and submucosal gland regeneration after acute hypoxia-ischaemia injury. In a tracheal graft model in mice, the basal and duct cells initially proliferate to re-epithelialize the basement membrane, then these cells proliferate further and differentiate to restore the function of the epithelium, while serous cells differentiate 4–5 days before club (Clara) cells and ciliated epithelium.8 These sequential cellular changes represent a dynamic cell regeneration process which can be used as a therapeutic guide for repair of airway disease. Chronic airway inflammation is common in chronic obstructive lung disease and may lead to airway remodelling. Lipopolysaccharide is one of the common factors that induce airway inflammation. Three aquaporins have been reported to be expressed in airway epithelium and to play an important role in airway rehydration.9 Lipopolysaccharide downregulates AQP5 expression, but not AQP3 and AQP4, through the p38/JNK pathway. It is known that AQP5 deletion or downregulation may decrease fluid secretion/osmotic fluid transport10 associated with thick mucus production.11 Thus, the mechanism of lipopolysaccharide induced downregulation of AQP5 may provide insight in to airway disease management based on water channel expression. The last decade has seen a rapid increase in clinical and preclinical research activity in the interstitial lung diseases (ILD), in particular idiopathic pulmonary fibrosis (IPF).12 Despite this, there have been relatively few developments in our understanding or treatment of sarcoidosis. Although the basic patho-mechanisms are understood, there remains much that is unknown; what is the initial disease trigger, what determines disease chronicity and end-organ fibrosis, why is the disease phenotype so enormously variable between individuals? With this in mind, it was welcoming to see a number of important papers relating to sarcoidosis being published in Respirology during 2012. Shaffiq et al. presented data demonstrating that the soluble form of A Disintegrin and Metalloprotease (ADAM) 33 protein is raised in the bronchoalveolar lavage fluid of individuals with sarcoid when compared with controls.13 ADAM 33 forms part of a family of transmembrane glycoproteins that play diverse roles in modulating cell surface remodelling, mediation of cell–cell and cell–matrix interactions and ectodomain shedding of growth factors and receptors. Transforming growth factor-β-induced post-translational modification results in ectodomain shedding of ADAM 33, thus giving rise to a soluble form. Polymorphisms in the gene for ADAM 33 have been shown to alter susceptibility to the development of asthma. Furthermore, increased levels of soluble ADAM 33 have been shown in the bronchoalveolar lavage of asthma patients, suggesting that the protein plays an important role in the airway inflammation and fibrosis that characterize the disease. Shaffiq et al. as well as demonstrating increased levels of soluble ADAM 33 in sarcoidosis, were able to show that soluble ADAM 33 levels inversely correlate with both forced vital capacity (FVC) and diffusing capacity of carbon monoxide (DLco). Soluble ADAM 33 may therefore be a biomarker of disease severity in sarcoidosis, but more importantly the results presented by this group raise interesting questions about the role played by ADAM 33 in the pathogenesis and progression of pulmonary sarcoid. In a questionnaire study, Wilsher et al. also probed the overlap that possibly exists between asthma and sarcoidosis.14 The authors hoped to disentangle whether the pathogenesis of sarcoidosis is driven by a skewed T helper 1/T helper 2 immuno-phenotype. Preclinical data suggest that individuals with sarcoid are likely to exhibit a predominantly T helper 1 phenotype. Asthma, by contrast, is known to be driven by T helper 2 cytokines. One might therefore expect individuals with sarcoid to be protected against asthma. The authors however found an identical incidence of asthma symptoms and atopy in 136 sarcoid subjects when compared with previously reported New Zealand population data. As argued, in an accompanying editorial by Zappala and Wells, there are a number of important confounders that make these results challenging to interpret.15 Nonetheless, they concur that the lack of a clear T helper 1/T helper 2 dichotomy supports the notion that autoimmune disease (including sarcoid) results from a loss of immune regulation in genetically and environmentally predisposed individuals following antigenic exposure. Sarcoidosis causes significant morbidity to sufferers as a consequence of organ-specific symptoms and also through constitutional upset.16 Both these aspects of sarcoid were explored in papers published in Respirology in 2012. Young et al. assessed 52 individuals with sarcoid and well-preserved lung function and demonstrated that 11% showed airway hyperresponsiveness following nebulization of hypertonic saline and 44% showed airway hyperresponsiveness in response to histamine.17 airway hyperresponsiveness was associated, in univariate analysis, with conglomerate perihilar fibrosis and a reticular pattern on high-resolution computed tomography. On multivariate analysis, airway hyperresponsiveness was inversely correlated with baseline forced expiratory volume in 1 s (FEV1). Overall, these findings suggest that airway hyperresponsiveness is an important problem in sarcoidosis that is likely to reflect the consequences of airway remodelling following inflammation. De Boer and Wilsher published a validation of the Sarcoidosis Health Questionnaire in a non-US population.18 In keeping with earlier studies utilizing this questionnaire, they were able to show that in a New Zealand population of predominant European origin that the Sarcoidosis Health Questionnaire correlated well with health-related quality of life and fatigue scores. IPF, with a median survival of 2.8–4.2 years, remains one of the most devastating of the ILD. This is despite recent advances in disease understanding and the publication of a number of landmark clinical trials. While pirfenidone has recently been licensed as a treatment for IPF in Japan and Europe,19 some guidelines, on the basis of the positive findings of the IFIGENIA trial,20 recommend the use of the anti-oxidant N-acetyl-cysteine.21 The study of Homma et al. published in Respirology during 2012 represents an interesting addition to our understanding of the potential role of N-acetyl-cysteine as a therapy for IPF.22 The authors undertook a 48-week study, in 76 subjects of nebulized N-acetyl-cysteine monotherapy (352.4 mg twice daily) compared with placebo. 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