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. At 48 weeks, there was no overall difference in the primary end-point of FVC change. However, there were a number of positive trends particularly in patients with more severe disease at baseline. Pending the results of the PANTHER trial (a study comparing oral N-acetyl-cysteine to placebo) in the USA, these data suggest that a larger, appropriately powered study of nebulized N-acetyl-cysteine may be warranted in the future. As well as clinical trials, another area of research interest in IPF is biomarker discovery. Fahim et al. reported that serum carcinoembryonic antigen levels correlated with baseline disease severity in 41 patients with IPF.23 Tasaka et al. looked at potential biomarkers in the bronchoalveolar lavage fluid of individuals with IPF alone and IPF combined with emphysema.24 They were able to demonstrate that the pro-inflammatory CXC chemokines CXCL5 and CXCL8 are associated with the presence of emphysema on high-resolution computed tomography. Levels of fibrocytes, circulating fibroblast progenitor cells, have previously been shown to predict prognosis in individuals with IPF.25 Interestingly, Fujiwara et al. were able to show that fibrocyte levels correlate with baseline disease severity in other fibrotic ILD.26 It remains to be seen, however, whether fibrocyte levels also predict prognosis in ILD other than IPF. While sarcoidosis and IPF are the commonest of the ILD, the combined incidence of other ILD, while significant, is less well recognized. In this regard, a work by Amar et al. utilizing the UK general practice database has provided interesting data on the burden of iatrogenic ILD in the UK.27 The authors report an incidence of drug- and radiation-induced ILD of 4.1 per million person years (this figure is likely to be an underestimate given the poor specificity of current coding systems in separating iatrogenic from other causes of ILD). Importantly, individuals with drug- or radiation-induced ILD had an all-cause mortality risk that was four times higher than age-matched cases. Another challenge with rarer ILD is in defining natural history. Kawabata et al. are therefore to be congratulated on their longitudinal study of individuals with desquamative interstitial pneumonia DIP.28 Of 31 patients studied, 14 were followed for over 5 years, and of these, five developed significant fibrosis and four developed lung cancer. These findings suggest that desquamative interstitial pneumonia is not the benign condition that other case series may have suggested. Estimating the effects of ILD on sufferers is another area that remains understudied. While there have been recent efforts to develop bespoke ILD quality of life tools such as the King's Brief Interstitial Lung Disease Questionnaire, other groups have sought to modify existing tools.29 Nagata et al. report that the chronic obstructive pulmonary disease (COPD) assessment test, a short quality of life questionnaire developed for COPD, shows a strong correlation with the St George's Respiratory Questionnaire in 55 individuals with ILD.30 In terms of treating ILD, rapidly progressive disease with respiratory failure represents a frequent challenge to pulmonologists. Decisions about the level of supportive care to provide in such instances are often coloured by the poor outcomes seen in the intensive care unit in individuals with IPF. Yokoyama and colleagues have provided timely data on the use of non-invasive ventilation (NIV) in this patient group.31 In a retrospective analysis of 38 patients admitted to their unit over 5 years with rapidly progressive interstitial pneumonia, they were able to show that early intervention with NIV was associated with a significantly improved chance of survival at 30 days. Connective tissue disease-associated ILD is a growing problem for pulmonologists, especially as rheumatological interventions for articular and non-pulmonary disease manifestations are improving. Nonetheless, understanding of the natural history of ILD in some of the rarer connective tissue disease is limited. Maldonado et al. assessed the outcome of autopsies in patients with known idiopathic inflammatory myopathy.32 Over a 29-year period, they identified 39 deaths with autopsy in individuals with idiopathic inflammatory myopathies. Of these cases, 33% died from respiratory complications, 28% from infectious disease and 26% from cardiovascular complications. Importantly, in a third of cases, the ultimate cause of death was not suspected ante-mortem. While improved diagnostics may reduce this issue in contemporary studies, this paper nonetheless highlights the importance of the need for prompt and correct diagnosis of respiratory complications and infectious disease in this patient group.33 The past few years has seen an increasing interest in the impact of abnormal breathing during sleep on daytime function and general health across a range of medical disorders. With increasing obesity in both developed and developing economies, and the well-recognized relationship between body mass index and sleep disordered breathing (SDB), understanding the mechanisms underpinning abnormal sleep breathing and its health consequences will be of increasing clinical importance. Over the course of 2012, Respirology published a number of articles in the area of sleep, with a particular emphasis on obesity and its impact on respiratory disease. Given the prevalence of obstructive sleep apnoea (OSA), it was not surprising that the focus of many of the papers was on this disorder. Isono34 provided a comprehensive review of the role obesity plays in the pathogenesis of upper airway collapse, with a particular emphasis on the consequences of fat deposition in the neck and surrounding the pharyngeal airway, as well as intra-abdominal fat distribution. The paper by Sutherland and colleagues35 discussed the interplay between obesity and craniofacial morphology in determining OSA risk. Craniofacial factors, particularly skeletal restriction, may be of greater importance for OSA risk in Asians, who develop more severe OSA at lower bodyweights than Caucasians. This has significant clinical consequences considering the increasing obesity levels in the Asia–Pacific region. Understanding the pathogenic aspects of OSA and how this is influenced by ethnicity may allow more targeted assessment and treatment strategies in OSA management in different regions. The complexity of factors contributing to OSA was further underscored in the article by Joosten and colleagues,36 who investigated a large cohort of patients with mild–moderate OSA. Using polysomnographic data, these authors identified six separate phenotypes, confirming the heterogeneity of this disorder and the need to consider these variations in analysing outcomes and therapies in patients with mild to moderate OSA. OSA and metabolic syndrome are both closely related to obesity and their frequent coexistence in the same individual has garnered significant interest in the role OSA plays in the development and worsening of cardiometabolic dysfunction. A review of this topic by Lam and colleagues37 provides an excellent analysis of the current state of knowledge in the area and highlights the complex relationship between obesity, OSA and metabolic syndrome. While it is known that obesity is closely related to OSA, it has been hypothesized that OSA could influence fat accumulation and deposition, and through the promotion of central obesity, contribute to metabolic dysfunction. Although continuous positive airway pressure (CPAP) remains the mainstay of therapy for OSA, obesity is the only major modifiable risk factor for OSA. Lam et al.37 stress the importance of diet, increased physical activity and weight loss in addition to CPAP in managing individuals with OSA and the metabolic syndrome. However, accomplishing weight loss is not easily achieved with conservative measures alone, and many severely obese individuals now look to surgical approaches for more permanent weight management. The paper by Schachter38 provides a valuable overview of the assessment and management of possible respiratory and sleep problems encountered by individuals undergoing bariatric surgery. Although weight loss achieved through surgery can have a significant impact on comorbid conditions including type II diabetes, we are reminded that OSA is rarely cured by bariatric surgery; postoperative monitoring of sleep breathing should be undertaken before considering cessation of CPAP therapy.38 Epidemiological evidence has shown that OSA is an independent predictor of mortality.39 In disorders such as obesity syndrome and COPD, the presence of daytime is associated with blood are not during sleep studies for OSA. the report by et was in that a cohort of patients with who sleep studies with and blood were followed for to In this study, the development of in to partial arterial carbon of and were of increased independent of obesity or disease. As identified in the accompanying editorial by it was from the study this group of individuals clinical practice in or intervention, given the increased mortality associated with these changes in individuals and therapy and would OSA has been to a range of cardiovascular disorders. Chronic plays an important role in this Using a model to of over different et found that chronic induced oxidative stress in the and the severity of the oxidative stress was significantly correlated with the of Over this response to likely a mechanism being into The authors that a understanding of such mechanisms could lead to new approaches in the management of cardiovascular complications of OSA. The role and arterial carbon plays in another type of central sleep was by et These authors investigated changes in (a of during partial to In to at to moderate of breathing over a significant increase in at This increase in was correlated with an increase in central sleep Furthermore, a relationship between the increase in central sleep apnoea and a in arterial carbon was The authors the more at may a of compared with lower This study with that of et the importance of the of to sleep disordered breathing and its This syndrome at the end of the of and is associated with significant and health diagnosis is often or The prevalence of cardiovascular morbidity seen in is in keeping with the greater of inflammatory blood and of the found in patients compared with obese In their and the importance not only of treating in but also the need to the of weight and in to impact on cardiometabolic NIV may have an important but still role in in this In a study, and looked at the effects of NIV in severe therapy with a significant in pulmonary pressure and increase in in capacity could not be to but to be related to in As by et the of NIV is associated with and improved this may be the to at physical activity and While the clinical of CPAP therapy in patients with moderate to severe OSA are well with therapy remains an One of the many factors that may influence to therapy is improved sleep quality on CPAP in rapid and sleep baseline can and have been with to However, what sleep and factors this have not been Using data from and CPAP studies, et found that an increase in sleep of and of in rapid sleep during the sleep and rapid Furthermore, they identified factors of sleep and rapid during pressure this may help to patients less likely to to therapy monitoring should be et reported and effects related to NIV in patients with chronic respiratory Although overall was at patients a greater the number of effects lower the need to strategies to and reduce effects that may on the use of daytime is a frequent by sleep and while it is associated with other causes need to be The sleep disorder is excellent review of this disorder by the interesting that have been found between and OSA, with evidence suggesting this may arise from to of the respiratory and systems are closely The of this for patient care was sleep quality is another by patients with a of medical disorders including et a large retrospective study sleep quality in patients with moderate to severe OSA. results of studies, these authors found sleep quality was poor with sleep increased sleep and rapid sleep compared with of In to some daytime than was associated with sleep the use of oxygen significantly sleep quality in these patients further investigation. The of clinical in the treatment and of patients with respiratory disease has increased over the last has also our understanding of how can help the severity and of disease and allow of prognosis and The of initial research in this area was on incremental in the but more there has been interest in that can be of the or such as the the and the incremental The primary of these are they are and less than the standard and may clinical and In Respirology in 2012, a number of studies made significant to this important area of and investigated the to three the incremental and the in patients with range and compared with a on a and ventilation were using a analysis system while and heart were also Importantly, the authors for the known with by the patients The primary of the study were that a oxygen and heart were achieved in while a significantly greater was during the compared with the These findings that can to the and provide results with As these may some important for assessing the of pulmonary and for to the more complex and In more common respiratory disorders COPD, interstitial pulmonary fibrosis and lung cancer the and of the have been relatively well However, two studies this investigated the of the in more conditions in patients undergoing upper and lung et the in patients the before undergoing upper surgery and investigated whether in the could predict pulmonary complications pneumonia, acute respiratory failure and However, in this relatively of patients, there were only pulmonary complications and the difference in could not the patients at higher risk. Wilsher et the and of the in patients with lung disease. It was demonstrated that there was between two 1 week correlation However, while the was reproducible and it not reflect the severity of lung disease as by lung function and high-resolution computed for of the The authors also demonstrate that was not in patients with

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