Year in review 2013: Acute lung injury, interstitial lung diseases, sleep and physiology

This Year in Review paper, the first in a series of three review papers, highlights the most relevant articles published in 2013 in Respirology and other respiratory medicine journals on acute lung injury, interstitial lung disease (ILD), sleep and pulmonary physiology. Yuanlin Song The outbreak of H7N9 avian influenza pneumonia in east China highlighted the significance of virus assortment in birds and the role played by transmission from birds to humans. Meanwhile, Middle East respiratory syndrome coronavirus has been an inhabitant in bats for many years and transmitted to humans with person-to-person transmission.1, 2 Analysis of 111 patients who had confirmed H7N9 infection showed high mortality with the majority of deaths due to severe pneumonia and acute respiratory distress syndrome (ARDS).1 Novel coronavirus infection showed respiratory distress and multiple organ damage with mortality around 65% in affected patients.2 Influenza virus infection is still a severe challenge to public health warranting continuous efforts on vaccine development. Sepsis is also a major cause of ARDS, and it is associated with high mortality in intensive care unit patients. A recent study showed prolonged hospitalization but no increased mortality in a group of ARDS patients who had positive blood stream culture.3 However, this finding needs further investigation in a large group of ARDS patients at multiple sites. Unlike traditional ARDS, influenza-induced ARDS features both epithelial and endothelial injury with the injured epithelium and endothelium being orchestrated to provoke massive inflammation in the lungs. This leads to capillary leakage and eventual inhomogeneous alveolar flooding.4, 5 Alveolar flooding is a process of fluid leakage with active/passive transport driven by ion movement or hydrostatic pressure. Cystic fibrosis transmembrane regulation conductance has shown participation in alveolar fluid transport to the capillary compartment. Inhibition of chloride transport worsens lung injury induced by lipopolysaccharide in a rodent model, suggesting inhibition of active fluid transport may delay lung injury recovery.6 Among various risk factors, bile acid aspiration induces lung injury through p38 and c-Jun N-terminal kinase phosphorylation, as well as cytosolic phospholipase A2 and cyclooxygenase-2 production, which results in attenuation of junctional proteins such as occludin, zonula occludens-1 and E-cadherin.7 Similarly in a Pseudomonas aeruginosa-induced lung injury model, claudins -3, -4 and -18 are significantly upregulated with the degree of bronchoalveolar lavage claudin level being associated with lung injury score.8 These results strongly suggested protection against lung injury occurs through junctional protein expression in alveolar epithelium. Angiotensin-converting enzyme (ACE) plays a role in the pathogenesis of ARDS. bronchoalveolar lavage samples from ARDS patients showed increased ACE-1 but decreased ACE-2 levels.9 ACE-2 cleaves Angiotensin II to form Angiotensin, while ACE-1 cleaves Angiotensin I to form Angiotensin II. An angiostatin inhibitor reduced lung injury in a lipopolysaccharide-induced mouse model,10 suggesting imbalance of ACE expression in ARDS and potential therapy through downregulation of ACE-1. Different manoeuvres have been developed to quantify lung oedema and extravascular lung water to guide management of ARDS.11 A recent study using computed tomography imaging showed inhomogeneous distribution of lung injury in ARDS patients, and the level of inhomogeneity was associated with mortality.12 Chest ultrasound has been applied in ARDS to quantify lung oedema through B-line and subpleural consolidation measurement.13 These imaging techniques provide additional information on lung water that may help clinical evaluation and management of fluid administration and mechanical ventilation setting. Low tidal volume (6 mL/kg) ventilation strategy has been shown to reduce mortality in ARDS. Does an even lower tidal volume provide additional benefit? A recent study showed ventilation with 3 mL/kg combined with extracorporeal CO2 removal significantly increased ventilation free days in severe hypoxic patients.14 Prone position ventilation has shown improved survival in severe ARDS, although the protocol might not be applicable in most medical centres.15 Regarding ventilation mode, adaptive support ventilation is equivalent to volume control ventilation on mortality in patients with ARDS,16 which is consistent with previous reports. The lung is eventually healed through organ-derived stem cell mobilization/repopulation and tissue regeneration. Exogenous stem cell has been extensively studied in different lung injury animal model to test the efficacy, administration route and underlying mechanism. So far, it is known that exogenous stem cells heal lung injury through engraftment, paracrine secretion, immune modulation, growth factor production and antibiotic peptide synthesis pathway.17 So far, there are more than 300 on-going clinical trials assessing stem cell therapies.18, 19 A number of respiratory conditions are being considered as targets for stem cell treatment including ARDS and chronic progressive diseases such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD).17, 20-22 The outcomes of these trials should be known in next few years. Bronchiectasis is characterized as vicious cycle of chronic purulent airway inflammation with bronchodilation. Neutrophils play an important role in airway inflammation, and so the activity of neutrophils has been studied in idiopathic bronchiectasis and control patients.23 The result showed similar response of neutrophils to granulocyte macrophage–colony stimulating factor in these two groups, suggesting neutrophil phagocytosis and generation of oxidative species have been preserved in bronchiectasis patients,23 although the exhaled condensation may not detect the difference.24, 25 Macrolide antibiotics including azithromycin has been shown to be beneficial in reducing symptoms and exacerbations,26 with an underlying mechanism thought to be biofilm disruption (which helps antibiotics penetration) and suppressive activity on airway inflammation. Toby M. Maher Chronic fibrotic ILD, encompassing a range of conditions including IPF and connective tissue disease-associated ILD, has gained increasing prominence over the last 2 or 3 years following the emergence of effective therapies such as pirfenidone and rituximab.27-29 Despite a rise in clinical trial activity, the pathobiology of fibrotic lung disease remains poorly understood.30 The development of IPF has previously been linked to abnormalities in lymphatic drainage and lymphangiogenesis.31 Data presented in Respirology, by Egashira et al. on the differential distribution of lymphatic drainage between upper and lower regions of the lung, are of particular interest for researchers trying to understand the development of fibrotic lung disease.32 Egashira and colleagues observed that lymphatic drainage in the upper lobes follows a bronchovascular distribution, while in the lower lobes, the lymphatics tend to be found in the subpleural regions. These differences may go some way to explain the typical pattern of distribution of fibrosis in individuals with IPF and merits further investigation in the context of fibrotic ILD. Cigarette smoking is a recognized risk factor for the development of a range of ILD including IPF, respiratory bronchiolitis-ILD and desquamative interstitial pneumonitis. Active smoking has also been associated with an increased risk of developing ILD in individuals with rheumatoid arthritis.33, 34 Furthermore, it is increasingly being recognized that ILD develops in a significant subset of individuals with emphysema.35 To explore the link between cigarette smoking, ILD and emphysema, Antoniou et al. compared the high-resolution computed tomography scans of individuals with IPF, RA-ILD and COPD.36 The authors found emphysema in a significant proportion of the patients with IPF and RA-ILD (35% and 48%, respectively). Interestingly, when compared with individuals with COPD, those with ILD and emphysema had significantly lower pack-year smoking histories. Although requiring prospective validation, this observation suggests that emphysema and pulmonary fibrosis share pathogenetic mechanisms.37 Individuals with fibrotic ILD, especially those with IPF, demonstrate highly variable rates of disease progression.38 This can make it challenging for clinicians to accurately convey information regarding prognosis at the point patients are diagnosed with the condition. In patients with early disease and preserved lung function determining prognosis can be especially challenging. Kondoh et al. have demonstrated that as is the case for individuals with more advanced disease, a typical computed tomography appearance of usual interstitial pneumonia and the extent of honeycombing identify individuals at a high risk of early progression.39 In IPF, it has previously been shown that the profusion of fibroblastic foci seen on surgical lung biopsy predicts subsequent disease progression.40 In a study of 50 subjects, Harada et al. extended this observation, demonstrating that the extent of fibroblastic foci in surgical lung biopsies correlates with disease severity and subsequent progression in both IPF and fibrotic NSIP.41 While of interest, this finding lacks clinical utility because of the requirement for biopsy material. Serum markers make an attractive target for biomarker development in ILD because of the ease of repeated sampling. Inokoshi et al. explored the potential of the extracellular matrix component, hyaluronan, as a diagnostic and prognostic biomarker in chronic fibrotic ILD.42 In their study of 49 subjects, hyluronan was elevated compared with healthy controls and rose further in individuals undergoing acute exacerbations. Procalcitonin, a small circulating amino acid precursor of calcitonin, has been investigated as a marker of bacterial pneumonia.43 Nagata et al. have shown that procalcitonin levels may be a useful discriminator between acute exacerbations of IPF (in which levels remain low) and bacterial-driven episodes of ARDS and pneumonia (in which, procalcitonin levels are markedly elevated).44 These observations, however, require validation in large prospective cohorts of patients.45 Sarcoidosis remains an enigmatic and multifaceted condition of unknown aetiology. A number of groups have previously reported a negative correlation between active cigarette smoking and the development of sarcoid.46-49 Hattori et al. sought to assess the relationship between sarcoidosis and cigarette smoking in Japan.50 In contrast with other studies undertaken, they found a strikingly high rate of smoking in their sarcoid patients (59.6% in men and 27.9% of women). Smoking was commoner in sarcoid patients than in age-matched controls in almost all deciles of age apart from men in their 30s. Interestingly, Hattori and colleagues noted a trend towards increased parenchymal involvement is sarcoid patients who smoked compared with those who had never smoked.50 While these data are thought provoking, they need to be caveated with the fact that the study was retrospective and relied on smoking prevalence data for the general Japanese population that was drawn from separately conducted research. Suchankova et al. undertook a study of myeloid cells isolated from the bronchoalveolar lavage of patients with sarcoid.51 They explored the expression pattern of triggering receptor expressed on myeloid cells-1 and -2. These two receptors belong to the immunoglobulin superfamily, play a role in the innate immune response to infection, and act to drive cell fusion and granuloma formation. Both triggering receptor expressed on myeloid cells-1 and -2 expressions were increased on the cell surface of bronchoalveolar lavage cells in sarcoid when compared with bronchoalveolar lavage cells isolated from individuals with other forms of ILD. These observations support a role for infection as a trigger for the development of sarcoid. 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