Regenerative Metaplastic Clones in COPD Lung Drive Inflammation and Fibrosis. Rao Wei,Wang Shan,Duleba Marcin,Niroula Suchan,Goller Kristina,Xie Jingzhong,Mahalingam Rajasekaran,Neupane Rahul,Liew Audrey-Ann,Vincent Matthew,Okuda Kenichi,O'Neal Wanda K,Boucher Richard C,Dickey Burton F,Wechsler Michael E,Ibrahim Omar,Engelhardt John F,Mertens Tinne C J,Wang Wei,Jyothula Soma S K,Crum Christopher P,Karmouty-Quintana Harry,Parekh Kalpaj R,Metersky Mark L,McKeon Frank D,Xian Wa Cell Chronic obstructive pulmonary disease (COPD) is a progressive condition of chronic bronchitis, small airway obstruction, and emphysema that represents a leading cause of death worldwide. While inflammation, fibrosis, mucus hypersecretion, and metaplastic epithelial lesions are hallmarks of this disease, their origins and dependent relationships remain unclear. Here we apply single-cell cloning technologies to lung tissue of patients with and without COPD. Unlike control lungs, which were dominated by normal distal airway progenitor cells, COPD lungs were inundated by three variant progenitors epigenetically committed to distinct metaplastic lesions. When transplanted to immunodeficient mice, these variant clones induced pathology akin to the mucous and squamous metaplasia, neutrophilic inflammation, and fibrosis seen in COPD. Remarkably, similar variants pre-exist as minor constituents of control and fetal lung and conceivably act in normal processes of immune surveillance. However, these same variants likely catalyze the pathologic and progressive features of COPD when expanded to high numbers. 10.1016/j.cell.2020.03.047
    Inflammatory mechanisms in patients with chronic obstructive pulmonary disease. Barnes Peter J The Journal of allergy and clinical immunology Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation affecting predominantly the lung parenchyma and peripheral airways that results in largely irreversible and progressive airflow limitation. This inflammation is characterized by increased numbers of alveolar macrophages, neutrophils, T lymphocytes (predominantly TC1, TH1, and TH17 cells), and innate lymphoid cells recruited from the circulation. These cells and structural cells, including epithelial and endothelial cells and fibroblasts, secrete a variety of proinflammatory mediators, including cytokines, chemokines, growth factors, and lipid mediators. Although most patients with COPD have a predominantly neutrophilic inflammation, some have an increase in eosinophil counts, which might be orchestrated by TH2 cells and type 2 innate lymphoid cells though release of IL-33 from epithelial cells. These patients might be more responsive to corticosteroids and bronchodilators. Oxidative stress plays a key role in driving COPD-related inflammation, even in ex-smokers, and might result in activation of the proinflammatory transcription factor nuclear factor κB (NF-κB), impaired antiprotease defenses, DNA damage, cellular senescence, autoantibody generation, and corticosteroid resistance though inactivation of histone deacetylase 2. Systemic inflammation is also found in patients with COPD and can worsen comorbidities, such as cardiovascular diseases, diabetes, and osteoporosis. Accelerated aging in the lungs of patients with COPD can also generate inflammatory protein release from senescent cells in the lung. In the future, it will be important to recognize phenotypes of patients with optimal responses to more specific therapies, and development of biomarkers that identify the therapeutic phenotypes will be important. 10.1016/j.jaci.2016.05.011
    Hallmarks of the ageing lung. Meiners Silke,Eickelberg Oliver,Königshoff Melanie The European respiratory journal Ageing is the main risk factor for major non-communicable chronic lung diseases, including chronic obstructive pulmonary disease, most forms of lung cancer and idiopathic pulmonary fibrosis. While the prevalence of these diseases continually increases with age, their respective incidence peaks at different times during the lifespan, suggesting specific effects of ageing on the onset and/or pathogenesis of chronic obstructive pulmonary disease, lung cancer and idiopathic pulmonary fibrosis. Recently, the nine hallmarks of ageing have been defined as cell-autonomous and non-autonomous pathways involved in ageing. Here, we review the available evidence for the involvement of each of these hallmarks in the pathogenesis of chronic obstructive pulmonary disease, lung cancer, or idiopathic pulmonary fibrosis. Importantly, we propose an additional hallmark, "dysregulation of the extracellular matrix", which we argue acts as a crucial modifier of cell-autonomous changes and functions, and as a key feature of the above-mentioned lung diseases. 10.1183/09031936.00186914
    Mechanisms of development of multimorbidity in the elderly. Barnes Peter J The European respiratory journal In ageing populations many patients have multiple diseases characterised by acceleration of the normal ageing process. Better understanding of the signalling pathways and cellular events involved in ageing shows that these are characteristic of many chronic degenerative diseases, such as chronic obstructive pulmonary disease (COPD), chronic cardiovascular and metabolic diseases, and neurodegeneration. Common mechanisms have now been identified in these diseases, which show evidence of cellular senescence with telomere shortening, activation of PI3K-AKT-mTOR signalling, impaired autophagy, mitochondrial dysfunction, stem cell exhaustion, epigenetic changes, abnormal microRNA profiles, immunosenescence and low grade chronic inflammation ("inflammaging"). Many of these pathways are driven by chronic oxidative stress. There is also a reduction in anti-ageing molecules, such as sirtuins and Klotho, which further accelerates the ageing process. Understanding these molecular mechanisms has identified several novel therapeutic targets and several drugs have already been developed that may slow the ageing process, as well as lifestyle interventions, such as diet and physical activity. This indicates that in the future new treatment approaches may target the common pathways involved in multimorbidity and this area of research should be given high priority. Thus, COPD should be considered as a component of multimorbidity and common disease pathways, particularly accelerated ageing, should be targeted. 10.1183/09031936.00229714
    Ageing and the border between health and disease. MacNee William,Rabinovich Roberto A,Choudhury Gourab The European respiratory journal Ageing is associated with a progressive degeneration of the tissues, which has a negative impact on the structure and function of vital organs and is among the most important known risk factors for most chronic diseases. Since the proportion of the world's population aged >60 years will double in the next four decades, this will be accompanied by an increased incidence of chronic age-related diseases that will place a huge burden on healthcare resources. There is increasing evidence that many chronic inflammatory diseases represent an acceleration of the ageing process. Chronic pulmonary diseases represents an important component of the increasingly prevalent multiple chronic debilitating diseases, which are a major cause of morbidity and mortality, particularly in the elderly. The lungs age and it has been suggested that chronic obstructive pulmonary disease (COPD) is a condition of accelerated lung ageing and that ageing may provide a mechanistic link between COPD and many of its extrapulmonary effects and comorbidities. In this article we will describe the physiological changes and mechanisms of ageing, with particular focus on the pulmonary effects of ageing and how these may be relevant to the development of COPD and its major extrapulmonary manifestations. 10.1183/09031936.00134014
    Tobacco smoke-induced lung fibrosis and emphysema. Morse Danielle,Rosas Ivan O Annual review of physiology Despite public health campaigns discouraging smoking, 1,000 American children every day become smokers, ensuring that tobacco-related health complications will be with us for decades to come. Smoking is the greatest risk factor for both chronic obstructive lung disease and interstitial lung disease. The facts that not every smoker develops chronic lung disease and that lung pathology differs markedly among smokers indicate that individual susceptibility must be a central determinant of lung injury responses to cigarette smoke. Comparative examination of pathogenic mechanisms of smoke-induced lung disease can shed light on the homeostatic pathways critical to maintaining lung health. In this review, we explore common and divergent biological forces tilting the lung homeostatic balance away from health and toward emphysema or pulmonary fibrosis. We emphasize recent insights that highlight the greatest contrasts or similarities in the pathogenesis of these two chronic lung disease phenotypes. 10.1146/annurev-physiol-021113-170411
    Pathogenesis of chronic obstructive pulmonary disease. Tuder Rubin M,Petrache Irina The Journal of clinical investigation The current epidemic of chronic obstructive pulmonary disease (COPD) has produced a worldwide health care burden, approaching that imposed by transmittable infectious diseases. COPD is a multidimensional disease, with varied intermediate and clinical phenotypes. This Review discusses the pathogenesis of COPD, with particular focus on emphysema, based on the concept that pulmonary injury involves stages of initiation (by exposure to cigarette smoke, pollutants, and infectious agents), progression, and consolidation. Tissue damage entails complex interactions among oxidative stress, inflammation, extracellular matrix proteolysis, and apoptotic and autophagic cell death. Lung damage by cigarette smoke ultimately leads to self-propagating processes, resulting in macromolecular and structural alterations - features similar to those seen in aging. 10.1172/JCI60324
    Abnormal lung aging in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Faner Rosa,Rojas Mauricio,Macnee William,Agustí Alvar American journal of respiratory and critical care medicine Aging is a natural process characterized by progressive functional impairment and reduced capacity to respond appropriately to environmental stimuli and injury. The incidence of two common chronic respiratory diseases (chronic obstructive pulmonary disease [COPD] and idiopathic pulmonary fibrosis [IPF]) increases with advanced age. It is plausible, therefore, that abnormal regulation of the mechanisms of normal aging may contribute to the pathobiology of both COPD and IPF. This review discusses the available evidence supporting a number of aging mechanisms, including oxidative stress, telomere length regulation, cellular and immunosenescence, as well as changes in a number of antiaging molecules and the extracellular matrix, which are abnormal in COPD and/or IPF. A better understanding of these abnormalities may help in the design of novel and better therapeutic interventions for these patients. 10.1164/rccm.201202-0282PP
    Oxidative stress-based therapeutics in COPD. Barnes Peter J Redox biology Oxidative stress is a major driving mechanism in the pathogenesis of COPD. There is increased oxidative stress in the lungs of COPD patients due to exogenous oxidants in cigarette smoke and air pollution and due to endogenous generation of reactive oxygen species by inflammatory and structural cells in the lung. Mitochondrial oxidative stress may be particularly important in COPD. There is also a reduction in antioxidant defences, with inactivation of several antioxidant enzymes and the transcription factors Nrf2 and FOXO that regulate multiple antioxidant genes. Increased systemic oxidative stress may exacerbate comorbidities and contribute to skeletal muscle weakness. Oxidative stress amplifies chronic inflammation, stimulates fibrosis and emphysema, causes corticosteroid resistance, accelerates lung aging, causes DNA damage and stimulates formation of autoantibodies. This suggests that treating oxidative stress by antioxidants or enhancing endogenous antioxidants should be an effective strategy to treat the underlying pathogenetic mechanisms of COPD. Most clinical studies in COPD have been conducted using glutathione-generating antioxidants such as N-acetylcysteine, carbocysteine and erdosteine, which reduce exacerbations in COPD patients, but it is not certain whether this is due to their antioxidant or mucolytic properties. Dietary antioxidants have so far not shown to be clinically effective in COPD. There is a search for more effective antioxidants, which include superoxide dismutase mimetics, NADPH oxidase inhibitors, mitochondria-targeted antioxidants and Nrf2 activators. 10.1016/j.redox.2020.101544
    Senotherapy: A New Horizon for COPD Therapy. Baker Jonathan R,Donnelly Louise E,Barnes Peter J Chest There is increasing evidence that COPD is a disease of accelerated lung aging, with the accumulation of senescent cells that lose their ability to repair and secrete multiple inflammatory proteins known as the senescence-associated secretory phenotype (SASP), which mimic the profile of inflammatory mediators secreted in COPD. This review discusses novel drugs (senotherapies) that target cellular senescence and which may be a promising therapeutic approach to prevent currently unaddressed disease progression and mortality in COPD. A major pathway leading to senescence is via the activation of phosphoinositide-3-kinase/mammalian target of rapamycin signaling. Existing drugs, such as rapamycin and metformin, target this pathway. Mitochondrial oxidative stress is a key driving mechanism for this pathway, and mitochondria-targeted antioxidants are promising. A key finding in COPD is loss of antiaging molecules such as sirtuin-1 and sirtuin-6, which are reduced by phosphoinositide-3-kinase/mammalian target of rapamycin signaling through microRNA-34a. Sirtuin activators are in development, and inhibiting microRNA-34a restores sirtuin expression experimentally in COPD cells. Senolytic therapies induce apoptosis and removal of senescent cells and reduce the senescence-associated secretory phenotype response in animal models of aging and in pilot clinical studies of other age-related diseases. A combination of senolytics and senostatics (drugs that inhibit cellular senescence) may be a valuable new approach to COPD, especially if started early in the disease process. Furthermore, COPD is associated with several comorbidities that share the same aging pathways which may be spread by extracellular vesicles, and thus a single treatment for all these diseases is feasible in the future to extend health span. 10.1016/j.chest.2020.01.027
    The Aging Lung: Is Lung Health Good Health for Older Adults? Bowdish Dawn M E Chest The prevalence of lung conditions, such as COPD and pulmonary fibrosis, and lung infections, such as pneumonia, increases sharply with age. The physiologic, cellular, and immunologic changes that occur during aging contribute to the development of lung disease. Studies of age-related changes in physiology and function are not only key to preventing or ameliorating disease, they are also essential for understanding healthy aging. Individuals with good lung function live longer, healthier lives, although the mechanisms by which this scenario occurs are not understood. The present article reviews changes in the aging lung that facilitate development of disease and the evidence supporting the idea that robust lung function reduces the risk of developing chronic inflammatory conditions that occur with age. 10.1016/j.chest.2018.09.003
    Lipid-based biomarkers for CVD, COPD, and aging - A translational perspective. Ekroos Kim,Lavrynenko Oksana,Titz Bjoern,Pater Calin,Hoeng Julia,Ivanov Nikolai V Progress in lipid research For many diseases, there is an unmet need for new or better biomarkers for improved disease risk assessment and monitoring, as available markers lack sufficient specificity. Lipids are drawing major interest as potential candidates for filling these gaps. This has recently been demonstrated by the identification of selective ceramides for prediction of cardiovascular mortality, enabling improved risk assessment of cardiovascular disease compared with conventional clinical markers. In this review, we discuss current lipid biomarker findings and the possible connection between cardiovascular disease, chronic obstructive pulmonary disease, and aging. Moreover, we discuss how to overcome the current roadblocks facing lipid biomarker research. We stress the need for improved quantification, standardization of methodologies, and establishment of initial reference values to allow for an efficient transfer path of research findings into the clinical landscape, and, ultimately, to put newly identified biomarkers into practical use. 10.1016/j.plipres.2020.101030
    Senescence in COPD and Its Comorbidities. Barnes Peter J Annual review of physiology Chronic obstructive pulmonary disease (COPD) is regarded as a disease of accelerated lung aging. This affliction shows all of the hallmarks of aging, including telomere shortening, cellular senescence, activation of PI3 kinase-mTOR signaling, impaired autophagy, mitochondrial dysfunction, stem cell exhaustion, epigenetic changes, abnormal microRNA profiles, immunosenescence, and a low-grade chronic inflammation (inflammaging). Many of these pathways are driven by chronic exogenous and endogenous oxidative stress. There is also a reduction in antiaging molecules, such as sirtuins and Klotho, which further accelerate the aging process. COPD is associated with several comorbidities (multimorbidity), such as cardiovascular and metabolic diseases, that share the same pathways of accelerated aging. Understanding these mechanisms has helped identify several novel therapeutic targets, and several drugs and dietary interventions are now in development to treat multimorbidity. 10.1146/annurev-physiol-022516-034314
    The Contribution of Small Airway Obstruction to the Pathogenesis of Chronic Obstructive Pulmonary Disease. Hogg James C,Paré Peter D,Hackett Tillie-Louise Physiological reviews The hypothesis that the small conducting airways were the major site of obstruction to airflow in normal lungs was introduced by Rohrer in 1915 and prevailed until Weibel introduced a quantitative method of studying lung anatomy in 1963. Green repeated Rohrer's calculations using Weibels new data in 1965 and found that the smaller conducting airways offered very little resistance to airflow. This conflict was resolved by seminal experiments conducted by Macklem and Mead in 1967, which confirmed that a small proportion of the total lower airways resistance is attributable to small airways <2 mm in diameter. Shortly thereafter, Hogg, Macklem, and Thurlbeck used this technique to show that small airways become the major site of obstruction in lungs affected by emphysema. These and other observations led Mead to write a seminal editorial in 1970 that postulated the small airways are a silent zone within normal lungs where disease can accumulate over many years without being noticed. This review provides a progress report since the 1970s on methods for detecting chronic obstructive pulmonary disease, the structural nature of small airways' disease, and the cellular and molecular mechanisms that are thought to underlie its pathogenesis. 10.1152/physrev.00025.2015
    The microbiome in respiratory medicine: current challenges and future perspectives. Faner Rosa,Sibila Oriol,Agustí Alvar,Bernasconi Eric,Chalmers James D,Huffnagle Gary B,Manichanh Chaysavanh,Molyneaux Philip L,Paredes Roger,Pérez Brocal Vicente,Ponomarenko Julia,Sethi Sanjay,Dorca Jordi,Monsó Eduard The European respiratory journal The healthy lung has previously been considered to be a sterile organ because standard microbiological culture techniques consistently yield negative results. However, culture-independent techniques report that large numbers of microorganisms coexist in the lung. There are many unknown aspects in the field, but available reports show that the lower respiratory tract microbiota: 1) is similar in healthy subjects to the oropharyngeal microbiota and dominated by members of the Firmicutes, Bacteroidetes and Proteobacteria phyla; 2) shows changes in smokers and well-defined differences in chronic respiratory diseases, although the temporal and spatial kinetics of these changes are only partially known; and 3) shows relatively abundant non-cultivable bacteria in chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis and bronchiectasis, with specific patterns for each disease. In all of these diseases, a loss of diversity, paralleled by an over-representation of Proteobacteria (dysbiosis), has been related to disease severity and exacerbations. However, it is unknown whether dysbiosis is a cause or a consequence of the damage to bronchoalveolar surfaces.Finally, little is known about bacterial functionality and the interactions between viruses, fungi and bacteria. It is expected that future research in bacterial gene expressions, metagenomics longitudinal analysis and host-microbiome animal models will help to move towards targeted microbiome interventions in respiratory diseases. 10.1183/13993003.02086-2016
    Breaking the In Vitro Barrier in Respiratory Medicine. Engineered Microphysiological Systems for Chronic Obstructive Pulmonary Disease and Beyond. Benam Kambez H,Königshoff Melanie,Eickelberg Oliver American journal of respiratory and critical care medicine 10.1164/rccm.201709-1795PP
    Pulmonary vascular endothelium: the orchestra conductor in respiratory diseases: Highlights from basic research to therapy. Huertas Alice,Guignabert Christophe,Barberà Joan A,Bärtsch Peter,Bhattacharya Jahar,Bhattacharya Sunita,Bonsignore Maria R,Dewachter Laurence,Dinh-Xuan Anh Tuan,Dorfmüller Peter,Gladwin Mark T,Humbert Marc,Kotsimbos Tom,Vassilakopoulos Theodoros,Sanchez Olivier,Savale Laurent,Testa Ugo,Wilkins Martin R The European respiratory journal The European Respiratory Society (ERS) Research Seminar entitled "Pulmonary vascular endothelium: orchestra conductor in respiratory diseases - highlights from basic research to therapy" brought together international experts in dysfunctional pulmonary endothelium, from basic science to translational medicine, to discuss several important aspects in acute and chronic lung diseases. This review will briefly sum up the different topics of discussion from this meeting which was held in Paris, France on October 27-28, 2016. It is important to consider that this paper does not address all aspects of endothelial dysfunction but focuses on specific themes such as: 1) the complex role of the pulmonary endothelium in orchestrating the host response in both health and disease (acute lung injury, chronic obstructive pulmonary disease, high-altitude pulmonary oedema and pulmonary hypertension); and 2) the potential value of dysfunctional pulmonary endothelium as a target for innovative therapies. 10.1183/13993003.00745-2017
    Targeting cytokines to treat asthma and chronic obstructive pulmonary disease. Barnes Peter J Nature reviews. Immunology Cytokines play a key role in orchestrating and perpetuating the chronic airway inflammation in asthma and chronic obstructive pulmonary disease (COPD), making them attractive targets for treating these disorders. Asthma and some cases of COPD are mainly driven by type 2 immune responses, which comprise increased airway eosinophils, T helper 2 (T2) cells and group 2 innate lymphoid cells (ILC2s) and the secretion of IL-4, IL-5 and IL-13. Clinical trials of antibodies that block these interleukins have shown reduced acute exacerbations and oral corticosteroid use and improvements in lung function and symptoms in selected patients. More recent approaches that block upstream cytokines, such as thymic stromal lymphopoietin (TSLP), show promise in improving patient outcome. Importantly, the clinical trials in cytokine blockade have highlighted the crucial importance of patient selection for the successful use of these expensive therapies and the need for biomarkers to better predict drug responses. 10.1038/s41577-018-0006-6
    Female Sex and Gender in Lung/Sleep Health and Disease. Increased Understanding of Basic Biological, Pathophysiological, and Behavioral Mechanisms Leading to Better Health for Female Patients with Lung Disease. Han MeiLan K,Arteaga-Solis Emilio,Blenis John,Bourjeily Ghada,Clegg Deborah J,DeMeo Dawn,Duffy Jeanne,Gaston Ben,Heller Nicola M,Hemnes Anna,Henske Elizabeth Petri,Jain Raksha,Lahm Tim,Lancaster Lisa H,Lee Joyce,Legato Marianne J,McKee Sherry,Mehra Reena,Morris Alison,Prakash Y S,Stampfli Martin R,Gopal-Srivastava Rashmi,Laposky Aaron D,Punturieri Antonello,Reineck Lora,Tigno Xenia,Clayton Janine American journal of respiratory and critical care medicine Female sex/gender is an undercharacterized variable in studies related to lung development and disease. Notwithstanding, many aspects of lung and sleep biology and pathobiology are impacted by female sex and female reproductive transitions. These may manifest as differential gene expression or peculiar organ development. Some conditions are more prevalent in women, such as asthma and insomnia, or, in the case of lymphangioleiomyomatosis, are seen almost exclusively in women. In other diseases, presentation differs, such as the higher frequency of exacerbations experienced by women with chronic obstructive pulmonary disease or greater cardiac morbidity among women with sleep-disordered breathing. Recent advances in -omics and behavioral science provide an opportunity to specifically address sex-based differences and explore research needs and opportunities that will elucidate biochemical pathways, thus enabling more targeted/personalized therapies. To explore the status of and opportunities for research in this area, the NHLBI, in partnership with the NIH Office of Research on Women's Health and the Office of Rare Diseases Research, convened a workshop of investigators in Bethesda, Maryland on September 18 and 19, 2017. At the workshop, the participants reviewed the current understanding of the biological, behavioral, and clinical implications of female sex and gender on lung and sleep health and disease, and formulated recommendations that address research gaps, with a view to achieving better health outcomes through more precise management of female patients with nonneoplastic lung disease. This report summarizes those discussions. 10.1164/rccm.201801-0168WS
    Chronic obstructive pulmonary disease subpopulations and phenotyping. Segal Leopoldo N,Martinez Fernando J The Journal of allergy and clinical immunology The diagnosis and treatment of chronic obstructive pulmonary disease (COPD) has been based largely on a one-size-fits-all approach. Diagnosis of COPD is based on meeting the physiologic criteria of fixed obstruction in forced expiratory flows and treatment focus on symptomatic relief, with limited effect on overall prognosis. However, patients with COPD have distinct features that determine very different evolutions of the disease. In this review we highlight distinct subgroups of COPD characterized by unique pathophysiologic derangements, response to treatment, and disease progression. It is likely that identification of subgroups of COPD will lead to discovery of much needed disease-modifying therapeutic approaches. We argue that a precision approach that integrates multiple dimensions (clinical, physiologic, imaging, and endotyping) is needed to move the field forward in the treatment of this disease. 10.1016/j.jaci.2018.02.035
    Key roles for lipid mediators in the adaptive immune response. Duffney Parker F,Falsetta Megan L,Rackow Ashley R,Thatcher Thomas H,Phipps Richard P,Sime Patricia J The Journal of clinical investigation Chronic inflammation is an underlying feature of many diseases, including chronic obstructive pulmonary disease, rheumatoid arthritis, asthma, and multiple sclerosis. There is an increasing appreciation of the dysregulation of adaptive immunity in chronic inflammatory and allergic diseases. The discovery of specialized pro-resolving lipid mediators (SPMs) that actively promote the resolution of inflammation has opened new avenues for the treatment of chronic inflammatory diseases. Much work has been done focusing on the impact of SPMs on innate immune cells. However, much less is known about the influence of SPMs on the development of antigen-specific adaptive immune responses. This Review highlights the important breakthroughs concerning the effects of SPMs on the key cell types involved in the development of adaptive immunity, namely dendritic cells, T cells, and B cells. 10.1172/JCI97951
    Why Does an Aging Smoker's Lung Develop Idiopathic Pulmonary Fibrosis and Not Chronic Obstructive Pulmonary Disease? Selman Moisés,Martinez Fernando J,Pardo Annie American journal of respiratory and critical care medicine 10.1164/rccm.201806-1166PP
    COPD biomarkers and phenotypes: opportunities for better outcomes with precision imaging. Washko George R,Parraga Grace The European respiratory journal A number of chronic diseases have benefited from both imaging and personalised medicine, but unfortunately, for patients with chronic obstructive pulmonary disease (COPD), there has been little clinical uptake or recognition of the key advances in thoracic imaging that might help detect disease early, or, perhaps more importantly, might help develop and phenotype patients for novel or personalised therapies that may halt disease progression. We outline our vision for how computed tomography and magnetic resonance imaging may be used to better inform COPD patient care, and, perhaps more importantly, how these may be used to help develop new therapies directed at early disease. We think that imaging and precision medicine should be considered and used together as "precision imaging" at specific stages of COPD when the major pathologies may be more responsive to therapy. While "precision medicine" is the tailoring of medical treatment to individual patients, we define "precision imaging" as the tailoring of specific therapies and interventions to individual patients with a detailed quantitative understanding of their specific imaging phenotypes and measurements. Finally, we stress the importance of "seeing" the pathology, because without this understanding, you can neither treat nor cure patients with COPD. 10.1183/13993003.01570-2018
    Cell Death in the Lung: The Apoptosis-Necroptosis Axis. Sauler Maor,Bazan Isabel S,Lee Patty J Annual review of physiology Regulated cell death is a major mechanism to eliminate damaged, infected, or superfluous cells. Previously, apoptosis was thought to be the only regulated cell death mechanism; however, new modalities of caspase-independent regulated cell death have been identified, including necroptosis, pyroptosis, and autophagic cell death. As an understanding of the cellular mechanisms that mediate regulated cell death continues to grow, there is increasing evidence that these pathways are implicated in the pathogenesis of many pulmonary disorders. This review summarizes our understanding of regulated cell death as it pertains to the pathogenesis of chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, and pulmonary arterial hypertension. 10.1146/annurev-physiol-020518-114320
    Current Status and Future Opportunities in Lung Precision Medicine Research with a Focus on Biomarkers. An American Thoracic Society/National Heart, Lung, and Blood Institute Research Statement. Wu Ann Chen,Kiley James P,Noel Patricia J,Amur Shashi,Burchard Esteban G,Clancy John P,Galanter Joshua,Inada Maki,Jones Tiffanie K,Kropski Jonathan A,Loyd James E,Nogee Lawrence M,Raby Benjamin A,Rogers Angela J,Schwartz David A,Sin Don D,Spira Avrum,Weiss Scott T,Young Lisa R,Himes Blanca E American journal of respiratory and critical care medicine BACKGROUND:Thousands of biomarker tests are either available or under development for lung diseases. In many cases, adoption of these tests into clinical practice is outpacing the generation and evaluation of sufficient data to determine clinical utility and ability to improve health outcomes. There is a need for a systematically organized report that provides guidance on how to understand and evaluate use of biomarker tests for lung diseases. METHODS:We assembled a diverse group of clinicians and researchers from the American Thoracic Society and leaders from the National Heart, Lung, and Blood Institute with expertise in various aspects of precision medicine to review the current status of biomarker tests in lung diseases. Experts summarized existing biomarker tests that are available for lung cancer, pulmonary arterial hypertension, idiopathic pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, sepsis, acute respiratory distress syndrome, cystic fibrosis, and other rare lung diseases. The group identified knowledge gaps that future research studies can address to efficiently translate biomarker tests into clinical practice, assess their cost-effectiveness, and ensure they apply to diverse, real-life populations. RESULTS:We found that the status of biomarker tests in lung diseases is highly variable depending on the disease. Nevertheless, biomarker tests in lung diseases show great promise in improving clinical care. To efficiently translate biomarkers into tests used widely in clinical practice, researchers need to address specific clinical unmet needs, secure support for biomarker discovery efforts, conduct analytical and clinical validation studies, ensure tests have clinical utility, and facilitate appropriate adoption into routine clinical practice. CONCLUSIONS:Although progress has been made toward implementation of precision medicine for lung diseases in clinical practice in certain settings, additional studies focused on addressing specific unmet clinical needs are required to evaluate the clinical utility of biomarkers; ensure their generalizability to diverse, real-life populations; and determine their cost-effectiveness. 10.1164/rccm.201810-1895ST
    Introduction to precision medicine in COPD. Leung Janice M,Obeidat Ma'en,Sadatsafavi Mohsen,Sin Don D The European respiratory journal Although there has been tremendous growth in our understanding of chronic obstructive pulmonary disease (COPD) and its pathophysiology over the past few decades, the pace of therapeutic innovation has been extremely slow. COPD is now widely accepted as a heterogeneous condition with multiple phenotypes and endotypes. Thus, there is a pressing need for COPD care to move from the current "one-size-fits-all" approach to a precision medicine approach that takes into account individual patient variability in genes, environment and lifestyle. Precision medicine is enabled by biomarkers that can: 1) accurately identify subgroups of patients who are most likely to benefit from therapeutics and those who will only experience harm (predictive biomarkers); 2) predict therapeutic responses to drugs at an individual level (response biomarkers); and 3) segregate patients who are at risk of poor outcomes from those who have relatively stable disease (prognostic biomarkers). In this essay, we will discuss the current concept of precision medicine and its relevance for COPD and explore ways to implement precision medicine for millions of patients across the world with COPD. 10.1183/13993003.02460-2018
    Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases. Barnes Peter J,Baker Jonathan,Donnelly Louise E American journal of respiratory and critical care medicine Cellular senescence is now considered an important driving mechanism for chronic lung diseases, particularly chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. Cellular senescence is due to replicative and stress-related senescence with activation of p53 and p16, respectively, leading to activation of p21 and cell cycle arrest. Senescent cells secrete multiple inflammatory proteins known as the senescence-associated secretory phenotype, leading to low-grade chronic inflammation, which further drives senescence. Loss of key antiaging molecules sirtuin-1 and sirtuin-6 may be important in acceleration of aging and arises from oxidative stress reducing phosphatase PTEN (phosphatase tensin homolog), thereby activating PI3K (phosphoinositide-3-kinase) and mTOR (mammalian target of rapamycin). MicroRNA-34a (miR-34a), which is regulated by PI3K-mTOR signaling, plays a pivotal role in reducing sirtuin-1/6, and its inhibition with an antagomir results in their restoration, reducing markers of senescence, reducing senescence-associated secretory phenotype, and reversing cell cycle arrest in epithelial cells from peripheral airways of patients with COPD. miR-570 is also involved in reduction of sirtuin-1 and cellular senescence and is activated by p38 mitogen-activated protein kinase. These miRNAs may be released from cells in extracellular vesicles that are taken up by other cells, thereby spreading senescence locally within the lung but also outside the lung through the circulation; this may account for comorbidities of COPD and other lung diseases. Understanding the mechanisms of cellular senescence may result in new treatments for chronic lung disease, either by inhibiting PI3K-mTOR signaling, by inhibiting specific miRNAs, or by deletion of senescent cells with senolytic therapies, already shown to be effective in experimental lung fibrosis. 10.1164/rccm.201810-1975TR
    Functional effects of the microbiota in chronic respiratory disease. Budden Kurtis F,Shukla Shakti D,Rehman Saima Firdous,Bowerman Kate L,Keely Simon,Hugenholtz Philip,Armstrong-James Darius P H,Adcock Ian M,Chotirmall Sanjay H,Chung Kian Fan,Hansbro Philip M The Lancet. Respiratory medicine The composition of the lung microbiome is increasingly well characterised, with changes in microbial diversity or abundance observed in association with several chronic respiratory diseases such as asthma, cystic fibrosis, bronchiectasis, and chronic obstructive pulmonary disease. However, the precise effects of the microbiome on pulmonary health and the functional mechanisms by which it regulates host immunity are only now beginning to be elucidated. Bacteria, viruses, and fungi from both the upper and lower respiratory tract produce structural ligands and metabolites that interact with the host and alter the development and progression of chronic respiratory diseases. Here, we review recent advances in our understanding of the composition of the lung microbiome, including the virome and mycobiome, the mechanisms by which these microbes interact with host immunity, and their functional effects on the pathogenesis, exacerbations, and comorbidities of chronic respiratory diseases. We also describe the present understanding of how respiratory microbiota can influence the efficacy of common therapies for chronic respiratory disease, and the potential of manipulation of the microbiome as a therapeutic strategy. Finally, we highlight some of the limitations in the field and propose how these could be addressed in future research. 10.1016/S2213-2600(18)30510-1
    Airway inflammation in COPD: progress to precision medicine. Brightling Christopher,Greening Neil The European respiratory journal Chronic obstructive pulmonary disease (COPD) is a significant cause of morbidity and mortality worldwide, and its prevalence is increasing. Airway inflammation is a consistent feature of COPD and is implicated in the pathogenesis and progression of COPD, but anti-inflammatory therapy is not first-line treatment. The inflammation has many guises and phenotyping this heterogeneity has revealed different patterns. Neutrophil-associated COPD with activation of the inflammasome, T1 and T17 immunity is the most common phenotype with eosinophil-associated T2-mediated immunity in a minority and autoimmunity observed in more severe disease. Biomarkers have enabled targeted anti-inflammatory strategies and revealed that corticosteroids are most effective in those with evidence of eosinophilic inflammation, whereas, in contrast to severe asthma, response to anti-interleukin-5 biologicals in COPD has been disappointing, with smaller benefits for the same intensity of eosinophilic inflammation questioning its role in COPD. Biological therapies beyond T2-mediated inflammation have not demonstrated benefit and in some cases increased risk of infection, suggesting that neutrophilic inflammation and inflammasome activation might be largely driven by bacterial colonisation and dysbiosis. Herein we describe current and future biomarker approaches to assess inflammation in COPD and how this might reveal tractable approaches to precision medicine and unmask important host-environment interactions leading to airway inflammation. 10.1183/13993003.00651-2019
    Update on the Pathogenesis of Chronic Obstructive Pulmonary Disease. Agustí Alvar,Hogg James C The New England journal of medicine 10.1056/NEJMra1900475
    Update on Clinical Aspects of Chronic Obstructive Pulmonary Disease. Celli Bartolomé R,Wedzicha Jadwiga A The New England journal of medicine 10.1056/NEJMra1900500
    Aging and Lung Disease. Cho Soo Jung,Stout-Delgado Heather W Annual review of physiology People worldwide are living longer, and it is estimated that by 2050, the proportion of the world's population over 60 years of age will nearly double. Natural lung aging is associated with molecular and physiological changes that cause alterations in lung function, diminished pulmonary remodeling and regenerative capacity, and increased susceptibility to acute and chronic lung diseases. As the aging population rapidly grows, it is essential to examine how alterations in cellular function and cell-to-cell interactions of pulmonary resident cells and systemic immune cells contribute to a higher risk of increased susceptibility to infection and development of chronic diseases, such as chronic obstructive pulmonary disease and interstitial pulmonary fibrosis. This review provides an overview of physiological, structural, and cellular changes in the aging lung and immune system that facilitate the development and progression of disease. 10.1146/annurev-physiol-021119-034610
    Genetics of COPD. Silverman Edwin K Annual review of physiology Although chronic obstructive pulmonary disease (COPD) risk is strongly influenced by cigarette smoking, genetic factors are also important determinants of COPD. In addition to Mendelian syndromes such as alpha-1 antitrypsin deficiency, many genomic regions that influence COPD susceptibility have been identified in genome-wide association studies. Similarly, multiple genomic regions associated with COPD-related phenotypes, such as quantitative emphysema measures, have been found. Identifying the functional variants and key genes within these association regions remains a major challenge. However, newly identified COPD susceptibility genes are already providing novel insights into COPD pathogenesis. Network-based approaches that leverage these genetic discoveries have the potential to assist in decoding the complex genetic architecture of COPD. 10.1146/annurev-physiol-021317-121224
    Blood Eosinophil Counts in Clinical Trials for Chronic Obstructive Pulmonary Disease. Singh Dave,Bafadhel Mona,Brightling Christopher E,Sciurba Frank C,Curtis Jeffrey L,Martinez Fernando J,Pasquale Cara B,Merrill Debora D,Metzdorf Norbert,Petruzzelli Stefano,Tal-Singer Ruth,Compton Christopher,Rennard Stephen,Martin Ubaldo J American journal of respiratory and critical care medicine 10.1164/rccm.201912-2384PP
    Proactive Integration of Geriatrics and Palliative Care Principles Into Practice for Chronic Obstructive Pulmonary Disease. Iyer Anand S,Curtis J Randall,Meier Diane E JAMA internal medicine 10.1001/jamainternmed.2020.1088
    Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis. Adams Taylor S,Schupp Jonas C,Poli Sergio,Ayaub Ehab A,Neumark Nir,Ahangari Farida,Chu Sarah G,Raby Benjamin A,DeIuliis Giuseppe,Januszyk Michael,Duan Qiaonan,Arnett Heather A,Siddiqui Asim,Washko George R,Homer Robert,Yan Xiting,Rosas Ivan O,Kaminski Naftali Science advances We provide a single-cell atlas of idiopathic pulmonary fibrosis (IPF), a fatal interstitial lung disease, by profiling 312,928 cells from 32 IPF, 28 smoker and nonsmoker controls, and 18 chronic obstructive pulmonary disease (COPD) lungs. Among epithelial cells enriched in IPF, we identify a previously unidentified population of aberrant basaloid cells that coexpress basal epithelial, mesenchymal, senescence, and developmental markers and are located at the edge of myofibroblast foci in the IPF lung. Among vascular endothelial cells, we identify an ectopically expanded cell population transcriptomically identical to bronchial restricted vascular endothelial cells in IPF. We confirm the presence of both populations by immunohistochemistry and independent datasets. Among stromal cells, we identify IPF myofibroblasts and invasive fibroblasts with partially overlapping cells in control and COPD lungs. Last, we confirm previous findings of profibrotic macrophage populations in the IPF lung. Our comprehensive catalog reveals the complexity and diversity of aberrant cellular populations in IPF. 10.1126/sciadv.aba1983
    Epithelial cell-specific loss of function of causes a spontaneous COPD-like phenotype and up-regulates expression in mice. Do-Umehara Hanh Chi,Chen Cong,Zhang Qiao,Misharin Alexander V,Abdala-Valencia Hiam,Casalino-Matsuda S Marina,Reyfman Paul A,Anekalla Kishore R,Gonzalez-Gonzalez Francisco J,Sala Marc A,Peng Chao,Wu Ping,Wong Catherine C L,Kalhan Ravi,Bharat Ankit,Perlman Harris,Ridge Karen M,Sznajder Jacob I,Sporn Peter H S,Chandel Navdeep S,Yu Jindan,Fu Xiangdong,Petrache Irina,Tuder Rubin,Budinger G R Scott,Liu Jing Science advances Cigarette smoking, the leading cause of chronic obstructive pulmonary disease (COPD), has been implicated as a risk factor for severe disease in patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we show that mice with lung epithelial cell-specific loss of function of , which we identified as a negative regulator of nuclear factor κB (NF-κB) signaling, spontaneously develop progressive age-related changes resembling COPD. Furthermore, loss of Miz1 up-regulates the expression of , the receptor for SARS-CoV-2. Concomitant partial loss of κ prevented the development of COPD-like phenotype in -deficient mice. Miz1 protein levels are reduced in the lungs from patients with COPD, and in the lungs of mice exposed to chronic cigarette smoke. Our data suggest that Miz1 down-regulation-induced sustained activation of NF-κB-dependent inflammation in the lung epithelium is sufficient to induce progressive lung and airway destruction that recapitulates features of COPD, with implications for COVID-19. 10.1126/sciadv.abb7238