Pulmonary Macrophages: A New Therapeutic Pathway in Fibrosing Lung Disease? Byrne Adam J,Maher Toby M,Lloyd Clare M Trends in molecular medicine Pulmonary fibrosis (PF) is a growing clinical problem which can result in breathlessness or respiratory failure and has an average life expectancy of 3 years from diagnosis. Therapeutic options for PF are limited and there is therefore a significant unmet clinical need. The recent resurgent interest in macrophage biology has led to a new understanding of lung macrophage origins, biology, and phenotypes. In this review we discuss fibrotic mechanisms and focus on the role of macrophages during fibrotic lung disease. Data from both human and murine studies are reviewed, highlighting novel macrophage-orientated biomarkers for disease diagnosis and potential targets for future anti-fibrotic therapies. 10.1016/j.molmed.2016.02.004
    Reversal of bleomycin-induced rat pulmonary fibrosis by a xenograft of human umbilical mesenchymal stem cells from Wharton's jelly. Chu Kuo-An,Wang Shih-Yao,Yeh Chang-Ching,Fu Tz-Win,Fu Yu-Yi,Ko Tsui-Ling,Chiu Mei-Miao,Chen Tien-Hua,Tsai Pei-Jiun,Fu Yu-Show Theranostics Pulmonary fibrosis (PF) is a progressive and irreversible condition with various causes, and no effective treatment has been found to rescue fibrotic lungs. Successful recovery from PF requires inhibiting inflammation, promoting collagen degradation and stimulating alveolar regeneration. Human umbilical mesenchymal stem cells (HUMSCs) not only regulate immune responses but also synthesize and release hyaluronan to improve lung regeneration. This study investigated the feasibility of HUMSC engraftment into rats with bleomycin (BLM)-induced PF to explore HUMSC therapeutic effects/outcomes. A unique BLM-induced left-lung-dominated PF animal model was established. Rats were transplanted with low-dose (5×10) or high-dose (2.5×10) HUMSCs on Day 21 after BLM injection. Combinations in co-culture of pulmonary macrophages, fibroblasts, HUMSCs treated with BLM and the same conditions on alveolar epithelia versus HUMSCs were evaluated. Rats with high-dose HUMSC engraftment displayed significant recovery, including improved blood oxygen saturation levels and respiratory rates. High-dose HUMSC transplantation reversed alveolar injury, reduced cell infiltration and ameliorated collagen deposition. One month posttransplantation, HUMSCs in the rats' lungs remained viable and secreted cytokines without differentiating into alveolar or vascular epithelial cells. Moreover, HUMSCs decreased epithelial-mesenchymal transition in pulmonary inflammation, enhanced macrophage matrix-metallopeptidase-9 (MMP-9) expression for collagen degradation, and promoted toll-like receptor-4 (TLR-4) expression in the lung for alveolar regeneration. In coculture studies, HUMSCs elevated the MMP-9 level in pulmonary macrophages, released hyaluronan into the medium and stimulated the TLR-4 quantity in the alveolar epithelium. Transplanted HUMSCs exhibit long-term viability in rat lungs and can effectively reverse rat PF. 10.7150/thno.33741
    Imatinib-loaded gold nanoparticles inhibit proliferation of fibroblasts and macrophages from systemic sclerosis patients and ameliorate experimental bleomycin-induced lung fibrosis. Codullo Veronica,Cova Emanuela,Pandolfi Laura,Breda Silvia,Morosini Monica,Frangipane Vanessa,Malatesta Manuela,Calderan Laura,Cagnone Maddalena,Pacini Chiara,Cavagna Lorenzo,Recalde Helios,Distler Jörg H W,Giustra Marco,Prosperi Davide,Colombo Miriam,Meloni Federica,Montecucco Carlomaurizio Journal of controlled release : official journal of the Controlled Release Society Interstitial lung involvement in Systemic Sclerosis (SSc-ILD) is a complication with high morbidity and mortality. Specifically, engineered gold nanoparticles (GNPs) are proposed as targeted delivery system increasing efficacy of drugs with antifibrotic effect, such as tyrosine kinases. We aimed to test in vitro and in vivo the activity of targeted Imatinib (Im)-loaded GNP on SSc-ILD patients derived cells and in experimental model of lung fibrosis. GNPs functionalized with anti-CD44 and loaded with Im (GNP-HCIm) were synthesized. Lung fibroblasts (LFs) and alveolar macrophages from bronchoalveolar lavage fluids of SSc-ILD patients were cultured in presence of nanoparticles. GNP-HCIm significantly inhibited proliferation and viability inducing apoptosis of LFs and effectively reduced IL-8 release, viability and M2 polarization in alveolar macrophages. Anti-fibrotic effect of tracheal instilled GNP-HCIm was evaluated on bleomycin lung fibrosis mouse model comparing effect with common route of Im administration. GNP-HCIm were able to reduce significantly lung fibrotic changes and collagen deposition. Finally, electron microscopy revealed the presence of GNPs inside alveolar macrophages. These data support the use of GNPs locally administered in the development of new therapeutic approaches to SSc-ILD. 10.1016/j.jconrel.2019.08.015
    Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. Misharin Alexander V,Morales-Nebreda Luisa,Reyfman Paul A,Cuda Carla M,Walter James M,McQuattie-Pimentel Alexandra C,Chen Ching-I,Anekalla Kishore R,Joshi Nikita,Williams Kinola J N,Abdala-Valencia Hiam,Yacoub Tyrone J,Chi Monica,Chiu Stephen,Gonzalez-Gonzalez Francisco J,Gates Khalilah,Lam Anna P,Nicholson Trevor T,Homan Philip J,Soberanes Saul,Dominguez Salina,Morgan Vince K,Saber Rana,Shaffer Alexander,Hinchcliff Monique,Marshall Stacy A,Bharat Ankit,Berdnikovs Sergejs,Bhorade Sangeeta M,Bartom Elizabeth T,Morimoto Richard I,Balch William E,Sznajder Jacob I,Chandel Navdeep S,Mutlu Gökhan M,Jain Manu,Gottardi Cara J,Singer Benjamin D,Ridge Karen M,Bagheri Neda,Shilatifard Ali,Budinger G R Scott,Perlman Harris The Journal of experimental medicine Little is known about the relative importance of monocyte and tissue-resident macrophages in the development of lung fibrosis. We show that specific genetic deletion of monocyte-derived alveolar macrophages after their recruitment to the lung ameliorated lung fibrosis, whereas tissue-resident alveolar macrophages did not contribute to fibrosis. Using transcriptomic profiling of flow-sorted cells, we found that monocyte to alveolar macrophage differentiation unfolds continuously over the course of fibrosis and its resolution. During the fibrotic phase, monocyte-derived alveolar macrophages differ significantly from tissue-resident alveolar macrophages in their expression of profibrotic genes. A population of monocyte-derived alveolar macrophages persisted in the lung for one year after the resolution of fibrosis, where they became increasingly similar to tissue-resident alveolar macrophages. Human homologues of profibrotic genes expressed by mouse monocyte-derived alveolar macrophages during fibrosis were up-regulated in human alveolar macrophages from fibrotic compared with normal lungs. Our findings suggest that selectively targeting alveolar macrophage differentiation within the lung may ameliorate fibrosis without the adverse consequences associated with global monocyte or tissue-resident alveolar macrophage depletion. 10.1084/jem.20162152
    Transcriptional and functional diversity of human macrophage repolarization. Gharib Sina A,McMahan Ryan S,Eddy William E,Long Matthew E,Parks William C,Aitken Moira L,Manicone Anne M The Journal of allergy and clinical immunology BACKGROUND:Macrophage plasticity allows cells to adopt different phenotypes, a property with important implications in disorders such as cystic fibrosis (CF) and asthma. OBJECTIVE:We sought to examine the transcriptional and functional significance of macrophage repolarization from an M1 to an M2 phenotype and assess the role of a common human genetic disorder (CF) and a prototypical allergic disease (asthma) in this transformation. METHODS:Monocyte-derived macrophages were collected from healthy subjects and patients with CF and polarized to an M2 state by using IL-4, IL-10, glucocorticoids, apoptotic PMNs, or azithromycin. We performed transcriptional profiling and pathway analysis for each stimulus. We assessed the ability of M2-repolarized macrophages to respond to LPS rechallenge and clear apoptotic neutrophils and used murine models to determine conserved functional responses to IL-4 and IL-10. We investigated whether M2 signatures were associated with alveolar macrophage phenotypes in asthmatic patients. RESULTS:We found that macrophages exhibit highly diverse responses to distinct M2-polarizing stimuli. Specifically, IL-10 activated proinflammatory pathways and abrogated LPS tolerance, allowing rapid restoration of LPS responsiveness. In contrast, IL-4 enhanced LPS tolerance, dampening proinflammatory responses after repeat LPS challenge. A common theme observed across all M2 stimuli was suppression of interferon-associated pathways. We found that CF macrophages had intact reparative and transcriptional responses, suggesting that macrophage contributions to CF-related lung disease are primarily shaped by their environment. Finally, we leveraged in vitro-derived signatures to show that allergen provocation induces distinct M2 state transcriptional patterns in alveolar macrophages. CONCLUSION:Our findings highlight the diversity of macrophage polarization, attribute functional consequences to different M2 stimuli, and provide a framework to phenotype macrophages in disease states. 10.1016/j.jaci.2018.10.046
    Type 2 immunity in tissue repair and fibrosis. Gieseck Richard L,Wilson Mark S,Wynn Thomas A Nature reviews. Immunology Type 2 immunity is characterized by the production of IL-4, IL-5, IL-9 and IL-13, and this immune response is commonly observed in tissues during allergic inflammation or infection with helminth parasites. However, many of the key cell types associated with type 2 immune responses - including T helper 2 cells, eosinophils, mast cells, basophils, type 2 innate lymphoid cells and IL-4- and IL-13-activated macrophages - also regulate tissue repair following injury. Indeed, these cell populations engage in crucial protective activity by reducing tissue inflammation and activating important tissue-regenerative mechanisms. Nevertheless, when type 2 cytokine-mediated repair processes become chronic, over-exuberant or dysregulated, they can also contribute to the development of pathological fibrosis in many different organ systems. In this Review, we discuss the mechanisms by which type 2 immunity contributes to tissue regeneration and fibrosis following injury. 10.1038/nri.2017.90
    Idiopathic Pulmonary Fibrosis: Novel Concepts of Proton Pump Inhibitors as Antifibrotic Drugs. Ghebre Yohannes T,Raghu Ganesh American journal of respiratory and critical care medicine The prevalence of abnormal acid gastroesophageal reflux (GER) is higher in patients with idiopathic pulmonary fibrosis (IPF) than in matched control subjects. Several studies demonstrated that more than one-third of patients with IPF have abnormal esophageal acid exposures. In addition, many of these studies indicate that the majority of patients with IPF have silent reflux with no symptoms of GER. Findings of abnormal reflux persist in a large proportion of patients with IPF placed on antacid therapy such as proton pump inhibitors (PPIs). This seemingly paradoxical observation suggests that either patients with IPF are somehow resistant to PPI-based intervention or PPIs are inherently unable to suppress acid GER. By contrast, patients with IPF who undergo Nissen fundoplication surgery are effectively relieved from the complications of GER, and retrospective studies suggest improved lung function. Retrospective, anecdotal data suggest a beneficial role of PPIs in IPF including stabilization of lung function, reduction in episodes of acute exacerbation, and enhanced longevity. The recent evidence-based guidelines for treatment of IPF approved conditional recommendation of PPIs for all patients with IPF regardless of their GER status. Recently, we have reported that PPIs possess antiinflammatory and antifibrotic activities by directly suppressing proinflammatory cytokines, profibrotic proteins, and proliferation of lung fibroblasts. Our study provides an alternative explanation for the beneficial effect of PPIs in IPF. In this Perspective, we reviewed emerging progress on antifibrotic effect of PPIs using IPF as a disease model. In addition, we summarized surgical and pharmacological interventions for GER and their downstream effect on lung physiology. 10.1164/rccm.201512-2316PP
    Idiopathic pulmonary fibrosis: lessons from clinical trials over the past 25 years. Raghu Ganesh The European respiratory journal Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease. A major breakthrough in treatment came when, after decades of clinical trials which failed to identify an efficacious treatment regimen, two therapies were successful in Phase-III trials. The advent of these therapies, nintedanib and pirfenidone, meant that for the first time IPF patients had two treatment options that could reduce disease progression. This review summarises the key lessons to be obtained from the clinical trials that led to the current international clinical practice guidelines for the treatment of IPF and provides insights for the design of future clinical trials that are needed if we are to improve outcomes that are clinically meaningful to IPF patients. 10.1183/13993003.01209-2017
    The diagnosis of idiopathic pulmonary fibrosis: current and future approaches. Martinez Fernando J,Chisholm Alison,Collard Harold R,Flaherty Kevin R,Myers Jeffrey,Raghu Ganesh,Walsh Simon L F,White Eric S,Richeldi Luca The Lancet. Respiratory medicine With the recent development of two effective treatments for patients with idiopathic pulmonary fibrosis, an accurate diagnosis is crucial. The traditional approach to diagnosis emphasises the importance of thorough clinical and laboratory evaluations to exclude secondary causes of disease. High-resolution CT is a critical initial diagnostic test and acts as a tool to identify patients who should undergo surgical lung biopsy to secure a definitive histological diagnosis of usual interstitial pneumonia pattern. This diagnostic approach faces several challenges. Many patients with suspected idiopathic pulmonary fibrosis present with atypical high-resolution CT characteristics but are unfit for surgical lung biopsy, therefore preventing a confident diagnosis. The state of the art suggests an iterative, multidisciplinary process that incorporates available clinical, laboratory, imaging, and histological features. Recent research has explored genomic techniques to molecularly phenotype patients with interstitial lung disease. In the future, clinicians will probably use blood-specific or lung-specific molecular markers in combination with other clinical, physiological, and imaging features to enhance diagnostic efforts, refine prognostic recommendations, and influence the initial or subsequent treatment options. There is an urgent and increasing need for well designed, large, prospective studies measuring the effect of different diagnostic approaches. Ultimately, this will help to inform the development of guidelines and tailor clinical practice for the benefit of patients. 10.1016/S2213-2600(16)30325-3
    Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis. Mora Ana L,Bueno Marta,Rojas Mauricio The Journal of clinical investigation Idiopathic pulmonary fibrosis (IPF) is a chronic age-related lung disease with high mortality that is characterized by abnormal scarring of the lung parenchyma. There has been a recent attempt to define the age-associated changes predisposing individuals to develop IPF. Age-related perturbations that are increasingly found in epithelial cells and fibroblasts from IPF lungs compared with age-matched cells from normal lungs include defective autophagy, telomere attrition, altered proteostasis, and cell senescence. These divergent processes seem to converge in mitochondrial dysfunction and metabolic distress, which potentiate maladaptation to stress and susceptibility to age-related diseases such as IPF. Therapeutic approaches that target aging processes may be beneficial for halting the progression of disease and improving quality of life in IPF patients. 10.1172/JCI87440
    Precision Medicine: The New Frontier in Idiopathic Pulmonary Fibrosis. Brownell Robert,Kaminski Naftali,Woodruff Prescott G,Bradford Williamson Z,Richeldi Luca,Martinez Fernando J,Collard Harold R American journal of respiratory and critical care medicine Precision medicine is defined by the National Institute of Health's Precision Medicine Initiative Working Group as an approach to disease treatment that takes into account individual variability in genes, environment, and lifestyle. There has been increased interest in applying the concept of precision medicine to idiopathic pulmonary fibrosis, in particular to search for genetic and molecular biomarker-based profiles (so called endotypes) that identify mechanistically distinct disease subgroups. The relevance of precision medicine to idiopathic pulmonary fibrosis is yet to be established, but we believe that it holds great promise to provide targeted and highly effective therapies to patients. In this manuscript, we describe the field's nascent efforts in genetic/molecular endotype identification and how environmental and behavioral subgroups may also be relevant to disease management. 10.1164/rccm.201601-0169CI
    Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease. Mora Ana L,Rojas Mauricio,Pardo Annie,Selman Moises Nature reviews. Drug discovery Idiopathic pulmonary fibrosis (IPF) is a fatal age-associated disease that is characterized by progressive and irreversible scarring of the lung. The pathogenesis of IPF is not completely understood and current therapies are limited to those that reduce the rate of functional decline in patients with mild-to-moderate disease. In this context, new therapeutic approaches that substantially improve the survival time and quality of life of these patients are urgently needed. Our incomplete understanding of the pathogenic mechanisms of IPF and the lack of appropriate experimental models that reproduce the key characteristics of the human disease are major challenges. As ageing is a major risk factor for IPF, age-related cell perturbations such as telomere attrition, senescence, epigenetic drift, stem cell exhaustion, loss of proteostasis and mitochondrial dysfunction are becoming targets of interest for IPF therapy. In this Review, we discuss current and emerging therapies for IPF, particularly those targeting age-related mechanisms, and discuss future therapeutic approaches. 10.1038/nrd.2017.170
    Update in Pulmonary Fibrosis 2018. Sgalla Giacomo,Kulkarni Tejaswini,Antin-Ozerkis Danielle,Thannickal Victor J,Richeldi Luca American journal of respiratory and critical care medicine 10.1164/rccm.201903-0542UP
    The effect of anti-acid therapy on survival in idiopathic pulmonary fibrosis: a methodological review of observational studies. Tran Tanja,Suissa Samy The European respiratory journal International treatment guidelines for idiopathic pulmonary fibrosis (IPF) give a conditional recommendation for anti-acid therapy. As some observational studies reported discrepant findings on the effectiveness of anti-acid therapy on mortality in IPF, we reviewed all studies to evaluate whether immortal time bias explains these discrepancies.We searched the Embase and MEDLINE databases up to July 2017 for observational studies assessing the effectiveness of anti-acid therapy on mortality in IPF. Hazard ratios of mortality with anti-acid therapy were pooled across studies using random-effect models, stratified by the presence of immortal time bias.We identified 10 observational studies. Four of the five studies reporting beneficial effects of anti-acid therapy use on mortality were affected by immortal time bias (pooled hazard ratio 0.46; 95% CI 0.30-0.69), while it was unclear whether the fifth was affected. The five studies that avoided immortal time bias reported no effect of anti-acid therapy on mortality (pooled hazard ratio 0.99; 95% CI 0.81-1.22).The apparent beneficial effects of anti-acid therapy on mortality in patients with IPF result from observational studies affected by immortal time bias. Thus, the effectiveness of anti-acid therapy in IPF remains uncertain and needs to be reassessed with more accurate observational study methods and randomised trials. 10.1183/13993003.00376-2018
    Antacid therapy in idiopathic pulmonary fibrosis: more questions than answers? Johannson Kerri A,Strâmbu Irina,Ravaglia Claudia,Grutters Jan C,Valenzuela Claudia,Mogulkoc Nesrin,Luppi Fabrizio,Richeldi Luca,Wells Athol U,Vancheri Carlo,Kreuter Michael, The Lancet. Respiratory medicine Idiopathic pulmonary fibrosis (IPF) is a progressive parenchymal lung disease of complex cause. Gastro-oesophageal reflux (GER) and microaspiration have been proposed as risk factors for the development and progression of IPF, but robust definitive data are few. A recent international guideline conditionally recommended the use of antacid therapy (proton pump inhibitors or histamine-2-receptor antagonists) for patients with IPF, in the absence of oesophageal reflux or symptoms. In this Position Paper, we summarise the literature addressing the association between GER and IPF, and also identify future research priorities that could clarify this issue. We shed light on the process through which the guideline recommendation was achieved and aim to contextualise the recommendation for providers caring for patients with IPF. 10.1016/S2213-2600(17)30219-9
    Approaching Clinical Trials in Childhood Interstitial Lung Disease and Pediatric Pulmonary Fibrosis. Deterding Robin R,DeBoer Emily M,Cidon Michal J,Robinson Terry E,Warburton David,Deutsch Gail H,Young Lisa R American journal of respiratory and critical care medicine Childhood interstitial lung disease (chILD) comprises a spectrum of rare diffuse lung disorders. chILD is heterogeneous in origin, with different disease manifestations occurring in the context of ongoing lung development. The large number of disorders in chILD, in combination with the rarity of each diagnosis, has hampered scientific and clinical progress within the field. Epidemiologic and natural history data are limited. The prognosis varies depending on the etiology, with some forms progressing to lung transplant or death. There are limited treatment options for patients with chILD. Although U.S. Food and Drug Administration-approved treatments are now available for adult patients with idiopathic pulmonary fibrosis, no clinical trials have been conducted in a pediatric population using agents designed to treat lung fibrosis. This review will focus on progressive chILD disorders and on the urgent need for meaningful objective outcome measures to define, detect, and monitor fibrosis in children. 10.1164/rccm.201903-0544CI
    Idiopathic pulmonary fibrosis. Richeldi Luca,Collard Harold R,Jones Mark G Lancet (London, England) Idiopathic pulmonary fibrosis is a prototype of chronic, progressive, and fibrotic lung disease. Healthy tissue is replaced by altered extracellular matrix and alveolar architecture is destroyed, which leads to decreased lung compliance, disrupted gas exchange, and ultimately respiratory failure and death. In less than a decade, understanding of the pathogenesis and management of this disease has been transformed, and two disease-modifying therapies have been approved, worldwide. In this Seminar, we summarise the presentation, pathophysiology, diagnosis, and treatment options available for patients with idiopathic pulmonary fibrosis. This disease has improved understanding of the mechanisms of lung fibrosis, and offers hope that similar approaches will transform the management of patients with other progressive fibrotic lung diseases. 10.1016/S0140-6736(17)30866-8
    Idiopathic pulmonary fibrosis: effects and optimal management of comorbidities. King Christopher S,Nathan Steven D The Lancet. Respiratory medicine Despite the development of pharmacological therapies that are effective in slowing the progression of idiopathic pulmonary fibrosis (IPF), it remains a debilitating and lethal condition. In addition to the adverse effects caused by pulmonary fibrosis, most patients with IPF have associated comorbid conditions, which might negatively affect functional status, quality of life, and survival. Comorbid conditions can be pulmonary or extrapulmonary. Pulmonary comorbidities include pulmonary hypertension, emphysema, and lung cancer, while non-pulmonary conditions include venous thromboembolism, coronary artery disease, congestive heart failure, sleep-disordered breathing, gastro-oesophageal reflux disease, and anxiety or depression. Although some of these comorbid conditions share risk factors with IPF, the likelihood for their presence or development in patients with IPF is still greater than expected. This might indicate that IPF fosters an environment for the development or perpetuation of comorbid conditions, or alternatively that they share causative factors. Optimal management of IPF therefore requires a comprehensive approach, which includes the identification and treatment of comorbid conditions to optimise patient outcomes. 10.1016/S2213-2600(16)30222-3
    Idiopathic Pulmonary Fibrosis: A Genetic Disease That Involves Mucociliary Dysfunction of the Peripheral Airways. Evans Christopher M,Fingerlin Tasha E,Schwarz Marvin I,Lynch David,Kurche Jonathan,Warg Laura,Yang Ivana V,Schwartz David A Physiological reviews Idiopathic pulmonary fibrosis (IPF) is an incurable complex genetic disorder that is associated with sequence changes in 7 genes (MUC5B, TERT, TERC, RTEL1, PARN, SFTPC, and SFTPA2) and with variants in at least 11 novel loci. We have previously found that 1) a common gain-of-function promoter variant in MUC5B rs35705950 is the strongest risk factor (genetic and otherwise), accounting for 30-35% of the risk of developing IPF, a disease that was previously considered idiopathic; 2) the MUC5B promoter variant can potentially be used to identify individuals with preclinical pulmonary fibrosis and is predictive of radiologic progression of preclinical pulmonary fibrosis; and 3) MUC5B may be involved in the pathogenesis of pulmonary fibrosis with MUC5B message and protein expressed in bronchiolo-alveolar epithelia of IPF and the characteristic IPF honeycomb cysts. Based on these considerations, we hypothesize that excessive production of MUC5B either enhances injury due to reduced mucociliary clearance or impedes repair consequent to disruption of normal regenerative mechanisms in the distal lung. In aggregate, these novel considerations should have broad impact, resulting in specific etiologic targets, early detection of disease, and novel biologic pathways for use in the design of future intervention, prevention, and mechanistic studies of IPF. 10.1152/physrev.00004.2016
    Diagnostic criteria for idiopathic pulmonary fibrosis: a Fleischner Society White Paper. Lynch David A,Sverzellati Nicola,Travis William D,Brown Kevin K,Colby Thomas V,Galvin Jeffrey R,Goldin Jonathan G,Hansell David M,Inoue Yoshikazu,Johkoh Takeshi,Nicholson Andrew G,Knight Shandra L,Raoof Suhail,Richeldi Luca,Ryerson Christopher J,Ryu Jay H,Wells Athol U The Lancet. Respiratory medicine This Review provides an updated approach to the diagnosis of idiopathic pulmonary fibrosis (IPF), based on a systematic search of the medical literature and the expert opinion of members of the Fleischner Society. A checklist is provided for the clinical evaluation of patients with suspected usual interstitial pneumonia (UIP). The role of CT is expanded to permit diagnosis of IPF without surgical lung biopsy in select cases when CT shows a probable UIP pattern. Additional investigations, including surgical lung biopsy, should be considered in patients with either clinical or CT findings that are indeterminate for IPF. A multidisciplinary approach is particularly important when deciding to perform additional diagnostic assessments, integrating biopsy results with clinical and CT features, and establishing a working diagnosis of IPF if lung tissue is not available. A working diagnosis of IPF should be reviewed at regular intervals since the diagnosis might change. Criteria are presented to establish confident and working diagnoses of IPF. 10.1016/S2213-2600(17)30433-2
    Is Progression of Pulmonary Fibrosis due to Ventilation-induced Lung Injury? Albert Richard K,Smith Bradford,Perlman Carrie E,Schwartz David A American journal of respiratory and critical care medicine 10.1164/rccm.201903-0497PP
    Acute Exacerbation of Idiopathic Pulmonary Fibrosis. An International Working Group Report. Collard Harold R,Ryerson Christopher J,Corte Tamera J,Jenkins Gisli,Kondoh Yasuhiro,Lederer David J,Lee Joyce S,Maher Toby M,Wells Athol U,Antoniou Katerina M,Behr Juergen,Brown Kevin K,Cottin Vincent,Flaherty Kevin R,Fukuoka Junya,Hansell David M,Johkoh Takeshi,Kaminski Naftali,Kim Dong Soon,Kolb Martin,Lynch David A,Myers Jeffrey L,Raghu Ganesh,Richeldi Luca,Taniguchi Hiroyuki,Martinez Fernando J American journal of respiratory and critical care medicine Acute exacerbation of idiopathic pulmonary fibrosis has been defined as an acute, clinically significant, respiratory deterioration of unidentifiable cause. The objective of this international working group report on acute exacerbation of idiopathic pulmonary fibrosis was to provide a comprehensive update on the topic. A literature review was conducted to identify all relevant English text publications and abstracts. Evidence-based updates on the epidemiology, etiology, risk factors, prognosis, and management of acute exacerbations of idiopathic pulmonary fibrosis are provided. Finally, to better reflect the current state of knowledge and improve the feasibility of future research into its etiology and treatment, the working group proposes a new conceptual framework for acute respiratory deterioration in idiopathic pulmonary fibrosis and a revised definition and diagnostic criteria for acute exacerbation of idiopathic pulmonary fibrosis. 10.1164/rccm.201604-0801CI
    Engineered cell and tissue models of pulmonary fibrosis. Sundarakrishnan Aswin,Chen Ying,Black Lauren D,Aldridge Bree B,Kaplan David L Advanced drug delivery reviews Pulmonary fibrosis includes several lung disorders characterized by scar formation and Idiopathic Pulmonary Fibrosis (IPF) is a particularly severe form of pulmonary fibrosis of unknown etiology with a mean life expectancy of 3years' post-diagnosis. Treatments for IPF are limited to two FDA approved drugs, pirfenidone and nintedanib. Most lead candidate drugs that are identified in pre-clinical animal studies fail in human clinical trials. Thus, there is a need for advanced humanized in vitro models of the lung to improve candidate treatments prior to moving to human clinical trials. The development of 3D tissue models has created systems capable of emulating human lung structure, function, and cell and matrix interactions. The specific models accomplish these features and preliminary studies conducted using some of these systems have shown potential for in vitro anti-fibrotic drug testing. Further characterization and improvements will enable these tissue models to extend their utility for in vitro drug testing, to help identify signaling pathways and mechanisms for new drug targets, and potentially reduce animal models as standard pre-clinical models of study. In the current review, we contrast different in vitro models based on increasing dimensionality (2D, 2.5D and 3D), with added focus on contemporary 3D pulmonary models of fibrosis. 10.1016/j.addr.2017.12.013
    Major lung complications of systemic sclerosis. Denton Christopher P,Wells Athol U,Coghlan John G Nature reviews. Rheumatology Systemic sclerosis (SSc) is associated with high mortality owing to internal organ complications, and lung disease is the leading cause of SSc-associated death. The most notable lung complications in SSc are fibrosis and pulmonary arterial hypertension (PAH). A major challenge for the management of lung disease in SSc is detecting those patients with severe pathology and those patients who are likely to benefit from available treatments. In the past few years, strategies for managing lung fibrosis and pulmonary hypertension, including PAH, have greatly progressed. For lung fibrosis, the tools to assess risk of progression and severity of the disease have been refined. Clinical trial results support the use of immunosuppression, including high-intensity regimens with autologous stem cell transplantation. New trials are underway to test other potential therapies including treatments that are approved for use in idiopathic lung fibrosis. For PAH, identifying individuals at high risk of disease development is critical. In addition, individuals who have borderline elevation of pulmonary arterial pressure need to be appropriately managed and followed up. Many approved drugs targeting PAH are now available, and results from large-scale clinical trials provide robust evidence that various treatments for SSc-associated PAH are associated with good long-term outcomes. 10.1038/s41584-018-0062-0
    Idiopathic Pulmonary Fibrosis. Lederer David J,Martinez Fernando J The New England journal of medicine 10.1056/NEJMra1705751
    Idiopathic pulmonary fibrosis. Martinez Fernando J,Collard Harold R,Pardo Annie,Raghu Ganesh,Richeldi Luca,Selman Moises,Swigris Jeffrey J,Taniguchi Hiroyuki,Wells Athol U Nature reviews. Disease primers Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by progressive lung scarring and the histological picture of usual interstitial pneumonia (UIP). It is associated with increasing cough and dyspnoea and impaired quality of life. IPF affects ∼3 million people worldwide, with incidence increasing dramatically with age. The diagnostic approach includes the exclusion of other interstitial lung diseases or overlapping conditions and depends on the identification of the UIP pattern, usually with high-resolution CT; lung biopsy might be required in some patients. The UIP pattern is predominantly bilateral, peripheral and with a basal distribution of reticular changes associated with traction bronchiectasis and clusters of subpleural cystic airspaces. The biological processes underlying IPF are thought to reflect an aberrant reparative response to repetitive alveolar epithelial injury in a genetically susceptible ageing individual, although many questions remain on how to define susceptibility. Substantial progress has been made in the understanding of the clinical management of IPF, with the availability of two pharmacotherapeutic agents, pirfenidone and nintedanib, that decrease physiological progression and likely improve progression-free survival. Current efforts are directed at identifying IPF early, potentially relying on combinations of biomarkers that include circulating factors, demographics and imaging data. 10.1038/nrdp.2017.74
    Itaconate controls the severity of pulmonary fibrosis. Ogger Patricia P,Albers Gesa J,Hewitt Richard J,O'Sullivan Brendan J,Powell Joseph E,Calamita Emily,Ghai Poonam,Walker Simone A,McErlean Peter,Saunders Peter,Kingston Shaun,Molyneaux Philip L,Halket John M,Gray Robert,Chambers Daniel C,Maher Toby M,Lloyd Clare M,Byrne Adam J Science immunology Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease in which airway macrophages (AMs) play a key role. Itaconate has emerged as a mediator of macrophage function, but its role during fibrosis is unknown. Here, we reveal that itaconate is an endogenous antifibrotic factor in the lung. Itaconate levels are reduced in bronchoalveolar lavage, and itaconate-synthesizing cis-aconitate decarboxylase expression () is reduced in AMs from patients with IPF compared with controls. In the murine bleomycin model of pulmonary fibrosis, mice develop persistent fibrosis, unlike wild-type (WT) littermates. Profibrotic gene expression is increased in tissue-resident AMs compared with WT, and adoptive transfer of WT monocyte-recruited AMs rescued mice from disease phenotype. Culture of lung fibroblasts with itaconate decreased proliferation and wound healing capacity, and inhaled itaconate was protective in mice in vivo. Collectively, these data identify itaconate as critical for controlling the severity of lung fibrosis, and targeting this pathway may be a viable therapeutic strategy. 10.1126/sciimmunol.abc1884