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Cell Mar 2021In many asthmatics, chronic airway inflammation is driven by IL-4-, IL-5-, and IL-13-producing Th2 cells or ILC2s. Type 2 cytokines promote hallmark features of the... (Review)
Review
In many asthmatics, chronic airway inflammation is driven by IL-4-, IL-5-, and IL-13-producing Th2 cells or ILC2s. Type 2 cytokines promote hallmark features of the disease such as eosinophilia, mucus hypersecretion, bronchial hyperresponsiveness (BHR), IgE production, and susceptibility to exacerbations. However, only half the asthmatics have this "type 2-high" signature, and "type 2-low" asthma is more associated with obesity, presence of neutrophils, and unresponsiveness to corticosteroids, the mainstay asthma therapy. Here, we review the underlying immunological basis of various asthma endotypes by discussing results obtained from animal studies as well as results generated in clinical studies targeting specific immune pathways.
Topics: Adaptive Immunity; Alveolar Epithelial Cells; Animals; Asthma; B-Lymphocytes; Biological Therapy; Humans; Immunoglobulin E
PubMed: 33711259
DOI: 10.1016/j.cell.2021.02.016 -
Nature Medicine Feb 2020Developmental processes underlying normal tissue regeneration have been implicated in cancer, but the degree of their enactment during tumor progression and under the...
Developmental processes underlying normal tissue regeneration have been implicated in cancer, but the degree of their enactment during tumor progression and under the selective pressures of immune surveillance, remain unknown. Here we show that human primary lung adenocarcinomas are characterized by the emergence of regenerative cell types, typically seen in response to lung injury, and by striking infidelity among transcription factors specifying most alveolar and bronchial epithelial lineages. In contrast, metastases are enriched for key endoderm and lung-specifying transcription factors, SOX2 and SOX9, and recapitulate more primitive transcriptional programs spanning stem-like to regenerative pulmonary epithelial progenitor states. This developmental continuum mirrors the progressive stages of spontaneous outbreak from metastatic dormancy in a mouse model and exhibits SOX9-dependent resistance to natural killer cells. Loss of developmental stage-specific constraint in macrometastases triggered by natural killer cell depletion suggests a dynamic interplay between developmental plasticity and immune-mediated pruning during metastasis.
Topics: Adenocarcinoma; Animals; Bronchi; Cell Differentiation; Cell Lineage; Cluster Analysis; Databases, Genetic; Disease Progression; Endoderm; Female; Humans; Hydrogels; Immune System; Killer Cells, Natural; Lung; Lung Neoplasms; Mice; Neoplasm Metastasis; Phenotype; Pulmonary Alveoli; Regeneration; Signal Transduction
PubMed: 32042191
DOI: 10.1038/s41591-019-0750-6 -
Thrombosis Research Jun 2021Pulmonary infarction results from occlusion of the distal pulmonary arteries leading to ischemia, hemorrhage and ultimately necrosis of the lung parenchyma. It is most... (Review)
Review
Pulmonary infarction results from occlusion of the distal pulmonary arteries leading to ischemia, hemorrhage and ultimately necrosis of the lung parenchyma. It is most commonly caused by acute pulmonary embolism (PE), with a reported incidence of around 30%. Following an occlusion of the pulmonary artery, the bronchial arteries are recruited as primary source of perfusion of the pulmonary capillaries. The relatively higher blood pressure in the bronchial circulation causes an increase in the capillary blood flow, leading to extravasation of erythrocytes (i.e. alveolar hemorrhage). If this hemorrhage cannot be resorbed, it results in tissue necrosis and infarction. Different definitions of pulmonary infarction are used in literature (clinical, radiological and histological), although the diagnosis is nowadays mostly based on radiological characteristics. Notably, the infarcted area is only replaced by a fibrotic scar over a period of months. Hence and formally, the diagnosis of pulmonary infarction cannot be confirmed upon diagnosis of acute PE. Little is known of the impact and relevance of pulmonary infarction in acute PE, and whether specific management strategies should be applied to prevent and/or treat complications such as pain, pneumonia or post-PE syndrome. In this review we will summarize current knowledge on the pathophysiology, epidemiology, diagnosis and prognosis of pulmonary infarction in the setting of acute PE. We highlight the need for dedicated studies to overcome the current knowledge gaps.
Topics: Acute Disease; Humans; Lung; Pulmonary Artery; Pulmonary Embolism; Pulmonary Infarction
PubMed: 33862471
DOI: 10.1016/j.thromres.2021.03.022 -
Allergology International : Official... Oct 2019Eosinophilic granulomatosis with polyangiitis (EGPA) (formerly Churg-Strauss syndrome) is a rare form of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis... (Review)
Review
Eosinophilic granulomatosis with polyangiitis (EGPA) (formerly Churg-Strauss syndrome) is a rare form of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis characterized by eosinophil-rich granulomatous inflammation and small to medium-size vessel vasculitis associated with bronchial asthma and eosinophilia. Its rarity and unique features such as eosinophilic inflammation have delayed progress of research regarding EGPA for several years, compared to other forms of ANCA-associated vasculitis. However, recently, attention to EGPA as a research subject has been gradually increasing. To resolve problems in existing criteria for EGPA, new classification criteria for EGPA generated by a large international cohort will be launched and is being expected to accelerate future studies. Pathogenesis and roles of ANCA in EGPA are still largely unknown; however, it has been reported that glomerulonephritis is more frequent in ANCA-positive patients than in ANCA-negative patients, while heart failure is more frequent in ANCA-negative patients than in ANCA-positive patients. In addition, a recent genome-wide association study has suggested the presence of two genetically distinct subgroups of EGPA, which correspond to ANCA-positive and -negative subgroups. Although responses to glucocorticoids in EGPA are generally good, patients with EGPA often experience a relapse. Currently, there is no standard therapy for EGPA based on accumulation of clinical trial results. Recently, clinical benefits of mepolizumab for EGPA were proved by a randomized controlled trial and mepolizumab was approved for EGPA. In addition, various new drugs are under evaluation. To find optimal use of these drugs and to resolve unmet needs, such as relapse prevention, will be needed in future.
Topics: Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Biopsy; Diagnosis, Differential; Disease Susceptibility; Eosinophilia; Eosinophils; Female; Granulomatosis with Polyangiitis; Humans; Male; Middle Aged; Phenotype
PubMed: 31266709
DOI: 10.1016/j.alit.2019.06.004 -
Physiological Research Mar 2020Asthma is a complex disease with a variable course. Efforts to identify biomarkers to predict asthma severity, the course of disease and response to treatment have not... (Review)
Review
Asthma is a complex disease with a variable course. Efforts to identify biomarkers to predict asthma severity, the course of disease and response to treatment have not been very successful so far. Biomarker research has expanded greatly with the advancement of molecular research techniques. An ideal biomarker should be suitable to identify the disease as well the specific endotype/phenotype, useful in the monitoring of the disease and to determine the prognosis, easily to obtain with minimum discomfort or risk to the patient. An ideal biomarker should be suitable to identify the disease as well the specific endotype/phenotype, useful in the monitoring of the disease and to determine the prognosis, easily to obtain with minimum discomfort or risk to the patient - exhaled breath analysis, blood cells and serum biomarkers, sputum cells and mediators and urine metabolites could be potential biomarkers of asthma bronchiale. Unfortunately, at the moment, an ideal biomarker doesn't exist and the overlap between the biomarkers is a reality. Using panels of biomarkers could improve probably the identification of asthma endotypes in the era of precision medicine.
Topics: Animals; Asthma; Biomarkers; Humans; Precision Medicine; Predictive Value of Tests; Sputum
PubMed: 32228009
DOI: 10.33549/physiolres.934398 -
American Family Physician Feb 2022Hemoptysis is the expectoration of blood from the lower respiratory tract, usually from bronchial arteries. The most common causes are acute respiratory infections,...
Hemoptysis is the expectoration of blood from the lower respiratory tract, usually from bronchial arteries. The most common causes are acute respiratory infections, cancer, bronchiectasis, and chronic obstructive pulmonary disease. No cause is identified in 20% to 50% of cases. Hemoptysis must be differentiated from pseudohemoptysis, which is blood that originates from nasopharyngeal or gastrointestinal sources. The initial evaluation includes determining the severity of bleeding and stability of the patient and may require bronchoscopy for airway protection. Mild hemoptysis comprises more than 90% of cases and has a good prognosis, whereas massive hemoptysis has a high mortality rate. A history and physical examination can assist in identifying an etiology, but diagnostic testing is often required. Chest radiography is a good initial test, but it has limited sensitivity for determining the site and etiology of the bleeding. Computed tomography and computed tomography angiography of the chest with intravenous contrast are the preferred modalities to determine the etiology of bleeding; however, bronchoscopy may also be needed. In addition to supportive medical treatment, management should include treatment of the underlying etiology because recurrence often takes place in the absence of treatment of the identified cause. Bronchial arterial embolization is used to treat massive hemoptysis, particularly when an involved artery is noted on computed tomography angiography. Surgery is reserved for patients whose medical treatment and embolization are not effective.
Topics: Angiography; Bronchial Arteries; Bronchoscopy; Embolization, Therapeutic; Hemoptysis; Humans
PubMed: 35166503
DOI: No ID Found -
Thorax Feb 2021The heterogeneity of chronic obstructive pulmonary disease (COPD) creates many diagnostic, prognostic, treatment and management challenges, as the pathogenesis of COPD... (Review)
Review
The heterogeneity of chronic obstructive pulmonary disease (COPD) creates many diagnostic, prognostic, treatment and management challenges, as the pathogenesis of COPD is highly complex and the underlying cellular and molecular mechanisms remain poorly understood. A reliable, easy-to-measure, clinically relevant biomarker would be invaluable for improving outcomes for patients. International and national guidance for COPD suggests using blood eosinophil counts as a biomarker to help estimate likely responsiveness to inhaled corticosteroids (ICS) and, potentially, to aid effective management strategies. However, with the mechanism underlying the association between higher eosinophil levels and ICS effect unknown, use of the blood eosinophil count in COPD continues to be widely debated by the respiratory community.Two international meetings involving respiratory medicine specialists, immunologists and primary and secondary care clinicians were held in November 2018 and March 2019, facilitated and funded by GlaxoSmithKline plc. The aims of these meetings were to explore the role of eosinophils in the disease processes of COPD and as prognostic and diagnostic markers, and to identify areas of deficient knowledge that warrant further research. The consensus views of the attendees on key topics, contextualised with current literature, are summarised in this review article, with the aim of aiding ongoing research into the disease processes of COPD and the development of biomarkers to aid clinical management.Under certain conditions, eosinophils can be recruited to the lung, and increasing evidence supports a role for eosinophilic inflammation in some patients with COPD. Infiltration of eosinophils across the bronchial vascular epithelium into the airways is promoted by the actions of immunoregulatory cells, cytokines and chemokines, where eosinophil-mediated inflammation is driven by the release of proinflammatory mediators.Multiple studies and two meta-analyses suggest peripheral blood eosinophils may correlate positively with an increased likelihood of exacerbation reduction benefits of ICS in COPD. The studies, however, vary in design and duration and by which eosinophil levels are viewed as predictive of an ICS response. Generally, the response was seen when eosinophil levels were 100-300 cells/µL (or higher), levels which are traditionally viewed within the normal range. Some success with interleukin-5-targeted therapy suggests that the eosinophilic phenotype may be a treatable trait.The use of biomarkers could help to stratify treatment for COPD-the goal of which is to improve patient outcomes. Some evidence supports eosinophils as a potential biomarker of a treatable trait in COPD, though it is still lacking and research is ongoing. A unified consensus and a practical, accessible and affordable method of utilising any biomarker for COPD was thought to be of most importance. Challenges around its utilisation may include presenting a clear and pragmatic rationale for biomarker-driven therapy, guidance on ICS withdrawal between primary and secondary care and a lack of financial incentives supporting broad application in clinical practice. Future treatments should, perhaps, be more targeted rather than assuming the primary disease label (COPD or asthma) will define treatment response.
Topics: Adrenal Cortex Hormones; Biomarkers; Eosinophils; Humans; Prognosis; Pulmonary Disease, Chronic Obstructive
PubMed: 33122447
DOI: 10.1136/thoraxjnl-2020-215167 -
Cellular & Molecular Immunology Jun 2020We elucidated the anti-inflammatory mechanisms of IL-38 in allergic asthma. Human bronchial epithelial cells and eosinophils were cocultured upon stimulation with the...
We elucidated the anti-inflammatory mechanisms of IL-38 in allergic asthma. Human bronchial epithelial cells and eosinophils were cocultured upon stimulation with the viral RLR ligand poly (I:C)/LyoVec or infection-related cytokine TNF-α to induce expression of cytokines/chemokines/adhesion molecules. House dust mite (HDM)-induced allergic asthma and humanized allergic asthma NOD/SCID murine models were established to assess anti-inflammatory mechanisms in vivo. IL-38 significantly inhibited induced proinflammatory IL-6, IL-1β, CCL5, and CXCL10 production, and antiviral interferon-β and intercellular adhesion molecule-1 expression in the coculture system. Mass cytometry and RNA-sequencing analysis revealed that IL-38 could antagonize the activation of the intracellular STAT1, STAT3, p38 MAPK, ERK1/2, and NF-κB pathways, and upregulate the expression of the host defense-related gene POU2AF1 and anti-allergic response gene RGS13. Intraperitoneal injection of IL-38 into HDM-induced allergic asthma mice could ameliorate airway hyperreactivity by decreasing the accumulation of eosinophils in the lungs and inhibiting the expression of the Th2-related cytokines IL-4, IL-5, and IL-13 in the bronchoalveolar lavage fluid (BALF) and lung homogenates. Histological examination indicated lung inflammation was alleviated by reductions in cell infiltration and goblet cell hyperplasia, together with reduced Th2, Th17, and innate lymphoid type 2 cell numbers but increased proportions of regulatory T cells in the lungs, spleen, and lymph nodes. IL-38 administration suppressed airway hyperreactivity and asthma-related IL-4 and IL-5 expression in humanized mice, together with significantly decreased CCR3 eosinophil numbers in the BALF and lungs, and a reduced percentage of human CD4CRTH2 Th2 cells in the lungs and mediastinal lymph nodes. Together, our results demonstrated the anti-inflammatory mechanisms of IL-38 and provided a basis for the development of a regulatory cytokine-based treatment for allergic asthma.
Topics: Adult; Animals; Anti-Inflammatory Agents; Asthma; Bronchi; Cells, Cultured; Cytokines; Down-Regulation; Eosinophils; Epithelial Cells; Gene Expression Regulation; Humans; Hypersensitivity; Inflammation; Inflammation Mediators; Injections, Intraperitoneal; Interleukins; Ligands; Male; Mice; Mice, Inbred BALB C; Models, Biological; Poly I-C; Pyroglyphidae; Recombinant Proteins; Signal Transduction; T-Lymphocytes, Regulatory; Tumor Necrosis Factor-alpha
PubMed: 31645649
DOI: 10.1038/s41423-019-0300-7 -
Frontiers in Immunology 2023Prosperous advances in understanding the cellular and molecular mechanisms of chronic inflammation and airway remodeling in asthma have been made over the past several... (Review)
Review
Prosperous advances in understanding the cellular and molecular mechanisms of chronic inflammation and airway remodeling in asthma have been made over the past several decades. Asthma is a chronic inflammatory disease of the airways characterized by reversible airway obstruction that is self-resolving or remits with treatment. Around half of asthma patients are "Type-2-high" asthma with overexpression of type 2 inflammatory pathways and elevated type 2 cytokines. When stimulated by allergens, airway epithelial cells secrete IL-25, IL-33, and TSLP to derive a Th2 immune response. First ILC2 followed by Th2 cells produces a series of cytokines such as IL-4, IL-5, and IL-13. T cells control IgE synthesis by secreting IL-4 to allergen-specific B cells. IL-5 promotes eosinophil inflammation, while IL-13 and IL-4 are involved in goblet cell metaplasia and bronchial hyperresponsiveness. Currently, "Type-2 low" asthma is defined as asthma with low levels of T2 biomarkers due to the lack of reliable biomarkers, which is associated with other Th cells. Th1 and Th17 are capable of producing cytokines that recruit neutrophils, such as IFN-γ and IL-17, to participate in the development of "Type-2-low" asthma. Precision medicine targeting Th cells and related cytokines is essential in the management of asthma aiming at the more appropriate patient selection and better treatment response. In this review, we sort out the pathogenesis of Th cells in asthma and summarize the therapeutic approaches involved as well as potential research directions.
Topics: Humans; Cytokines; Immunity, Innate; Interleukin-13; Interleukin-4; Interleukin-5; Asthma; Inflammation; Allergens; Th17 Cells
PubMed: 37377958
DOI: 10.3389/fimmu.2023.1149203