Airway inflammation in COPD- progress to precision medicine

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. This 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-IL5 biologics 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 shall 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

Novel therapeutic strategies in Asthma COPD Overlap

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The Plant Derivative Compound A Inhibits the Production of Corticosteroid-resistant Chemokines by Airway Smooth Muscle Cells.

Preclinical models of human conditions including asthma showed the therapeutic potential of compound A (CpdA), a dissociated glucocorticoid (GC) receptor (GRα) ligand. Whether CpdA inhibits GC resistance, a central feature of severe asthma, has not been addressed. We investigated whether CpdA modulates cytokine-induced GC resistance in human airway smooth muscle (ASM) cells. Healthy and asthmatic ASM cells were treated with TNFα/IFNγ for 24 hr in the presence or absence of CpdA. ELISA and qPCR assays were used to assess the effect of CpdA on chemokine expression. Activation of GRα by CpdA was assessed by qPCR, immunostaining and receptor antagonism using RU486. An effect of CpdA on the transcription factor IRF-1 was investigated using immunoblot, immunostaining and siRNA knockdown. CpdA inhibited production of fluticasone-resistant chemokines CCL5, CX3CL1, and CXCL10 at protein and mRNA levels in both asthmatic and healthy cells. CpdA failed to induce expression of Glucocorticoid-induced Leucine Zipper (GILZ) while transiently inducing MAPK phosphatase 1 (MKP-1) at both mRNA and protein levels. CpdA inhibitory action was not associated with GRαnuclear translocation nor prevented by RU486 antagonism. Activation of IRF-1 by TNFα/IFNγ was inhibited by CpdA. IRF-1 siRNA knockdown reduced cytokine-induced CCL5 and CX3CL1 production. siRNA MKP-1 prevented the inhibitory effect of CpdA on cytokine-induced CXCL10 production. For the first time, we show that CpdA inhibits the production of GC-resistant chemokines via GRα-independent mechanisms involving the inhibition of IRF-1 and up-regulation of MKP-1. Thus, targeting CpdA sensitive pathways in ASM cells represents an alternative therapeutic approach to treat GC resistance in asthma

Modelling the effect of gravity on inert-gas washout outputs

Multiple-breath washout (MBW) is a pulmonary function test (PFT) that is used to infer lung function through measurement of ventilation heterogeneity (VH). However, the body position that a test is taken in may also influence VH, due to the "Slinky" effect of gravity on the lungs. In healthy subjects this has minimal effect, but in unhealthy groups, PFT outputs have been seen to change drastically with body position. In this study, we used a combined computational and clinical approach to better understand the response of outputs from the MBW to body position. A patient-specific model of the MBW was developed, then validated against clinically measured washout data, as well as broader results in the literature. This model was then used to compare changes in MBW outputs with respect to body position, showing that output changes sensitively predict regional airway size differences between lobes. We then highlight cases in which body position effects may bias MBW outputs, leading to elevated or masked responses to bronchoconstriction. We close by placing this result in context with broader clinical practice, and showing how it can help improve interpretation of test outputs

COPD exacerbation severity and frequency is associated with impaired macrophage efferocytosis of eosinophils

Background: Eosinophilic airway inflammation is observed in 10-30% of COPD subjects. Whether increased eosinophils or impairment in their clearance by macrophages is associated with the severity and frequency of exacerbations is unknown. Methods: We categorised 103 COPD subjects into 4 groups determined by the upper limit of normal for their cytoplasmic macrophage red hue (<6%), an indirect measure of macrophage efferocytosis of eosinophils, and area under the curve sputum eosinophil count (≥3%/year). Eosinophil efferocytosis by monocyte-derived macrophages was studied in 17 COPD subjects and 8 normal controls. Results: There were no differences in baseline lung function, health status or exacerbation frequency between the groups: A-low red hue, high sputum eosinophils (n = 10), B-high red hue, high sputum eosinophils (n = 16), C-low red hue, low sputum eosinophils (n = 19) and D- high red hue, low sputum eosinophils (n = 58). Positive bacterial culture was lower in groups A (10%) and B (6%) compared to C (44%) and D (21%) (p = 0.01). The fall in FEV1 from stable to exacerbation was greatest in group A (ΔFEV1 [95 % CI] -0.41 L [-0.65 to -0.17]) versus group B (-0.16 L [-0.32 to -0.011]), C (-0.11 L [-0.23 to -0.002]) and D (-0.16 L [-0.22 to -0.10]; p = 0.02). Macrophage efferocytosis of eosinophils was impaired in COPD versus controls (86 [75 to 92]% versus 93 [88 to 96]%; p = 0.028); was most marked in group A (71 [70 to 84]%; p = 0.0295) and was inversely correlated with exacerbation frequency (r = -0.63; p = 0.006). Conclusions: Macrophage efferocytosis of eosinophils is impaired in COPD and is related to the severity and frequency of COPD exacerbations

Airway smooth muscle NOX4 is upregulated and modulates ROS generation in COPD

The burden of oxidative stress is increased in chronic obstructive pulmonary disease (COPD). However, whether the intra-cellular mechanisms controlling the oxidant/anti-oxidant balance in structural airway cells such as airway smooth muscle in COPD is altered is unclear. We sought to determine whether the expression of the NADPH oxidase (NOX)-4 is increased in airway smooth muscle in COPD both in vivo and primary cells in vitro and its role in hydrogen peroxide-induced reactive oxygen species generation. We found that in vivo NOX4 expression was up-regulated in the airway smooth muscle bundle in COPD (n = 9) and healthy controls with >20 pack year history (n = 4) compared to control subjects without a significant smoking history (n = 6). In vitro NOX4 expression was increased in airway smooth muscle cells from subjects with COPD (n = 5) compared to asthma (n = 7) and upregulated following TNF-α stimulation. Hydrogen peroxide-induced reactive oxygen species generation by airway smooth muscle cells in COPD (n = 5) was comparable to healthy controls (n = 9) but lower than asthma (n = 5); and was markedly attenuated by NOX4 inhibition. Our findings demonstrate that NOX4 expression is increased in vivo and in vitro in COPD and although we did not observe an intrinsic increase in oxidant-induced reactive oxygen species generation in COPD, it was reduced markedly by NOX4 inhibition supporting a potential therapeutic role for NOX4 in COPD

Additional file 1: Table S1. of Characteristics and longitudinal progression of chronic obstructive pulmonary disease in GOLD B patients

Baseline characteristics of patients categorised as GOLD C and D. (DOCX 17 kb

Lung Computational Models and the Role of the Small Airways in Asthma

Rationale: Asthma is characterized by disease within the small airways. Several studies have suggested that forced oscillation technique–derived resistance at 5 Hz (R5) 2 resistance at 20 Hz (R20) is a measure of small airway disease; however, there has been limited validation of this measurement to date. Objectives: To validate the use of forced oscillation R5 2 R20 as a measure of small airway narrowing in asthma, and to investigate the role that small airway narrowing plays in asthma. Methods: Patient-based complete conducting airway models were generated from computed tomography scans to simulate the impact of different degrees of airway narrowing at different levels of the airway tree on forced oscillation R5 2 R20 (n = 31). The computational models were coupled with regression models in an asthmatic cohort (n = 177) to simulate the impact of small airway narrowing on asthma control and quality of life. The computational models were used to predict the impact on small airway narrowing of type-2 targeting biologics using pooled data from two similarly design randomized, placebo-controlled biologic trials (n = 137). Measurements and Main Results: Simulations demonstrated that narrowing of the small airways had a greater impact on R5 2 R20 than narrowing of the larger airways and was associated (above a threshold of approximately 40% narrowing) with marked deterioration in both asthma control and asthma quality of life, above the minimal clinical important difference. The observed treatment effect on R5 2 R20 in the pooled trials equated to a predicted small airway narrowing reversal of approximately 40%. Conclusions: We have demonstrated, using computational modeling, that forced oscillation R5 2 R20 is a direct measure of anatomical narrowing in the small airways and that small airway narrowing has a marked impact on both asthma control and quality of life and may be modified by biologics