scholarly journals Mechanisms and Points of Control in the Spread of Inflammation: A Mathematical Investigation

2020 ◽  
Vol 82 (4) ◽  
Author(s):  
A. Bayani ◽  
J. L. Dunster ◽  
J. J. Crofts ◽  
M. R. Nelson
Keyword(s):  
Inflammatory Mediators ◽  
Homogeneous Model ◽  
Neutrophil Migration ◽  
Turn Of The Century ◽  
Therapeutic Interventions ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Inflammatory Damage ◽  
Spatial Mechanisms ◽  
Attractive Therapeutic Target

Abstract Understanding the mechanisms that control the body’s response to inflammation is of key importance, due to its involvement in myriad medical conditions, including cancer, arthritis, Alzheimer’s disease and asthma. While resolving inflammation has historically been considered a passive process, since the turn of the century the hunt for novel therapeutic interventions has begun to focus upon active manipulation of constituent mechanisms, particularly involving the roles of apoptosing neutrophils, phagocytosing macrophages and anti-inflammatory mediators. Moreover, there is growing interest in how inflammatory damage can spread spatially due to the motility of inflammatory mediators and immune cells. For example, impaired neutrophil chemotaxis is implicated in causing chronic inflammation under trauma and in ageing, while neutrophil migration is an attractive therapeutic target in ailments such as chronic obstructive pulmonary disease. We extend an existing homogeneous model that captures interactions between inflammatory mediators, neutrophils and macrophages to incorporate spatial behaviour. Through bifurcation analysis and numerical simulation, we show that spatially inhomogeneous outcomes can present close to the switch from bistability to guaranteed resolution in the corresponding homogeneous model. Finally, we show how aberrant spatial mechanisms can play a role in the failure of inflammation to resolve and discuss our results within the broader context of seeking novel inflammatory treatments.

SR stress in locomotor muscles of patients with chronic obstructive pulmonary disease

2020 ◽  
Author(s):  
Rizwan Qaisar ◽  
Mughal Qayyum ◽  
Tahir Muhammad
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Skeletal Muscle ◽  
Pulmonary Disease ◽  
Vastus Lateralis ◽  
Therapeutic Interventions ◽  
Chronic Obstructive ◽  
Potential Contribution ◽  
Healthy Controls ◽  
Obstructive Pulmonary Disease ◽  
Locomotor Muscles

Abstract Background The potential contribution of chronic dysregulation of sarcoplasmic reticulum (SR) protein homeostasis (a condition called SR stress) to skeletal muscle loss is poorly understood. We investigated the degree of activation of SR stress in locomotor muscles of patients with chronic obstructive pulmonary disease (COPD), a respiratory disease with systemic manifestations. Methods We analyzed the markers of SR stress and associated pathologies in vastus lateralis muscles of 60-65 years old male healthy controls and patients with mild (COPD stages 1 & 2) and advanced (COPD stages 3 & 4) COPD (N = 6-8 / group). Results Skeletal muscle proteins expressions of GRP94, BiP, CHOP and ATF were significantly elevated in advanced COPD (≈53%, ≈3.6 fold, ≈3.5 fold and ≈3.2 fold, respectively) compared with healthy controls. The expression of downstream markers of SR stress including apoptosis, inflammation and autophagy was increased, while the maximal activity of SR Ca2+ ATPase (SERCA) enzyme was significantly reduced in advanced COPD (≈41%) than healthy controls. Single muscle fiber diameter and cytoplasmic domain per myonucleus were significantly smaller (≈14% and 13%, respectively) in patients with advanced COPD than healthy controls. These changes in SR dysfunction were accompanied by substantially elevated levels of global oxidative stress including lipid peroxidation and mitochondrial ROS production. Conclusion Taken together, our data suggests that the muscle weakness in advanced COPD is in part driven by elevated SR stress and its pathological consequences. The data provided can lead to potential therapeutic interventions of SR dysfunction for muscle detriment in COPD.

scholarly journals Muscarinic M3 receptors on structural cells regulate cigarette smoke-induced neutrophilic airway inflammation in mice

2015 ◽  
Vol 308 (1) ◽  
pp. L96-L103 ◽  
Author(s):  
Loes E. M. Kistemaker ◽  
Ronald P. van Os ◽  
Albertina Dethmers-Ausema ◽  
I. Sophie T. Bos ◽  
Machteld N. Hylkema ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cigarette Smoke ◽  
Neutrophil Migration ◽  
Inflammatory Cells ◽  
Cell Types ◽  
Chronic Obstructive ◽  
Wild Type ◽  
Obstructive Pulmonary Disease ◽  
Neutrophilic Inflammation ◽  
Relative Contribution

Anticholinergics, blocking the muscarinic M3 receptor, are effective bronchodilators for patients with chronic obstructive pulmonary disease. Recent evidence from M3 receptor-deficient mice (M3R−/−) indicates that M3 receptors also regulate neutrophilic inflammation in response to cigarette smoke (CS). M3 receptors are present on almost all cell types, and in this study we investigated the relative contribution of M3 receptors on structural cells vs. inflammatory cells to CS-induced inflammation using bone marrow chimeric mice. Bone marrow chimeras (C56Bl/6 mice) were generated, and engraftment was confirmed after 10 wk. Thereafter, irradiated and nonirradiated control animals were exposed to CS or fresh air for four consecutive days. CS induced a significant increase in neutrophil numbers in nonirradiated and irradiated control animals (4- to 35-fold). Interestingly, wild-type animals receiving M3R−/− bone marrow showed a similar increase in neutrophil number (15-fold). In contrast, no increase in the number of neutrophils was observed in M3R−/− animals receiving wild-type bone marrow. The increase in keratinocyte-derived chemokine (KC) levels was similar in all smoke-exposed groups (2.5- to 5.0-fold). Microarray analysis revealed that fibrinogen-α and CD177, both involved in neutrophil migration, were downregulated in CS-exposed M3R−/− animals receiving wild-type bone marrow compared with CS-exposed wild-type animals, which was confirmed by RT-qPCR (1.6–2.5 fold). These findings indicate that the M3 receptor on structural cells plays a proinflammatory role in CS-induced neutrophilic inflammation, whereas the M3 receptor on inflammatory cells does not. This effect is probably not mediated via KC release, but may involve altered adhesion and transmigration of neutrophils via fibrinogen-α and CD177.

scholarly journals Responsiveness of Various Exercise-Testing Protocols to Therapeutic Interventions in COPD

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Benoit Borel ◽  
Steeve Provencher ◽  
Didier Saey ◽  
François Maltais
Keyword(s):  
Exercise Testing ◽  
Exercise Tolerance ◽  
Work Rate ◽  
Therapeutic Interventions ◽  
Exercise Intolerance ◽  
Chronic Obstructive ◽  
Exercise Tests ◽  
Obstructive Pulmonary Disease ◽  
Constant Work Rate ◽  
Testing Protocols

Exercise intolerance is a key element in the pathophysiology and course of Chronic Obstructive Pulmonary Disease (COPD). As such, evaluating exercise tolerance has become an important part of the management of COPD. A wide variety of exercise-testing protocols is currently available, each protocol having its own strengths and weaknesses relative to their discriminative, methodological, and evaluative characteristics. This paper aims to review the responsiveness of several exercise-testing protocols used to evaluate the efficacy of pharmacological and nonpharmacological interventions to improve exercise tolerance in COPD. This will be done taking into account the minimally important difference, an important concept in the interpretation of the findings about responsiveness of exercise testing protocols. Among the currently available exercise-testing protocols (incremental, constant work rate, or self-paced), constant work rate exercise tests (cycle endurance test and endurance shuttle walking test) emerge as the most responsive ones for detecting and quantifying changes in exercise capacity after an intervention in COPD.

scholarly journals Interleukin-1α drives the dysfunctional cross-talk of the airway epithelium and lung fibroblasts in COPD

2016 ◽  
Vol 48 (2) ◽  
pp. 359-369 ◽  
Author(s):  
Emmanuel T. Osei ◽  
Jacobien A. Noordhoek ◽  
Tillie L. Hackett ◽  
Anita I.R. Spanjer ◽  
Dirkje S. Postma ◽  
...  
Keyword(s):  
Inflammatory Mediators ◽  
Airway Epithelium ◽  
Fetal Lung ◽  
Bronchial Epithelial Cell ◽  
Airway Epithelial Cells ◽  
Lung Fibroblast ◽  
Lung Fibroblasts ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
And Control

Chronic obstructive pulmonary disease (COPD) has been associated with aberrant epithelial–mesenchymal interactions resulting in inflammatory and remodelling processes. We developed a co-culture model using COPD and control-derived airway epithelial cells (AECs) and lung fibroblasts to understand the mediators that are involved in remodelling and inflammation in COPD.AECs and fibroblasts obtained from COPD and control lung tissue were grown in co-culture with fetal lung fibroblast or human bronchial epithelial cell lines. mRNA and protein expression of inflammatory mediators, pro-fibrotic molecules and extracellular matrix (ECM) proteins were assessed.Co-culture resulted in the release of pro-inflammatory mediators interleukin (IL)-8/CXCL8 and heat shock protein (Hsp70) from lung fibroblasts, and decreased expression of ECM molecules (e.g. collagen, decorin) that was not different between control and COPD-derived primary cells. This pro-inflammatory effect was mediated by epithelial-derived IL-1α and increased upon epithelial exposure to cigarette smoke extract (CSE). When exposed to CSE, COPD-derived AECs elicited a stronger IL-1α response compared with control-derived airway epithelium and this corresponded with a significantly enhanced IL-8 release from lung fibroblasts.We demonstrate that, through IL-1α production, AECs induce a pro-inflammatory lung fibroblast phenotype that is further enhanced with CSE exposure in COPD, suggesting an aberrant epithelial–fibroblast interaction in COPD.

scholarly journals Elevated levels of arginase activity are related to inflammation in patients with COPD exacerbation

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Marcel Jose Rodríguez-Guzmán ◽  
Germán Peces-Barba Romero ◽  
Sandra Pérez Rial ◽  
Cristina Serrano del Castillo ◽  
Miguel Ángel Palomero Rodríguez ◽  
...  
Keyword(s):  
T Cells ◽  
Inflammatory Mediators ◽  
Study Groups ◽  
Arginase Activity ◽  
Stable Phase ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients ◽  
Key Enzyme ◽  
Exacerbation Of Copd

Abstract Introduction Within the pathogenesis of the chronic obstructive pulmonary disease (COPD) there are interactions between different inflammatory mediators that are enhanced during an exacerbation. Arginase is present in bronchial epithelial cells, endothelial, fibroblasts and alveolar macrophages, which make it a probable key enzyme in the regulation of inflammation and remodelling. We aimed to find a potential relationship between arginase activity, inflammatory mediators in COPD patients in stable phase and during exacerbations. Methods We performed a prospective, observational study of cases and controls, with 4 study groups (healthy controls, stable COPD, COPD during an exacerbation and COPD 3 months after exacerbation). We measured arginase, inflammation markers (IL-6, IL-8, TNF-∝, IFN-γ and C reactive protein), and mediators of immunity: neutrophils, monocytes, total TCD3 + lymphocytes (CD3ζ), CD4 + T cells, CD8 + T cells, NK cells. Results A total of 49 subjects were recruited, average age of 69.73 years (59.18% male). Arginase activity is elevated during an exacerbation of COPD, and this rise is related to an increase in IL-6 production. The levels of IL-6 and IL-8 remained elevated in patients with COPD at 3 months after hospital exacerbation. We did not find a clear relationship between arginase activity, immunity or with the degree of obstruction in COPD patients. Conclusions Arginase activity is elevated during an exacerbation of COPD, and it could be related to an increase in the production of IL-6. Levels of IL-6, IL-8, and arginase activity remain elevated in patients with COPD at 3 months after hospital exacerbation. Arginase activity could contribute to the development of COPD.

Increased neutrophil migration in smokers with or without chronic obstructive pulmonary disease

Respirology ◽  
2012 ◽  
Vol 17 (5) ◽  
pp. 854-860 ◽  
Author(s):  
KRISTIN BLIDBERG ◽  
LENA PALMBERG ◽  
BARBRO DAHLÉN ◽  
ANN-SOFIE LANTZ ◽  
KJELL LARSSON
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Neutrophil Migration ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease

scholarly journals Inspiratory Capacity during Exercise: Measurement, Analysis, and Interpretation

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Jordan A. Guenette ◽  
Roberto C. Chin ◽  
Julia M. Cory ◽  
Katherine A. Webb ◽  
Denis E. O'Donnell
Keyword(s):  
Comprehensive Evaluation ◽  
Cardiopulmonary Exercise Testing ◽  
Therapeutic Interventions ◽  
Peak Exercise ◽  
Chronic Obstructive ◽  
Valuable Insight ◽  
Inspiratory Capacity ◽  
Expiratory Flow Limitation ◽  
Obstructive Pulmonary Disease ◽  
Measurement Analysis

Cardiopulmonary exercise testing (CPET) is an established method for evaluating dyspnea and ventilatory abnormalities. Ventilatory reserve is typically assessed as the ratio of peak exercise ventilation to maximal voluntary ventilation. Unfortunately, this crude assessment provides limited data on the factors that limit the normal ventilatory response to exercise. Additional measurements can provide a more comprehensive evaluation of respiratory mechanical constraints during CPET (e.g., expiratory flow limitation and operating lung volumes). These measurements are directly dependent on an accurate assessment of inspiratory capacity (IC) throughout rest and exercise. Despite the valuable insight that the IC provides, there are no established recommendations on how to perform the maneuver during exercise and how to analyze and interpret the data. Accordingly, the purpose of this manuscript is to comprehensively examine a number of methodological issues related to the measurement, analysis, and interpretation of the IC. We will also briefly discuss IC responses to exercise in health and disease and will consider how various therapeutic interventions influence the IC, particularly in patients with chronic obstructive pulmonary disease. Our main conclusion is that IC measurements are both reproducible and responsive to therapy and provide important information on the mechanisms of dyspnea and exercise limitation during CPET.

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