Summary
Fibrosis is a medical condition characterized by an excessive deposition of extracellular matrix compounds such as collagen in tissues. Fibrotic lesions are present in many diseases and can ...affect all organs. The excessive extracellular matrix accumulation in these conditions can often have serious consequences and in many cases be life‐threatening. A typical event seen in many fibrotic conditions is a profound accumulation of mast cells (MCs), suggesting that these cells can contribute to the pathology. Indeed, there is now substantialv evidence pointing to an important role of MCs in fibrotic disease. However, investigations from various clinical settings and different animal models have arrived at partly contradictory conclusions as to how MCs affect fibrosis, with many studies suggesting a detrimental role of MCs whereas others suggest that MCs can be protective. Here, we review the current knowledge of how MCs can affect fibrosis.
Mast cells are major effector cells of inflammation and there is strong evidence that mast cells play a significant role in asthma pathophysiology. There is also a growing body of evidence that mast ...cells contribute to other inflammatory and fibrotic lung diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. This review discusses the role that mast cells play in airway diseases and highlights how mast cell microlocalisation within specific lung compartments and their cellular interactions are likely to be critical for their effector function in disease.
Background Eosinophilic airway inflammation is heterogeneous in asthmatic patients. We recently described a distinct subtype of asthma defined by the expression of genes inducible by TH 2 cytokines ...in bronchial epithelium. This gene signature, which includes periostin, is present in approximately half of asthmatic patients and correlates with eosinophilic airway inflammation. However, identification of this subtype depends on invasive airway sampling, and hence noninvasive biomarkers of this phenotype are desirable. Objective We sought to identify systemic biomarkers of eosinophilic airway inflammation in asthmatic patients. Methods We measured fraction of exhaled nitric oxide (F eno ), peripheral blood eosinophil, periostin, YKL-40, and IgE levels and compared these biomarkers with airway eosinophilia in asthmatic patients. Results We collected sputum, performed bronchoscopy, and matched peripheral blood samples from 67 asthmatic patients who remained symptomatic despite maximal inhaled corticosteroid treatment (mean FEV1 , 60% of predicted value; mean Asthma Control Questionnaire ACQ score, 2.7). Serum periostin levels are significantly increased in asthmatic patients with evidence of eosinophilic airway inflammation relative to those with minimal eosinophilic airway inflammation. A logistic regression model, including sex, age, body mass index, IgE levels, blood eosinophil numbers, F eno levels, and serum periostin levels, in 59 patients with severe asthma showed that, of these indices, the serum periostin level was the single best predictor of airway eosinophilia ( P = .007). Conclusion Periostin is a systemic biomarker of airway eosinophilia in asthmatic patients and has potential utility in patient selection for emerging asthma therapeutics targeting TH 2 inflammation.
Poor adherence is common in difficult-to-control asthma. Distinguishing patients with difficult-to-control asthma who respond to inhaled corticosteroids (ICS) from refractory asthma is an important ...clinical challenge.
Suppression of fractional exhaled nitric oxide (Fe
) with directly observed ICS therapy over 7 days can identify nonadherence to ICS treatment in difficult-to-control asthma. We examined the feasibility and utility of Fe
suppression testing in routine clinical care within UK severe asthma centers using remote monitoring technologies.
A web-based interface with integrated remote monitoring technology was developed to deliver Fe
suppression testing. We examined the utility of Fe
suppression testing to demonstrate ICS responsiveness and clinical benefit on electronically monitored treatment with standard high-dose ICS and long-acting β
-agonist treatment.
Clinical response was assessed using the Asthma Control Questionnaire-5, spirometry, and biomarker measurements (Fe
and peripheral blood eosinophil count). Of 250 subjects, 201 completed the test with 130 positive suppression tests. Compared with a negative suppression test, a positive test identified a Fe
-low population when adherent with ICS/long-acting β
-agonist (median, 26 ppb interquartile range, 16-36 ppb vs. 43 ppb interquartile range, 38-73 ppb) with significantly greater FEV
% (mean, 88.2 ± 16.4 vs. 74.1 ± 20.9; P < 0.01). Asthma Control Questionnaire-5 improved significantly in both groups (positive test: mean difference, -1.2; 95% confidence interval, -0.9 to -1.5; negative test: mean difference, -0.9; 95% confidence interval, -0.4 to -1.3).
Remote Fe
suppression testing is an effective means of identifying nonadherence to ICS in subjects with difficult-to-control asthma and the substantial population of subjects who derive important clinical benefits from optimized ICS/long-acting β
-agonist treatment.
A theoretical risk of "rebound" worsening of eosinophilic airway inflammation associated with negative outcomes has been suggested3 on the basis of in vitro observations that anti-IL-5 therapy is ...associated with upregulation of IL-5 synthesis by TH2 cells, upregulation of IL-5R expression by eosinophils, and persistence of preformed IL-5 in complex with the drug for a variable period of time after cessation of therapy.4 As part of a follow-up analysis, subjects completing a 12-month study of mepolizumab in refractory asthma1 were observed for 12 months with assessments every 3 months. The rise in exacerbations at 3 to 6 months after stopping mepolizumab was preceded by a rise in sputum and blood eosinophils, supporting suggestions that these events are related but have different time courses.5-8 The finding of increased asthma symptoms following cessation of mepolizumab was unexpected because symptoms were not modified significantly during the treatment period.1 However, mean symptom scores for subjects receiving mepolizumab were lower than for subjects in the placebo group at the end of the treatment phase of the study.
Asthma exacerbations are characterized by increased symptoms of cough and chest tightness, diminished expiratory airflow, and increased numbers of inflammatory cells in the sputum. In these two small ...“proof of concept” trials involving patients with eosinophilic asthma and a history of exacerbations, patients treated with an antibody directed against interleukin-5 had fewer exacerbations than did those given placebo.
Asthma exacerbations are characterized by increased symptoms of cough and chest tightness, diminished expiratory airflow, and increased numbers of inflammatory cells in the sputum. In these two small “proof of concept” trials involving patients with eosinophilic asthma and a history of exacerbations, patients treated with an antibody directed against interleukin-5 had fewer exacerbations than did those given placebo.
Asthma is a complex chronic inflammatory disorder of the bronchial tree. Persons with asthma present with variable symptoms of cough, breathlessness, and wheezing; these episodes may be punctuated by periods of more severe and sustained deterioration in control of symptoms — termed exacerbations — that necessitate emergency treatment. Exacerbations are associated with substantial morbidity and mortality and with considerable health care costs.
1
Exacerbations differ from day-to-day symptoms in that they respond poorly to usual inhaled therapy and are more closely linked to increased airway inflammation.
2
The link to eosinophilic airway inflammation may be particularly important, since infiltration of the airway . . .
Increasing evidence suggests that asthma is a heterogeneous disorder regulated by distinct molecular mechanisms. In a cross-sectional study of asthmatics of varying severity (n = 51), endobronchial ...tissue gene expression analysis revealed three major patient clusters: TH2-high, TH17-high, and TH2/17-low. TH2-high and TH17-high patterns were mutually exclusive in individual patient samples, and their gene signatures were inversely correlated and differentially regulated by interleukin-13 (IL-13) and IL-17A. To understand this dichotomous pattern of T helper 2 (TH2) and TH17 signatures, we investigated the potential of type 2 cytokine suppression in promoting TH17 responses in a preclinical model of allergen-induced asthma. Neutralization of IL-4 and/or IL-13 resulted in increased TH17 cells and neutrophilic inflammation in the lung. However, neutralization of IL-13 and IL-17 protected mice from eosinophilia, mucus hyperplasia, and airway hyperreactivity and abolished the neutrophilic inflammation, suggesting that combination therapies targeting both pathways may maximize therapeutic efficacy across a patient population comprising both TH2 and TH17 endotypes.
Ige expresses insights about the mechanism of mast cell (MCs) activation in severe asthma. MCs are present in all heathy human tissues and exhibit marked heterogeneity with respect to their ...development, mediator content, ultrastructure, and function. MCs release their mediators in response to all stimuli considered important for the development of asthma, day-today symptoms, and exacerbations. The author discusses that Tiotiu and colleagues have used gene set variation analysis to interrogate MC activation signatures in the sputum of the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) asthma and healthy volunteer cohort, cross-validated with the ADEPT (Airways Disease Endotyping for Personalized Therapeutics) cohort (with which there was moderate agreement).
Mast cell-airway smooth muscle (ASM) interactions play a major role in the immunoglobulin (Ig)E- dependent bronchoconstriction seen in asthma but less is known about IgE-independent mechanisms of ...mast cell activation. Transient receptor potential cation channel, subfamily V, member 4 (TRPV4) activation causes contraction of human ASM
the release of cysteinyl leukotrienes (cysLTs) but the mechanism is unknown. The objective of the present study was to investigate a role for IgE-independent, mast cell-ASM interaction in TRPV4-induced bronchospasm.Bronchoconstriction was measured in anaesthetised guinea pigs and contraction of human and guinea-pig airway tissue assessed using isometric tension measurements. Increases in intracellular Ca
were imaged using the Ca
-sensitive dye FURA2, and time-lapse ptychography was utilised as a surrogate for contraction of ASM cells.The TRPV4 agonist GSK1016790A caused contraction
in the guinea pig, and in human and guinea-pig tracheal tissue, which was inhibited by the TRPV4 antagonist GSK2193874. GSK1016790A increased Ca
and released ATP in human ASM cells without causing contraction. TRPV4 and ATP evoked contraction in isolated tracheal tissue but co-culture experiments indicated a requirement for human lung mast cells. Expression profiling and pharmacological studies demonstrated that mast cell activation was dependent upon ATP activating the P2X4 receptor. Trypsin was shown to evoke contraction of tracheal tissue
activation of PAR-2-TRPV4-ATP-cysLT axis indicating the potential disease relevance of this signalling pathway.TRPV4 activation increases Ca
and releases ATP from ASM cells triggering P2X4-dependent release of cysLTs from mast cells resulting in ASM contraction. This study delineates a novel mast cell-ASM interaction and TRPV4 as a driver of IgE-independent mast cell-dependent bronchospasm.
Asthma affects 10% of the UK population and is an important cause of morbidity and mortality at all ages. Current treatments are either ineffective or carry unacceptable side effects for a number of ...patients; in consequence, development of new approaches to therapy are important. Ion channels are emerging as attractive therapeutic targets in a variety of non‐excitable cells. Ion channels conducting K+ modulate the activity of several structural and inflammatory cells which play important roles in the pathophysiology of asthma. Two channels of particular interest are the voltage‐gated K+ channel Kv1.3 and the intermediate conductance Ca2+‐activated K+ channel KCa3.1 (also known as IKCa1 or SK4). Kv1.3 is expressed in IFNγ‐producing T cells while KCa3.1 is expressed in T cells, mast cells, macrophages, airway smooth muscle cells, fibroblasts and epithelial cells. Both channels play important roles in cell activation, migration, and proliferation through the regulation of membrane potential and calcium signalling. We hypothesize that KCa3.1‐ and/or Kv1.3‐dependent cell processes are one of the common denominators in asthma pathophysiology. If true, these channels might serve as novel targets for the treatment of asthma. Emerging evidence lends support to this hypothesis. Further validation through the study of the role that these channels play in normal and asthmatic airway cell (patho)physiology and in vivo models will provide further justification for the assessment of small molecule blockers of Kv1.3 and KCa3.1 in the treatment of asthma.
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