Fulfilling the Promise of Breathomics: Considerations for the Discovery and Validation of Exhaled Volatile Biomarkers.

The exhaled breath represents an ideal matrix for noninvasive biomarker discovery, and exhaled metabolomics have the potential to be clinically useful in the era of precision medicine. In this concise translational review, we specifically address volatile organic compounds in the breath, with a view toward fulfilling the promise of these as actionable biomarkers, in particular, for lung diseases. We review the literature paying attention to seminal work linked to key milestones in breath research; discuss potential applications for breath biomarkers across disease areas and healthcare systems, including the perspectives of industry; and outline critical aspects of study design that will need to be considered for any pivotal research going forward if breath analysis is to provide robust validated biomarkers that meet the requirements for future clinical implementation.

ARL5b inhibits human rhinovirus 16 propagation and impairs macrophage-mediated bacterial clearance.

Human rhinovirus is the most frequently isolated virus during severe exacerbations of chronic respiratory diseases, like chronic obstructive pulmonary disease. In this disease, alveolar macrophages display significantly diminished phagocytic functions that could be associated with bacterial superinfections. However, how human rhinovirus affects the functions of macrophages is largely unknown.

IL-33 Expression Is Lower in Current Smokers at both Transcriptomic and Protein Levels.

IL-33 is a proinflammatory cytokine thought to play a role in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). A recent clinical trial using an anti-IL-33 antibody showed a reduction in exacerbation and improved lung function in ex-smokers but not current smokers with COPD. This study aimed to understand the effects of smoking status on IL-33.

Examining the Role of Type 2 Inflammation in Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is a chronic type 2 inflammatory disease characterized by an eosinophilic inflammatory infiltrate in the esophagus, leading to remodeling, stricture formation, and fibrosis. Triggered by food and aeroallergens, type 2 cytokines interleukin (IL)-4, IL-13, IL-5 produced by CD4+ T helper 2 cells (Th2), eosinophils, mast cells, basophils, and type 2 innate lymphoid cells alter the esophageal epithelial barrier and increase inflammatory cell tissue infiltration. Clustering analysis based on the expression of type 2 inflammatory genes demonstrated the diversity of EoE endotypes.

Human Lung Conventional Dendritic Cells Orchestrate Lymphoid Neogenesis during Chronic Obstructive Pulmonary Disease.

Emerging evidence supports a crucial role for tertiary lymphoid organs (TLOs) in chronic obstructive pulmonary disease (COPD) progression. However, mechanisms of immune cell activation leading to TLOs in COPD remain to be defined. To examine the role of lung dendritic cells (DCs) in T follicular helper (Tfh)-cell induction, a T-cell subset critically implicated in lymphoid organ formation, in COPD.

Dual Role For A MEK Inhibitor As A Modulator Of Inflammation And Host Defense Mechanisms With Potential Therapeutic Application In COPD.

Background: Unlike p38 mitogen-activated protein Kinases (MAPK) that has been extensively studied in the context of lung-associated pathologies in COPD, the role of the dual-specificity mitogen-activated protein kinase kinase (MEK1/2) or its downstream signaling molecule extracellular signal-regulated kinases 1/2 (ERK1/2) in COPD is poorly understood.

Objectives: The aim of this study was to address whether MEK1/2 pathway activation is linked to COPD and that targeting this pathway can improve lung inflammation through decreased immune-mediated inflammatory responses without compromising bacterial clearance.

Methods: Association of MEK1/2 pathway activation to COPD was investigated by immunohistochemistry using lung tissue biopsies from COPD and healthy individuals and through analysis of sputum gene expression data from COPD patients.

Design, Synthesis, and Biological Evaluation of MEK PROTACs.

PROteolysis TArgeting Chimeras (PROTACs) targeting the degradation of MEK have been designed based on allosteric MEK inhibitors. Inhibition of the phosphorylation of ERK1/2 was less effective with the PROTACs than a small-molecule inhibitor; the best PROTACs, however, were more effective in inhibiting proliferation of A375 cells than an inhibitor.

Arpin is critical for phagocytosis in macrophages and is targeted by human rhinovirus.

Human rhinovirus is a causative agent of severe exacerbations of chronic obstructive pulmonary disease (COPD). COPD is characterised by an increased number of alveolar macrophages with diminished phagocytic functions, but how rhinovirus infection affects macrophage function is still unknown. Here, we describe that human rhinovirus 16 impairs bacterial uptake and receptor-mediated phagocytosis in macrophages.

Dynamics of IFN-β Responses during Respiratory Viral Infection. Insights for Therapeutic Strategies.

Viral infections are major drivers of exacerbations and clinical burden in patients with asthma and chronic obstructive pulmonary disease (COPD). IFN-β is a key component of the innate immune response to viral infection. To date, studies of inhaled IFN-β treatment have not demonstrated a significant effect on asthma exacerbations.

Use of precision cut lung slices as a translational model for the study of lung biology.

Animal models remain invaluable for study of respiratory diseases, however, translation of data generated in genetically homogeneous animals housed in a clean and well-controlled environment does not necessarily provide insight to the human disease situation. In vitro human systems such as air liquid interface (ALI) cultures and organ-on-a-chip models have attempted to bridge the divide between animal models and human patients. However, although 3D in nature, these models struggle to recreate the architecture and complex cellularity of the airways and parenchyma, and therefore cannot mimic the complex cell-cell interactions in the lung.

The lung environment controls alveolar macrophage metabolism and responsiveness in type 2 inflammation.

Fine control of macrophage activation is needed to prevent inflammatory disease, particularly at barrier sites such as the lungs. However, the dominant mechanisms that regulate the activation of pulmonary macrophages during inflammation are poorly understood. We found that alveolar macrophages (AlvMs) were much less able to respond to the canonical type 2 cytokine IL-4, which underpins allergic disease and parasitic worm infections, than macrophages from lung tissue or the peritoneal cavity.

HRV16 Impairs Macrophages Cytokine Response to a Secondary Bacterial Trigger.

Human rhinovirus is frequently seen as an upper respiratory tract infection but growing evidence proves the virus can cause lower respiratory tract infections in patients with chronic inflammatory lung diseases including chronic obstructive pulmonary disease (COPD). In addition to airway epithelial cells, macrophages are crucial for regulating inflammatory responses to viral infections. However, the response of macrophages to HRV has not been analyzed in detail.

A Disintegrin and A Metalloproteinase-9 (ADAM9): A Novel Proteinase Culprit with Multifarious Contributions to COPD.

Introduction: Proteinases with a disintegrin and a metalloproteinase domain (ADAMs) have not been well studied in COPD. We investigated whether ADAM9 is linked to COPD in humans and mice.

Methods: ADAM9 blood and lung levels were measured in COPD patients versus controls, and air- versus cigarette smoke (CS)-exposed wild-type (WT) mice.

A Disintegrin and Metalloproteinase Domain-8: A Novel Protective Proteinase in Chronic Obstructive Pulmonary Disease.

Rationale: ADAM8 (a disintegrin and metalloproteinase domain-8) is expressed by leukocytes and epithelial cells in health, but its contribution to the pathogenesis of chronic obstructive pulmonary disease (COPD) is unknown.

Objectives: To determine whether the expression of ADAM8 is increased in the lungs of patients with COPD and cigarette smoke (CS)-exposed mice, and whether ADAM8 promotes the development of COPD.

Methods: ADAM8 levels were measured in lung, sputum, plasma, and/or BAL fluid samples from patients with COPD, smokers, and nonsmokers, and wild-type (WT) mice exposed to CS versus air.

Differential anti-inflammatory effects of budesonide and a p38 MAPK inhibitor AZD7624 on COPD pulmonary cells.

Background: The effects of anti-inflammatory drugs in COPD patients may vary between different cell types. The aim of the current study was to assess the anti-inflammatory effects of the corticosteroid budesonide and a p38 MAPK inhibitor (AZD7624) on different cell types obtained from COPD patients and healthy controls.

Methods: Eight healthy smokers, 16 COPD infrequent exacerbators, and 16 frequent COPD exacerbators (≥2 exacerbations in the last year) were recruited for bronchoscopy and blood sampling.

The development of AZD7624 for prevention of exacerbations in COPD: a randomized controlled trial.

Background: p38 mitogen-activated protein kinase (MAPK) plays a central role in the regulation and activation of pro-inflammatory mediators. COPD patients have increased levels of activated p38 MAPK, which correlate with increased lung function impairment, alveolar wall inflammation, and COPD exacerbations.

Objectives: These studies aimed to assess the effect of p38 inhibition with AZD7624 in healthy volunteers and patients with COPD.

AZD7624, an Inhaled p38 Inhibitor, Demonstrates Local Lung Inhibition of LPS-Induced TNF with Minimal Systemic Exposure.

Inhaled drugs generally aim to drive a local pharmacological effect in lung, at the same time minimizing systemic exposure, in order to obtain efficacy in lung disease without unwanted systemic effects. Here, we demonstrate that inhaled delivery of a p38 inhibitor (AZD7624) can provide superior pharmacokinetic exposure and superior pharmacodynamic lung effects. In rats, inhaled AZD7624 had a five times higher dose-adjusted lung exposure compared with intravenous dosing.

Design of a Chemical Probe for the Bromodomain and Plant Homeodomain Finger-Containing (BRPF) Family of Proteins.

The bromodomain and plant homeodomain finger-containing (BRPF) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Here, we describe NI-57 (16) as new pan-BRPF chemical probe of the bromodomain (BRD) of the BRPFs. Inhibitor 16 preferentially bound the BRD of BRPF1 and BRPF2 over BRPF3, whereas binding to BRD9 was weaker.

Role of B Cell-Activating Factor in Chronic Obstructive Pulmonary Disease.

Rationale: B cell-activating factor (BAFF) plays a major role in activation of B cells and in adaptive humoral immune responses. In chronic obstructive pulmonary disease (COPD), lymphoid follicles have been associated with disease severity, and overexpression of BAFF has been demonstrated within lymphoid follicles of patients with severe COPD.

Objectives: To investigate expression and localization of BAFF in the lungs of patients with COPD and to study the role of BAFF in COPD by antagonizing BAFF in a mouse model of chronic cigarette smoke (CS) exposure.

Role of CXCL13 in cigarette smoke-induced lymphoid follicle formation and chronic obstructive pulmonary disease.

Rationale: The B cell-attracting chemokine CXCL13 is an important mediator in the formation of tertiary lymphoid organs (TLOs). Increased numbers of ectopic lymphoid follicles have been observed in lungs of patients with severe chronic obstructive pulmonary disease (COPD). However, the role of these TLOs in the pathogenesis of COPD remains unknown.