Publications

Abstract

Persistent and unresolved inflammation is a common underlying factor observed in several and seemingly unrelated human diseases, including cardiovascular and neurodegenerative diseases. Particularly, in atopic conditions, acute inflammatory responses such as those triggered by insect venom, food or drug allergies possess also a life-threatening potential. However, respiratory allergies predominantly exhibit late immune responses associated with chronic inflammation, that can eventually progress into a severe phenotype displaying similar features as those observed in other chronic inflammatory diseases, as is the case of uncontrolled severe asthma. This review aims to explore the different facets and systems involved in chronic allergic inflammation, including processes such as tissue remodelling and immune cell dysregulation, as well as genetic, metabolic and microbiota alterations, which are common to other inflammatory conditions. Our goal here was to deepen on the understanding of an entangled disease as is chronic allergic inflammation and expose potential avenues for the development of better diagnostic and intervention strategies.

Abstract

Childhood asthma is a common chronic disease of the airways that results from host and environment interactions. Most risk factor studies of asthma point to the first year of life as a susceptibility window of mucosal exposure that directly impacts the airway epithelium and airway epithelial cell development. The development of the airway epithelium, which forms a competent barrier resulting from coordinated interactions of different specialized cell subsets, occurs during a critical time frame in normal postnatal development in the first year of life. Understanding the normal and aberrant developmental trajectory of airway epithelial cells is important in identifying pathways that may contribute to barrier dysfunction and asthma pathogenesis. Respiratory viruses make first contact with and infect the airway mucosa. Human rhinovirus (HRV) and respiratory syncytial virus (RSV) are mucosal pathogens that are consistently identified as asthma risk factors. Respiratory viruses represent a unique early life exposure, different from passive irritant exposures which injure the developing airway epithelium. To replicate, respiratory viruses take over the host cell transcriptional and translational processes and exploit host cell energy metabolism. This takeover impacts the development and differentiation processes of airway epithelial cells. Therefore, delineating the mechanisms through which early life respiratory viral infections alter airway epithelial cell development will allow us to understand the maturation and heterogeneity of asthma and develop tools tailored to prevent disease in specific children. This review will summarize what is understood about the impact of early life respiratory viruses on the developing airway epithelium and define critical gaps in our knowledge.

Abstract

Severe asthma is associated with an increased risk for exacerbations, reduced lung function, fixed airflow obstruction, and substantial morbidity and mortality. The concept of remission in severe asthma as a new treatment goal has recently gained attention due to the growing use of monoclonal antibody therapies, which target specific pathologic pathways of inflammation. This review evaluates the current definitions of asthma remission and unveils some of the barriers for achieving this state in the severe asthma population. Although there is no unified definition, the concept of clinical remission in asthma should be based on a sustained period of symptom control, elimination of oral corticosteroid exposure and exacerbations, and stabilization of pulmonary function. The conjugation of these criteria seems a realistic treatment target in a minority of asthmatic patients. Some unmet needs in severe asthma may affect the achievement of clinical remission. Late intervention with targeted therapies in the severe asthma population may increase the risk of corticosteroid exposure and the development of irreversible structural airway changes. Moreover, airway infection is an important component in persistent exacerbations in patients on biologic therapies. Phenotyping exacerbations may be useful to guide therapy decisions and to avoid the liberal use of oral corticosteroids. Another challenge associated with the aim of clinical remission in severe asthma is the multifaceted interaction between the disease and its associated comorbidities. Behavioural factors should be evaluated in case of persistent symptoms despite optimised treatment, and assessing biomarkers and targeting treatable traits may allow for a more objective way of reaching remission. The concept of clinical remission will benefit from an international consensus to establish unifying criteria for its assessment, and it should be addressed in the future management guidelines.

Abstract

The long-term goal of asthma management is to achieve disease control, comprising the assessment of 2 main domains: (1) symptom control and (2) future risk of adverse outcomes. Decades of progress in asthma management have correlated with increasingly ambitious disease control targets. Moreover, the introduction of precision medicines, such as biologics, has further expanded the limits of what can be achieved in terms of disease control. It is now believed that clinical remission, a term rarely associated with asthma, may be an achievable treatment goal. An expert framework published in 2020 took the first step toward developing a commonly accepted definition of clinical remission in asthma. However, there remains a widespread discussion about the clinical parameters and thresholds that should be included in a standardized definition of clinical remission. This review aims to discuss on-treatment clinical remission as an aspirational outcome in asthma management, drawing on experiences from other chronic diseases where remission has long been a goal. We also highlight the integral role of shared decision-making between patients and health care professionals and the need for a common understanding of the individual patient journey to remission as foundational elements in reducing disease burden and improving outcomes for patients with asthma.

Abstract

Studies have shown that eosinophilic COPD (eCOPD) is a distinct phenotype of the disease. It is well established that innate lymphoid cells are involved in the development of eosinophilic inflammation. Interleukin(IL)-25, thymic stromal lymphopoietin (TSLP) and IL-33 are a group of cytokines produced by epithelium in response to danger signals, e.g., cigarette smoke, and potent activators of ILC2s. In the present study, we examined circulating and sputum ILC2 numbers and expression of intracellular IL-5 as well as receptors for TSLP, IL-33 and IL-25 by ILC2s in non-atopic COPD patients with and without (neCOPD) airway eosinophilic inflammation and healthy smokers. In addition, we examined the association between ILC2s and clinical indicators of COPD burden (i.e., symptom intensity and risk of exacerbations). ILC2s were enumerated in peripheral blood and induced sputum by means of flow cytometry. We noted significantly greater numbers of airway IL-5+ILC2s and TSLPR+ILC2s in eCOPD compared with neCOPD (p < 0.05 and p < 0.01, respectively) and HSs (p < 0.001 for both). In addition, we showed that IL-5+ILC2s, IL-17RB+ILC2s and ST2+ILC2s are significantly increased in the sputum of eCOPD patients compared with HSs. In all COPD patients, sputum ILC2s positively correlated with sputum eosinophil percentage (r = 0.48, p = 0.002). We did not find any significant correlations between sputum ILC2s and dyspnea intensity as measured by the modified Medical Research Council scale (mMRC) and symptom intensity measured by the COPD Assessment Test (CAT). These results suggest the involvement of epithelial alarmin-activated ILC2s in the pathobiology of eosinophilic COPD.

Abstract

Our epithelium represents a battle ground against a variety of insults including pathogens and danger signals. It encodes multiple sensors that detect and respond to such insults, playing an essential role in maintaining and defending tissue homeostasis. One key set of defense mechanisms is our inflammasomes which drive innate immune responses including, sensing and responding to pathogen attack, through the secretion of pro-inflammatory cytokines and cell death. Identification of physiologically relevant triggers for inflammasomes has greatly influenced our ability to decipher the mechanisms behind inflammasome activation. Furthermore, identification of patient mutations within inflammasome components implicates their involvement in a range of epithelial diseases. This review will focus on exploring the roles of inflammasomes in epithelial immunity and cover: the diversity and differential expression of inflammasome sensors amongst our epithelial barriers, their ability to sense local infection and damage and the contribution of the inflammasomes to epithelial homeostasis and disease.

Abstract

The epithelial barrier theory links the recent rise in chronic non-communicable diseases, notably autoimmune and allergic disorders, to environmental agents disrupting the epithelial barrier. Global pollution and environmental toxic agent exposure have worsened over six decades because of uncontrolled growth, modernization, and industrialization, affecting human health. Introducing new chemicals without any reasonable control of their health effects through these years has led to documented adverse effects, especially on the skin and mucosal epithelial barriers. These substances, such as particulate matter, detergents, surfactants, food emulsifiers, micro- and nano-plastics, diesel exhaust, cigarette smoke, and ozone, have been shown to compromise the epithelial barrier integrity. This disruption is linked to the opening of the tight-junction barriers, inflammation, cell death, oxidative stress, and metabolic regulation. Consideration must be given to the interplay of toxic substances, underlying inflammatory diseases, and medications, especially in affected tissues. This review article discusses the detrimental effect of environmental barrier-damaging compounds on human health and involves cellular and molecular mechanisms.

Abstract

Tight junction (TJ) proteins establish a physical barrier between epithelial cells, playing a crucial role in maintaining tissue homeostasis by safeguarding host tissues against pathogens, allergens, antigens, irritants, etc. Recently, an increasing number of studies have demonstrated that abnormal expression of TJs plays an essential role in the development and progression of inflammatory airway diseases, including chronic obstructive pulmonary disease, asthma, allergic rhinitis, and chronic rhinosinusitis (CRS) with or without nasal polyps. Among them, CRS with nasal polyps is a prevalent chronic inflammatory disease that affects the nasal cavity and paranasal sinuses, leading to a poor prognosis and significantly impacting patients' quality of life. Its pathogenesis primarily involves dysfunction of the nasal epithelial barrier, impaired mucociliary clearance, disordered immune response, and excessive tissue remodeling. Numerous studies have elucidated the pivotal role of TJs in both the pathogenesis and response to traditional therapies in CRS. We therefore to review and discuss potential factors contributing to impair and repair of TJs in the nasal epithelium based on their structure, function, and formation process.

Abstract

Epithelial barrier damage plays a central role in the development and maintenance of allergic inflammation. Rises in the epithelial barrier permeability of airways alter tissue homeostasis and allow the penetration of allergens and other external agents. Different factors contribute to barrier impairment, such as eosinophilic infiltration and allergen protease action-eosinophilic cationic proteins' effects and allergens' proteolytic activity both contribute significantly to epithelial damage. In the airways, allergen proteases degrade the epithelial junctional proteins, allowing allergen penetration and its uptake by dendritic cells. This increase in allergen-immune system interaction induces the release of alarmins and the activation of type 2 inflammatory pathways, causing or worsening the main symptoms at the skin, bowel, and respiratory levels. We aim to highlight the molecular mechanisms underlying allergenic protease-induced epithelial barrier damage and the role of immune response in allergic asthma onset, maintenance, and progression. Moreover, we will explore potential clinical and radiological biomarkers of airway remodeling in allergic asthma patients.

Abstract

Epithelial cells provide a first line of immune defense by maintaining barrier function, orchestrating mucociliary clearance, secreting antimicrobial molecules, and generating sentinel signals to both activate innate immune cells and shape adaptive immunity. Although epithelial alarmins play a particularly important role in the initiation of type 2 inflammation in response to allergens, the mechanisms by which epithelial cells sense the environment and regulate the generation and release of alarmins have been poorly understood. Recent studies have identified new sensors and signaling pathways used by barrier epithelial cells to elicit type 2 inflammation, including a novel pathway for the release of interleukin-33 from the nucleus that depends on apoptotic signaling. These recent findings have implications in the development of allergic diseases, from atopic eczema to food allergy, rhinitis, and asthma.

Abstract

Backgroud: Presently, the impact of Chronic rhinosinusitis with nasal polyps (CRSwNP) on asthma onset is unknown. Aims: To evaluate the role of CRSwNP in asthma onset. Materials and methods: A total of 3107 CRSwNP patients were retrospectively screened from 1 January 2018, to 31 May 2021; 624 patients were enrolled. Clinical data regarding nasal symptoms, Lund-Mackay scores, blood eosinophil percentage, and onset of asthma were analyzed. Patients were divided into different groups according to past history of nasal polyps, Lund-Mackay score, and the extent of blood eosinophilia. Asthma-free rates between these subgroups were analyzed by Kaplan-Meier curves and Cox regression models. Results: The prevalence of asthma was 10.90% in patients with CRSwNP, and new-onset asthma occurred in 3.14% of these patients. Higher Lund-Mackay scores for ethmoid sinus and maxillary sinus (E/M) and blood eosinophil percentages were two independent risk factors for new-onset asthma, with hazard ratios of 1.267 (95%CI, 1.155-1.390) and 1.224 (95%CI, 1.054-1.422), respectively. CRSwNP patients with an E/M ratio > 2.33 or a blood Eos percentage > 5.5% were at risk for asthma onset. Conclusions and significance: Blood eosinophilia and a higher E/M score ratio were associated with new-onset asthma in patients with CRSwNP.

Abstract

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) accounts for 545 million people living with chronic respiratory disorders and is the third leading cause of morbidity and mortality around the world. COPD is a progressive disease, characterized by episodes of acute worsening of symptoms such as cough, dyspnea, and sputum production. AREAS COVERED: Airway inflammation is a prominent feature of COPD. Chronic airway inflammation results in airway structural remodeling and emphysema. Persistent airway inflammation is a treatable trait of COPD and plays a significant role in disease development and progression. In this review, the authors summarize the current and emerging biomarkers that reveal the heterogeneity of airway inflammation subtypes, clinical outcomes, and therapeutic response in COPD. EXPERT OPINION: Airway inflammation can be broadly categorized as eosinophilic (type 2 inflammation) and non-eosinophilic (non-type 2 inflammation) in COPD. Currently, blood eosinophil counts are incorporated in clinical practice guidelines to identify COPD patients who are at a higher risk of exacerbations and lung function decline, and who are likely to respond to inhaled corticosteroids. As new therapeutics are being developed for the chronic management of COPD, it is essential to identify biomarkers that will predict treatment response.

Abstract

Air pollution plays an important role in the mortality and morbidity of chronic airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Particulate matter (PM) is a significant fraction of air pollutants, and studies have demonstrated that it can cause airway inflammation and injury. The airway epithelium forms the first barrier of defense against inhaled toxicants, such as PM. Airway epithelial cells clear airways from inhaled irritants and orchestrate the inflammatory response of airways to these irritants by secreting various lipid mediators, growth factors, chemokines, and cytokines. Studies suggest that PM plays an important role in the pathogenesis of chronic airway diseases by impairing mucociliary function, deteriorating epithelial barrier integrity, and inducing the production of inflammatory mediators while modulating the proliferation and death of airway epithelial cells. Furthermore, PM can modulate epithelial plasticity and airway remodeling, which play central roles in asthma and COPD. This review focuses on the effects of PM on airway injury and epithelial plasticity, and the underlying mechanisms involving mucociliary activity, epithelial barrier function, airway inflammation, epithelial-mesenchymal transition, mesenchymal-epithelial transition, and airway remodeling.

Abstract

This is an exciting time to be conducting asthma research. The recent development of targeted asthma biologics has validated the power of basic research to discover new molecules amenable to therapeutic intervention. Advances in high-throughput sequencing are providing a wealth of "omics" data about genetic and epigenetic underpinnings of asthma, as well as about new cellular interacting networks and potential endotypes in asthma. Airway epithelial cells have emerged not only as key sensors of the outside environment but also as central drivers of dysregulated mucosal immune responses in asthma. Emerging data suggest that the airway epithelium in asthma remembers prior encounters with environmental exposures, resulting in potentially long-lasting changes in structure and metabolism that render asthmatic individuals susceptible to subsequent exposures. Here we summarize recent insights into asthma biology, focusing on studies using human cells or tissue that were published in the past 2 years. The studies are organized thematically into 6 content areas to draw connections and spur future research (on genetics and epigenetics, prenatal and early-life origins, microbiome, immune and inflammatory pathways, asthma endotypes and biomarkers, and lung structural alterations). We highlight recent studies of airway epithelial dysfunction and response to viral infections and conclude with a framework for considering how bidirectional interactions between alterations in airway structure and mucosal immunity can lead to sustained lung dysfunction in asthma.

Abstract

Epithelial cells form a resilient barrier and orchestrate defensive and reparative mechanisms to maintain tissue stability. This review focuses on gut and airway epithelia, which are positioned where the body interfaces with the outside world. We review the many signaling pathways and mechanisms by which epithelial cells at the interface respond to invading pathogens to mount an innate immune response and initiate adaptive immunity and communicate with other cells, including resident microbiota, to heal damaged tissue and maintain homeostasis. We compare and contrast how airway and gut epithelial cells detect pathogens, release antimicrobial effectors, collaborate with macrophages, Tregs and epithelial stem cells to mount an immune response and orchestrate tissue repair. We also describe advanced research models for studying epithelial communication and behaviors during inflammation, tissue injury and disease.

Abstract

The epithelial lining of the respiratory tract and intestine provides a critical physical barrier to protect host tissues against environmental insults, including dietary antigens, allergens, chemicals, and microorganisms. In addition, specialized epithelial cells communicate directly with hematopoietic and neuronal cells. These epithelial-immune and epithelial-neuronal interactions control host immune responses and have important implications for inflammatory conditions associated with defects in the epithelial barrier, including asthma, allergy, and inflammatory bowel diseases. In this review, we discuss emerging research that identifies the mechanisms and impact of epithelial-immune and epithelial-neuronal cross talk in regulating immunity, inflammation, and tissue homeostasis at mucosal barrier surfaces. Understanding the regulation and impact of these pathways could provide new therapeutic targets for inflammatory diseases at mucosal sites.

Abstract

The term alarmin denotes a broad class of molecules rapidly released to alert the immune system through the engagement of specific receptors on immune cells. Three alarmin cytokines-thymic stromal lymphopoietin, IL-33, and IL-25-are released from epithelial and certain stromal cells. TNF-like cytokine 1A (TL1A) is a member of the TNF cytokine superfamily, first identified in human endothelial cells. TL1A is now considered a novel alarmin expressed by human and mouse bronchial and intestinal epithelial cells. TL1A exerts its biological activities by binding to a trimeric receptor DR3 (death receptor 3), expressed on a wide spectrum of immune and structural cells, including lung fibroblasts, endothelial cells, and bronchial epithelial cells. TL1A has been implicated in experimental and human inflammatory bowel diseases as well as in airway inflammation and remodeling in severe asthma. A monoclonal antibody anti-TL1A (tulisokibart) is effective in inducing clinical remission in ulcerative colitis patients. Increasing evidence suggests that TL1A is also involved in certain autoimmune disorders, such as rheumatoid arthritis and psoriasis. These emerging findings broaden the role of TL1A in various human inflammatory conditions. Several clinical trials are currently evaluating the safety and efficacy of monoclonal antibodies targeting TL1A in asthma or inflammatory bowel disease patients.

Abstract

Bronchial asthma (asthma) is a respiratory disease characterized by chronic inflammation, airway hyperresponsiveness, and airway remodeling. Numerous studies have delved into asthma's pathogenesis, among which epithelial mesenchymal transition (EMT) is considered one of the important mechanisms in the pathogenesis of asthma. EMT refers to the transformation of epithelial cells, which lose their original features and acquire a migratory and invasive stromal phenotype. EMT contributes to normal physiological functions like growth, development, and wound healing. However, EMT is also involved in the occurrence and development of many diseases. Currently, the precise regulatory mechanism linking EMT and asthma remain obscure. Increasing evidence suggests that airway EMT contributes to asthma pathogenesis via dysregulation of associated control mechanisms. This review explores EMT's significance in asthma and the regulatory networks associated with EMT in this context.

Abstract

While primarily a sensory organ, the mammalian olfactory epithelium (OE) also plays a critical role as an immune barrier. Mechanisms governing interactions between the immune system and this specialized chemosensory tissue are gaining interest, in part sparked by the COVID-19 pandemic. Regulated inflammation is intrinsic to normal mucosal healing and homeostasis, but prolonged OE inflammation is associated with persistent loss of smell, belying the intertwining of local mucosal immunology and olfactory function. Evidence supports bidirectional communication between OE cells and the immune system in health and disease. Recent investigations suggest that neuro-immune cross-talk modulates olfactory stem cell behavior and neuronal regeneration dynamics, prioritizing the epithelial-like non-neuronal framework with immune barrier function at the expense of the neurosensory organ in chronic inflammation.

Abstract

Allergic rhinitis (AR) is a widespread allergic condition, with its prevalence continuing to rise globally. This disease has a significant impact on patients' quality of life. Understanding the underlying pathophysiology is important to develop better-targeted therapies. For decades, the primary assumption has been that an allergy is caused by unbalanced and overactive immunological responses against allergens, driven mainly by activated T helper 2 (Th2) cells and due to aberrant T-regulatory cells. The more recent hypothesis that is gaining attention relies on the dysregulation of the epithelial barrier, which might result in allergen uptake as a primary defect in the pathogenesis of allergic reactions. The nasal epithelial barrier is considered a crucial first line of defense in the upper airway, as it protects the host's immune system from exposure to allergens. Thus, this review will discuss AR's epidemiology, predisposing factors, clinical manifestations, laboratory characteristics, and pathogenic mechanisms.

Abstract

Environmental pollution continues to increase with industrial development and has become a threat to human health. Atmospheric particulate matter (PM) was designated as a Group 1 carcinogen by the International Agency for Research on Cancer in 2013 and is an emerging global environmental risk factor that is a major cause of death related to cardiovascular and respiratory diseases. PM is a complex composed of highly reactive organic matter, chemicals, and metal components, which mainly cause excessive production of reactive oxygen species (ROS) that can lead to DNA and cell damage, endoplasmic reticulum stress, inflammatory responses, atherosclerosis, and airway remodeling, contributing to an increased susceptibility to and the exacerbation of various diseases and infections. PM has various effects on human health depending on the particle size, physical and chemical characteristics, source, and exposure period. PM smaller than 5 mum can penetrate and accumulate in the alveoli and circulatory system, causing harmful effects on the respiratory system, cardiovascular system, skin, and brain. In this review, we describe the relationship and mechanism of ROS-mediated cell damage, oxidative stress, and inflammatory responses caused by PM and the health effects on major organs, as well as comprehensively discuss the harmfulness of PM.

Abstract

INTRODUCTION:

Obstructive airway diseases asthma and COPD represent a significant healthcare burden. Airway hyperresponsiveness (AHR), a salient feature of these two diseases, remains the main therapeutic target. Airway smooth muscle (ASM) cell is pivotal for bronchomotor tone and development of AHR in airway diseases. The contractile and relaxation processes in ASM cells maintain a homeostatic bronchomotor tone. It is critical to understand the molecular mechanisms that disrupt the homeostasis to identify novel therapeutic strategies for AHR.

AREAS COVERED:

Based on review of literature and published findings from our laboratory, we describe intrinsic and extrinsic factors - disease phenotype, toxicants, inflammatory/remodeling mediators- that amplify excitation-contraction (E-C) coupling and ASM shortening and or diminish relaxation to alter bronchomotor homeostasis. We posit that an understanding of the ASM mechanisms involved in bronchomotor tone imbalance will provide platforms to develop novel therapeutic approaches to treat AHR in asthma and COPD.

EXPERT OPINION:

Contractile and relaxation processes in ASM cell are modulated by intrinsic and extrinsic factors to elicit bronchomotor tone imbalance. Innovative experimental approaches will serve as essential tools for elucidating the imbalance mechanisms and to identify novel therapeutic targets for AHR.

Abstract

INTRODUCTION:

In genetically predisposed individuals, exposure to aeroallergens and infections from RNA viruses shape epithelial barrier function, leading to Allergic Asthma (AA). Here, activated pattern recognition receptors (PRRs) in lower airway sentinel cells signal epithelial injury-repair pathways leading to cell-state changes [epithelial mesenchymal plasticity (EMP)], barrier disruption and sensitization.

AREAS COVERED:

1. Characteristics of sentinel epithelial cells of the bronchoalveolar junction,
2. The effect of aeroallergens on epithelial PRRs,
3. Role of tight junctions (TJs) in barrier function and how aeroallergens disrupt their function,
4. Induction of mucosal TGF autocrine loops activating type-2 innate lymphoid cells (ICL2s) leading to Th2 polarization, and
5. How respiratory syncytial virus (RSV) directs goblet cell hyperplasia, and 6. Coupling of endoplasmic reticulum (ER) stress to metabolic adaptations and effects on basal lamina remodeling.

EXPERT OPINION:

When aeroallergens or viral infections activate innate immunity in sentinel cells of the bronchoalveolar junction, normal barrier function is disrupted, promoting chronic inflammation and Th2 responses. An improved mechanistic understanding of how activated PRRs induce EMP couples with TJ disruption, metabolic reprogramming and ECM deposition provides new biologically validated targets to restore barrier function, reduce sensitization, and remodeling in AA.

Abstract

Asthma is a chronic, heterogeneous disease of the airways, often characterised by structural changes known collectively as airway remodelling. In response to environmental insults, including pathogens, allergens and pollutants, the epithelium can initiate remodelling via an inflammatory cascade involving a variety of mediators that have downstream effects on both structural and immune cells. These mediators include the epithelial cytokines thymic stromal lymphopoietin, interleukin (IL)-33 and IL-25, which facilitate airway remodelling through cross-talk between epithelial cells and fibroblasts, and between mast cells and airway smooth muscle cells, as well as through signalling with immune cells such as macrophages. The epithelium can also initiate airway remodelling independently of inflammation in response to the mechanical stress present during bronchoconstriction. Furthermore, genetic and epigenetic alterations to epithelial components are believed to influence remodelling. Here, we review recent advances in our understanding of the roles of the epithelium and epithelial cytokines in driving airway remodelling, facilitated by developments in genetic sequencing and imaging techniques. We also explore how new and existing therapeutics that target the epithelium and epithelial cytokines could modify airway remodelling.

Abstract

Thymic stromal lymphopoietin (TSLP), mainly expressed by epithelial cells, plays a central role in asthma. In humans, TSLP exists in two variants: the long form TSLP (lfTSLP) and a shorter TSLP isoform (sfTSLP). Macrophages (HLMs) and mast cells (HLMCs) are in close proximity in the human lung and play key roles in asthma. We evaluated the early proteolytic effects of tryptase and chymase released by HLMCs on TSLP by mass spectrometry. We also investigated whether TSLP and its fragments generated by these enzymes induce angiogenic factor release from HLMs. Mass spectrometry (MS) allowed the identification of TSLP cleavage sites caused by tryptase and chymase. Recombinant human TSLP treated with recombinant tryptase showed the production of 1-97 and 98-132 fragments. Recombinant chymase treatment of TSLP generated two peptides, 1-36 and 37-132. lfTSLP induced the release of VEGF-A, the most potent angiogenic factor, from HLMs. By contrast, the four TSLP fragments generated by tryptase and chymase failed to activate HLMs. Long-term TSLP incubation with furin generated two peptides devoid of activating property on HLMs. These results unveil an intricate interplay between mast cell-derived proteases and TSLP. These findings have potential relevance in understanding novel aspects of asthma pathobiology.

Abstract

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is released
from the airway epithelium in response to various environmental triggers, inducing a type-2 inflammatory response, and is associated with airway inflammation, airway hyperresponsiveness (AHR), and exacerbations. TSLP may also induce AHR via a direct effect on airway smooth muscle and mast cells, independently of type-2 inflammation, although association between airway TSLP and AHR across asthma phenotypes has been described sparsely.

OBJECTIVES: This study sought to investigate the association between AHR and levels of TSLP in serum, sputum, and bronchoalveolar lavage in patients with asthma with and without type-2 inflammation.

METHODS: A novel ultrasensitive assay was used to measure levels of TSLP in patients with asthma (serum, n=182; sputum, n=81; bronchoalveolar lavage, n=85) and healthy controls (serum, n=47). The distribution and association among airway and systemic TSLP, measures of AHR, type-2 inflammation, and severity of disease were assessed.

RESULTS: TSLP in sputum was associated with AHR independently of levels of eosinophils and fractional exhaled nitric oxide (r=0.49, P=.005). Serum TSLP was higher in both eosinophil-high and eosinophil-low asthma compared to healthy controls: geometric mean: 1600 fg/mL (95% CI: 1468-1744 fg/mL) and 1294 fg/mL (95% CI: 1167-1435 fg/mL) versus 846 fg/mL (95% CI: 661-1082 fg/mL), but did not correlate with the level of AHR. Increasing age, male sex, and eosinophils in blood were associated with higher levels of TSLP in serum, whereas lung function, inhaled corticosteroid dose, and symptom score were not.

CONCLUSIONS: The association between TSLP in sputum and AHR to mannitol irrespective of markers of type-2 inflammation further supports a role of TSLP in AHR that is partially independent of eosinophilic inflammation.

Abstract

BACKGROUND: Macrophages are the predominant immune cells in the human lung and play a central role in airway inflammation, including asthma and chronic obstructive pulmonary disease (COPD). Thymic stromal lymphopoietin (TSLP), a pleiotropic cytokine mainly expressed by bronchial epithelial cells, plays a key role in asthma and COPD pathobiology. TSLP exists in two variants: the long form (lfTSLP) and a shorter TSLP isoform (sfTSLP). We aimed to localize TSLP in human lung macrophages (HLMs) and investigate the mechanisms of its release from these cells. We also evaluated the effects of the two variants of TSLP on the release of angiogenic factor from HLMs.

METHODS: We employed immunofluorescence and Western blot to localize intracellular TSLP in HLMs purified from human lung parenchyma. HLMs were activated by T2-high (IL-4, IL-13) and T2-low (lipopolysaccharide: LPS) immunological stimuli.

RESULTS: TSLP was detected in HLMs and subcellularly localized in the cytoplasm. IL-4 and LPS induced TSLP release from HLMs. Preincubation of macrophages with brefeldin A, known to disrupt the Golgi apparatus, inhibited TSLP release induced by LPS and IL-4. lfTSLP concentration-dependently induced the release of vascular endothelial growth factor-A (VEGF-A), the most potent angiogenic factor, from HLMs. sfTSLP neither activated nor interfered with the activating property of lfTSLP on macrophages.

CONCLUSIONS: Our results highlight a novel immunologic circuit between HLMs and TSLP. Given the central role of macrophages in airway inflammation, this autocrine loop holds potential translational relevance in understanding innovative aspects of the pathobiology of asthma and chronic inflammatory lung disorders.

Abstract

This study delves into the critical role of alarmins in chronic spontaneous urticaria (CSU), focusing on their impact on disease severity and the quality of life (QoL) of patients. We investigated the alterations in alarmin levels in CSU patients and their correlations with the Urticaria Activity Score (UAS7) and the Dermatology Life Quality Index (DLQI). We analyzed serum levels of interleukin-25 (IL-25), interleukin-33 (IL-33), and thymic stromal lymphopoietin (TSLP) in 50 CSU patients, comparing these to 38 healthy controls. The study examined the relationship between alarmin levels and clinical outcomes, including disease severity and QoL. Elevated levels of IL-33 and TSLP in CSU patients (p < 0.0001) highlight their potential role in CSU pathogenesis. Although IL-25 showed higher levels in CSU patients, this did not reach statistical significance (p = 0.0823). Crucially, IL-33’s correlation with both UAS7 and DLQI scores underscores its potential as a biomarker for CSU diagnosis and severity assessment. Of the alarmins analyzed, IL-33 emerges as particularly significant for further exploration as a diagnostic and prognostic biomarker in CSU. Its substantial correlation with disease severity and impact on QoL makes it a compelling candidate for future research, potentially serving as a target for therapeutic interventions. Given these findings, IL-33 deserves additional investigation to confirm its role and effectiveness as a biomarker and therapeutic target in CSU.

Abstract

Interleukin (IL)-33 is an alarmin of the IL-1 superfamily localized to the nucleus of expressing cells, such as endothelial cells, epithelial cells, and fibroblasts. In response to cellular damage or stress, IL-33 is released and activates innate immune responses in some immune and structural cells via its receptor interleukin-1 receptor like-1 (IL-1RL1 or ST2). Recently, IL-33 has become a hot topic of research because of its role in pulmonary inflammation. The IL-33-ST2 signaling pathway plays a pro-inflammatory role by activating the type 2 inflammatory response, producing type 2 cytokines and chemokines. Elevated levels of IL-33 and ST2 have been observed in chronic pulmonary obstructive disease (COPD). Notably, IL-33 is present in COPD induced by cigarette smoke or acute inflammations. The role of IL-33 in sepsis is becoming increasingly prominent, and understanding its significance in the treatment of sepsis associated with high mortality is critical. In addition to its pro-inflammatory effects, the IL-33-ST2 axis appears to play a role in bacterial clearance and tissue repair. In this review, we focused on the role of the IL-33-ST2 axis in sepsis, asthma, and COPD and summarized the therapeutic targets associated with this axis, providing a basis for future treatment.

Abstract

Cryptococcus neoformans and Cryptococcus gattii are pathogenic fungi that infect the human respiratory system and cause life-threatening pulmonary cryptococcosis. The immunopathology of cryptococcosis is completely different from that of other fungal allergies. In murine cryptococcal infection models, cryptococcal cells are usually injected via nasal or intratracheal routes. After the infection, the alveolar epithelial cells are impaired and release IL-33, an IL-1 family cytokine that functions as an alarmin. This cytokine detrimentally amplifies allergic responses, and also induces a protective immune response against parasitic infection. In the pulmonary cryptococcosis model, type-II alveolar epithelial cells are the major source of IL-33, and the alveolar epithelial cells, ILC2, and Th2 cells express the IL-33 receptor (ST2). In IL-33- or ST2-deficient mice, allergy-like immune responses are attenuated after the C. neoformans infection. The numbers of ILC2 and Th2 cells and the levels of type 2 cytokines, including IL-4, IL-5, and IL-13, are decreased in the mouse lungs in both models. In association with these changes, total blood IgE, bronchus mucus production, and the number of eosinophils are decreased. Conversely, lung neutrophils and M1-type macrophages are increased. These are protective immune subsets suppressing cryptococcal growth. As a result, the lung fungal burden of IL-33- and ST2-deficient mice is decreased post-infection, and both deficient mice show significantly improved mortality. This pathogenesis varies depending on the cryptococcal and murine strains used in the animal experiments. Here, we overview and discuss the itmmunopathology of the IL-33/ST2 axis in a murine lethal cryptococcal infection model.

Abstract

PURPOSE OF REVIEW: Compelling evidence over the past decade supports the central role of epithelial barrier dysfunction in the pathophysiology of eosinophilic esophagitis (EoE). The purpose of this review is to summarize the genetic, environmental, and immunologic factors driving epithelial barrier dysfunction, and how this impaired barrier can further promote the inflammatory response in EoE. 

RECENT FINDINGS: Common environmental exposures, such as detergents, may have a direct impact on the esophageal epithelial barrier. In addition, the effects of IL-13 on barrier dysfunction may be reduced by 17β-estradiol, Vitamin D, and the short chain fatty acids butyrate and propionate, suggesting novel therapeutic targets. There are many genetic, environmental, and immunologic factors that contribute to epithelial barrier dysfunction in EoE. This leads to further skewing of the immune response to a "Th2" phenotype, alterations in the esophageal microbiome, and penetration of relevant antigens into the esophageal mucosa, which are central to the pathophysiology of EoE.

Abstract

The airway epithelium is a critical component of the respiratory system, serving as a barrier against inhaled pathogens and toxins. It is composed of various cell types, each with specific functions essential to proper airway function. Chronic respiratory diseases can disrupt the cellular composition of the airway epithelium, leading to a decrease in multiciliated cells (MCCs) and an increase in secretory cells (SCs). Basal cells (BCs) have been identified as the primary stem cells in the airway epithelium, capable of self-renewal and differentiation into MCCs and SCs. This review emphasizes the role of transcription factors in the differentiation process from BCs to MCCs and SCs. Recent advancements in single-cell RNA sequencing (scRNAseq) techniques have provided insights into the cellular composition of the airway epithelium, revealing specialized and rare cell types, including neuroendocrine cells, tuft cells, and ionocytes. Understanding the cellular composition and differentiation processes within the airway epithelium is crucial for developing targeted therapies for respiratory diseases. Additionally, the maintenance of BC populations and the involvement of Notch signaling in BC self-renewal and differentiation are discussed. Further research in these areas could provide valuable insights into the mechanisms underlying airway epithelial homeostasis and disease pathogenesis.

Abstract

The epithelial barriers of the skin, gut, and respiratory tract are critical interfaces between the environment and the host, and they orchestrate both homeostatic and pathogenic immune responses. The mechanisms underlying epithelial barrier dysfunction in allergic and inflammatory conditions, such as atopic dermatitis, food allergy, eosinophilic oesophagitis, allergic rhinitis, chronic rhinosinusitis, and asthma, are complex and influenced by the exposome, microbiome, individual genetics, and epigenetics. Here, we review the role of the epithelial barriers of the skin, digestive tract, and airways in maintaining homeostasis, how they influence the occurrence and progression of allergic and inflammatory conditions, how current treatments target the epithelium to improve symptoms of these disorders, and what the unmet needs are in the identification and treatment of epithelial disorders.

Abstract

Since the 1960s, our health has been compromised by exposure to over 350,000 newly introduced toxic substances, contributing to the current pandemic in allergic, autoimmune and metabolic diseases. The "Epithelial Barrier Theory" postulates that these diseases are exacerbated by persistent periepithelial inflammation (epithelitis) triggered by exposure to a wide range of epithelial barrier-damaging substances as well as genetic susceptibility. The epithelial barrier serves as the body's primary physical, chemical, and immunological barrier against external stimuli. A leaky epithelial barrier facilitates the translocation of the microbiome from the surface of the afflicted tissues to interepithelial and even deeper subepithelial locations. In turn, opportunistic bacterial colonization, microbiota dysbiosis, local inflammation and impaired tissue regeneration and remodelling follow. Migration of inflammatory cells to susceptible tissues contributes to damage and inflammation, initiating and aggravating many chronic inflammatory diseases. The objective of this review is to highlight and evaluate recent studies on epithelial physiology and its role in the pathogenesis of chronic diseases in light of the epithelial barrier theory.

Abstract

Epithelial/immune interactions are characterized by the different properties of the various epithelial tissues, the mediators involved, and the varying immune cells that initiate, sustain, or abrogate allergic diseases on the surface. The intestinal mucosa, respiratory mucosa, and regular skin feature structural differences according to their primary function and surroundings. In the context of these specialized functions, the active role of the epithelium in shaping immune responses is increasingly recognizable. Crosstalk between epithelial and immune cells plays an important role in maintaining homeostatic conditions. While cells of the myeloid cell lineage, mainly macrophages, are the dominating immune cell population in the skin and the respiratory tract, lymphocytes comprise most intraepithelial immune cells in the intestine under healthy conditions. Common to all surface epithelia is the fact that innate immune cells represent the first line of immunosurveillance that either directly defeats invading pathogens or initiates and coordinates more effective successive immune responses involving adaptive immune cells and effector cells. Pharmacological approaches for the treatment of allergic and chronic inflammatory diseases involving epithelial barriers target immunological mediators downstream of the epithelium (such as IL-4, IL-5, IL-13, and IgE). The next generation of therapeutics involves upstream events of the inflammatory cascade, such as epithelial-derived alarmins and related mediators.

Abstract

The epithelial barrier represents the point of contact between the host and the external environment. It is the first line of defense against external insults in the skin and in the gastrointestinal and upper and lower respiratory tracts. The steep increase in chronic disorders in recent decades, including allergies and autoimmune disorders, has prompted studies to investigate the immune mechanisms of their underlying pathogeneses, all of which point to a thought-provoking shared finding: disrupted epithelial barriers. Climate change with global warming has increased the frequency of unpredictable extreme weather events, such as wildfires, droughts, floods, and aberrant and longer pollination seasons, among many others. These increasingly frequent natural disasters can synergistically damage the epithelial barrier integrity in the presence of environmental pollution. A disrupted epithelial barrier induces proinflammatory activation of epithelial cells and alarmin production, namely, epithelitis. The "opened" epithelial barrier facilitates the entry of the external exposome into and underneath the epithelium, triggering an expulsion response driven by inflammatory cells in the area and chronic inflammation. These changes are associated with microbial dysbiosis with colonizing opportunistic pathogens and decreased commensals. These cellular and molecular events are key mechanisms in the pathogenesis of numerous chronic inflammatory disorders. This review summarizes the impact of global warming on epithelial barrier functions in the context of allergic diseases. Further studies in the impact of climate change on the dysfunction of the epithelial barriers are warranted to improve our understanding of epithelial barrier-related diseases and raise awareness of the environmental insults that pose a threat to our health.

Abstract

Allergic diseases are a major public health problem with increasing prevalence. These immune-mediated diseases are characterized by defective epithelial barriers, which are explained by the epithelial barrier theory and continuously emerging evidence. Environmental exposures (exposome) including global warming, changes and loss of biodiversity, pollution, pathogens, allergens and mites, laundry and dishwasher detergents, surfactants, shampoos, body cleaners and household cleaners, microplastics, nanoparticles, toothpaste, enzymes and emulsifiers in processed foods, and dietary habits are responsible for the mucosal and skin barrier disruption. Exposure to barrier-damaging agents causes epithelial cell injury and barrier damage, colonization of opportunistic pathogens, loss of commensal bacteria, decreased microbiota diversity, bacterial translocation, allergic sensitization, and inflammation in the periepithelial area. Here, we review scientific evidence on the environmental components that impact epithelial barriers and microbiome composition and their influence on asthma and allergic diseases. We also discuss the historical overview of allergic diseases and the evolution of the hygiene hypothesis with theoretical evidence.

Abstract

Environmental allergens that interact with the airway epithelium can activate cellular stress pathways that lead to the release of danger signals known as alarmins. The mechanisms of alarmin release are distinct from damage-associated molecular patterns (DAMPs), which typically escape from cells after loss of plasma membrane integrity. Oxidative stress represents a form of allergen-induced cellular stress that stimulates oxidant-sensing mechanisms coupled to pathways, which facilitate alarmin mobilization and efflux across the plasma membrane. In this review, we highlight examples of alarmin release and discuss their roles in the initiation of type 2 immunity and allergic airway inflammation. In addition, we discuss the concept of alarmin amplification, where "primary" alarmins, which are directly released in response to a specific cellular stress, stimulate additional signaling pathways that lead to secretion of "secondary" alarmins that include proinflammatory cytokines, such as IL-33, as well as genomic and mitochondrial DNA that coordinate or amplify type 2 immunity. Accordingly, allergen-evoked cellular stress can elicit a hierarchy of alarmin signaling responses from the airway epithelium that trigger local innate immune reactions, impact adaptive immunity, and exacerbate diseases including asthma and other chronic inflammatory conditions that affect airway function.

Abstract

Chronic rhinosinusitis (CRS) is a pathological condition characterized by persistent inflammation in the upper respiratory tract and paranasal sinuses. The epithelium serves as the first line of defense against potential threats and protects the nasal mucosa. The fundamental mechanical barrier is formed by the cell-cell contact and mucociliary clearance (MCC) systems. The physical-mechanical barrier is comprised of many cellular structures, including adhesion junctions and tight junctions (TJs). To this end, different factors, such as the dysfunction of MCC, destruction of epithelial barriers, and tissue remodeling, are related to the onset and development of CRS. Recently published studies reported the critical role of different microorganisms, such as Staphylococcus aureus and Pseudomonas aeruginosa, in the induction of the mentioned factors. Bacteria could result in diminished ciliary stimulation capacity, and enhance the chance of CRS by reducing basal ciliary beat frequency. Additionally, bacterial exoproteins have been demonstrated to disrupt the epithelial barrier and induce downregulation of transmembrane proteins such as occludin, claudin, and tricellulin. Moreover, bacteria exert an influence on TJ proteins, leading to an increase in the permeability of polarized epithelial cells. Noteworthy, it is evident that the activation of TLR2 by staphylococcal enterotoxin can potentially undermine the structural integrity of TJs and the epithelial barrier through the induction of pro-inflammatory cytokines. The purpose of this article is an attempt to investigate the possible role of the most important microorganisms associated with CRS and their pathogenic mechanisms against mucosal surfaces and epithelial barriers in the paranasal sinuses.

Abstract

Viral infections are the most common cause of upper respiratory infections; they frequently infect adults once or twice and children 6 to 8 times annually. In most cases, these infections are self-limiting and resolve. However, many patients with chronic rhinosinusitis (CRS) relay that their initiating event began with an upper respiratory infection that progressed in both symptom severity and duration. Viruses bind to sinonasal epithelia through specific receptors, thereby entering cells and replicating within them. Viral infections stimulate interferon-mediated innate immune responses. Recent studies suggest that viral infections may also induce type 2 immune responses and stimulate the aberrant production of cytokines that can result in loss of barrier function, which is a hallmark in CRS. The main purpose of this review will be to highlight common viruses and their associated binding receptors and highlight pathophysiologic mechanisms associated with alterations in mucociliary clearance, epithelial barrier function, and dysfunctional immune responses that might lead to a further understanding of the pathogenesis of CRS.

Abstract

Asthma is a disease of heterogeneous pathology, typically characterized by excessive inflammatory and bronchoconstrictor responses to the environment. The clinical expression of the disease is a consequence of the interaction between environmental factors and host factors over time, including genetic susceptibility, immune dysregulation and airway remodelling. As a critical interface between the host and the environment, the airway epithelium plays an important role in maintaining homeostasis in the face of environmental challenges. Disruption of epithelial integrity is a key factor contributing to multiple processes underlying asthma pathology. In this review, we first discuss the unmet need in asthma management and provide an overview of the structure and function of the airway epithelium. We then focus on key pathophysiological changes that occur in the airway epithelium, including epithelial barrier disruption, immune hyperreactivity, remodelling, mucus hypersecretion and mucus plugging, highlighting how these processes manifest clinically and how they might be targeted by current and novel therapeutics.

Abstract

Over the last years, technological advances in the field of asthma have led to the identification of two disease endotypes, namely, type 2-high and type 2-low asthma, characterized by different pathophysiologic mechanisms at a cellular and molecular level. Although specific immune cells are important contributors to each of the recognized asthma endotype, the lung epithelium is now regarded as a crucial player able to orchestrate responses to inhaled environmental triggers such as allergens and microbes. The impact of the epithelium goes beyond its physical barrier. It is nowadays considered as a part of the innate immune system that can actively respond to insults. Activated epithelial cells, by producing a specific set of cytokines, trigger innate and adaptive immune cells to cause pathology. Here, we review how the epithelium contributes to the development of Th2 sensitization to allergens and asthma with a "type 2-high" signature, in both murine models and human studies of this asthma endotype. We also discuss epithelial responses to respiratory viruses, such as rhinovirus, respiratory syncytial virus, and SARS-CoV-2, and how these triggers influence not only asthma development but also asthma exacerbation. Finally, we also summarize the results of promising clinical trials using biologicals targeting epithelial-derived cytokines in asthmatic patients.

Abstract

Chronic airway inflammation is the cornerstone on which bronchial asthma arises, and in turn, chronic inflammation arises from a complex interplay between environmental factors such as allergens and pathogens and immune cells as well as structural cells constituting the airway mucosa. Airway epithelial cells (AECs) are at the center of these processes. On the one hand, they represent the borderline separating the body from its environment in order to keep inner homeostasis. The airway epithelium forms a multi-tiered, self-cleaning barrier that involves an unstirred, discontinuous mucous layer, the dense and rigid mesh of the glycocalyx, and the cellular layer itself, consisting of multiple, densely interconnected cell types. On the other hand, the airway epithelium represents an immunologically highly active tissue once its barrier has been penetrated: AECs play a pivotal role in releasing protective immunoglobulin A. They express a broad spectrum of pattern recognition receptors, enabling them to react to environmental stressors that overcome the mucosal barrier. By releasing alarmins-proinflammatory and regulatory cytokines-AECs play an active role in the formation, strategic orientation, and control of the subsequent defense reaction. Consequently, the airway epithelium is of vital importance to chronic inflammatory diseases, such as asthma.

Abstract

Asthma is a chronic inflammatory airway disease characterized by respiratory symptoms, variable airflow obstruction, bronchial hyperresponsiveness, and airway inflammation. Exposure to air pollution has been linked to an increased risk of asthma development and exacerbation. This review aims to comprehensively summarize recent data on the impact of air pollution on asthma development and exacerbation. Specifically, we reviewed the effects of air pollution on the pathogenic pathways of asthma, including type 2 and non-type 2 inflammatory responses, and airway epithelial barrier dysfunction. Air pollution promotes the release of epithelial cytokines, driving TH2 responses, and induces oxidative stress and the production of proinflammatory cytokines. The enhanced type 2 inflammation, furthered by air pollution-induced dysfunction of the airway epithelial barrier, may be associated with the exacerbation of asthma. Disruption of the TH17/regulatory T cell balance by air pollutants is also related to asthma exacerbation. As the effects of air pollution exposure may accumulate over time, with potentially stronger impacts in the development of asthma during certain sensitive life periods, we also reviewed the effects of air pollution on asthma across the lifespan. Future research is needed to better characterize the sensitive period contributing to the development of air pollution-induced asthma and to map air pollution-associated epigenetic biomarkers contributing to the epigenetic ages onto asthma-related genes.

Abstract

Though asthma is a common and relatively easy to diagnose disease, attempts at primary or secondary prevention, and cure, have been disappointing. The widespread use of inhaled steroids has dramatically improved asthma control but has offered nothing in terms of altering long-term outcomes or reversing airway remodeling and impairment in lung function. The inability to cure asthma is unsurprising given our limited understanding of the factors that contribute to disease initiation and persistence. New data have focused on the airway epithelium as a potentially key factor orchestrating the different stages of asthma. In this review we summarize for the clinician the current evidence on the central role of the airway epithelium in asthma pathogenesis and the factors that may alter epithelial integrity and functionality.

Abstract

BACKGROUND: Respiratory syncytial virus (RSV) infection has been identified to serve as the primary cause of acute lower respiratory infectious diseases in children under the age of one and a significant risk factor for the emergence and development of pediatric recurrent wheezing and asthma, though the exact mechanism is still unknown. 

METHODS AND RESULTS: In this study, we discuss the key routes that lead to recurrent wheezing and bronchial asthma following RSV infection. It is interesting to note that following the coronavirus disease 2019 (COVID-19) epidemic, the prevalence of RSV changes significantly. This presents us with a rare opportunity to better understand the associated mechanism for RSV infection, its effects on the respiratory system, and the immunological response to RSV following the COVID-19 epidemic. To better understand the associated mechanisms in the occurrence and progression of pediatric asthma, we thoroughly described how the RSV infection directly destroys the physical barrier of airway epithelial tissue, promotes inflammatory responses, enhances airway hyper-responsiveness, and ultimately causes the airway remodeling. More critically, extensive discussion was also conducted regarding the potential impact of RSV infection on host pulmonary immune response. 

CONCLUSION: In conclusion, this study offers a comprehensive perspective to better understand how the RSV infection interacts in the control of the host's pulmonary immune system, causing recurrent wheezing and the development of asthma, and it sheds fresh light on potential avenues for pharmaceutical therapy in the future.

Abstract

Over 3% of asthmatic patients are affected by a particularly severe form of the disease ("severe asthma", SA) which is often refractory to standard treatment. Airway remodeling (AR), which can be considered a critical characteristic of approximately half of all patients with SA and currently thought to be the main mechanism triggering fixed airway obstruction (FAO), seems to be a key factor affecting a patient's outcome. Despite the collective efforts of internationally renowned experts, to date only a few biomarkers indicative of AR and no recognizable biomarkers of lung parenchymal remodeling have been identified. This work examines the pathogenesis of airway and lung parenchymal remodeling and the serum biomarkers that may be able to identify the severe asthmatic patients who may develop FAO. The study also aims to examine if Krebs von den Lungen-6 (KL-6) could be considered a diagnostic biomarker of lung structural damage in SA.

Abstract

BACKGROUND: Rhinovirus infections commonly evoke asthma exacerbations in children and adults. Recurrent asthma exacerbations are associated with injury-repair responses in the airways that collectively contribute to airway remodeling. The physiological consequences of airway remodeling can manifest as irreversible airway obstruction and diminished responsiveness to bronchodilators. Structural cells of the airway, including epithelial cells, smooth muscle, fibroblasts, myofibroblasts, and adjacent lung vascular endothelial cells represent an understudied and emerging source of cellular and extracellular soluble mediators and matrix components that contribute to airway remodeling in a rhinovirus-evoked inflammatory environment. 

MAIN BODY: While mechanistic pathways associated with rhinovirus-induced airway remodeling are still not fully characterized, infected airway epithelial cells robustly produce type 2 cytokines and chemokines, as well as pro-angiogenic and fibroblast activating factors that act in a paracrine manner on neighboring airway cells to stimulate remodeling responses. Morphological transformation of structural cells in response to rhinovirus promotes remodeling phenotypes including induction of mucus hypersecretion, epithelial-to-mesenchymal transition, and fibroblast-to-myofibroblast transdifferentiation. Rhinovirus exposure elicits airway hyperresponsiveness contributing to irreversible airway obstruction. This obstruction can occur as a consequence of sub-epithelial thickening mediated by smooth muscle migration and myofibroblast activity, or through independent mechanisms mediated by modulation of the β2 agonist receptor activation and its responsiveness to bronchodilators. Differential cellular responses emerge in response to rhinovirus infection that predispose asthmatic individuals to persistent signatures of airway remodeling, including exaggerated type 2 inflammation, enhanced extracellular matrix deposition, and robust production of pro-angiogenic mediators. 

CONCLUSIONS: Few therapies address symptoms of rhinovirus-induced airway remodeling, though understanding the contribution of structural cells to these processes may elucidate future translational targets to alleviate symptoms of rhinovirus-induced exacerbations.

Abstract

Airway hyperresponsiveness (AHR) is a key clinical feature of asthma. The presence of AHR in people with asthma provides the substrate for bronchoconstriction in response to numerous diverse stimuli, contributing to airflow limitation and symptoms including breathlessness, wheeze and chest tightness. Dysfunctional airway smooth muscle (ASM) significantly contributes to AHR and is displayed as increased sensitivity to direct pharmacological bronchoconstrictor stimuli, such as inhaled histamine and methacholine (direct AHR), or to endogenous mediators released by activated airway cells such as mast cells (indirect AHR). Research in in vivo human models has shown that the disrupted airway epithelium plays an important role in driving inflammation that mediates indirect AHR in asthma, through the release of cytokines such as TSLP and IL-33. These cytokines upregulate type 2 cytokines promoting airway eosinophilia and induce the release of bronchoconstrictor mediators from mast cells such as histamine, prostaglandin D2 and cysteine leukotrienes. While bronchoconstriction is largely due to ASM constriction, airway structural changes termed 'remodelling', likely mediated in part by epithelial-derived mediators, also lead to airflow obstruction and may enhance AHR. In this review, we outline the current knowledge of the role of the airway epithelium in AHR in asthma and its implications on the wider disease. Increased understanding of airway epithelial biology may contribute to better treatment options, particularly in precision medicine.

Abstract

Background:

Epithelial barrier impairment is associated with many skin and mucosal inflammatory disorders. Laundry detergents have been demonstrated to affect epithelial barrier function in vitro using air–liquid interface cultures of human epithelial cells.

Methods:

Back skin of C57BL/6 mice was treated with two household laundry detergents at several dilutions. Barrier function was assessed by electric impedance spectroscopy (EIS) and transepidermal water loss (TEWL) measurements after the 4 h of treatments with detergents. RNA sequencing (RNA-seq) and targeted multiplex proteomics analyses in skin biopsy samples were performed. The 6-h treatment effect of laundry detergent and sodium dodecyl sulfate (SDS) was investigated on ex vivo human skin.

Results:

Detergent-treated skin showed a significant EIS reduction and TEWL increase compared to untreated skin, with a relatively higher sensitivity and dose–response in EIS. The RNA-seq showed the reduction of the expression of several genes essential for skin barrier integrity, such as tight junctions and adherens junction proteins. In contrast, keratinization, lipid metabolic processes, and epidermal cell differentiation were upregulated. Proteomics analysis showed that the detergents treatment generally downregulated cell adhesion-related proteins, such as epithelial cell adhesion molecule and contactin-1, and upregulated proinflammatory proteins, such as interleukin 6 and interleukin 1 beta. Both detergent and SDS led to a significant decrease in EIS values in the ex vivo human skin model.

Conclusion:

The present study demonstrated that laundry detergents and its main component, SDS impaired the epidermal barrier in vivo and ex vivo human skin. Daily detergent exposure may cause skin barrier disruption and may contribute to the development of atopic diseases.