Novel therapeutic strategies for lung disorders associated with airway remodelling and fibrosis

Inflammatory cell infiltration, cytokine release, epithelial damage, airway/lung remodelling and fibrosis are central features of inflammatory lung disorders, which include asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome and idiopathic pulmonary fibrosis. Although the lung has some ability to repair itself from acute injury, in the presence of ongoing pathological stimuli and/or insults that lead to chronic disease, it no longer retains the capacity to heal, resulting in fibrosis, the final common pathway that causes an irreversible loss of lung function. Despite inflammation, genetic predisposition/factors, epithelial–mesenchymal transition and mechanotransduction being able to independently contribute to airway remodelling and fibrosis, current therapies for inflammatory lung diseases are limited by their ability to only target the inflammatory component of the disease without having any marked effects on remodelling (epithelial damage and fibrosis) that can cause lung dysfunction independently of inflammation. Furthermore, as subsets of patients suffering from these diseases are resistant to currently available therapies (such as corticosteroids), novel therapeutic approaches are required to combat all aspects of disease pathology. This review discusses emerging therapeutic approaches, such as trefoil factors, relaxin, histone deacetylase inhibitors and stem cells, amongst others that have been able to target airway inflammation and airway remodelling while improving related lung dysfunction. A better understanding of the mode of action of these therapies and their possible combined effects may lead to the identification of their clinical potential in the setting of lung disease, either as adjunct or alternative therapies to currently available treatments.     

Intestinal microbiota in the treatment of metabolically associated fatty liver disease

Metabolically associated fatty liver disease (MAFLD) is a common cause of chronic liver disease, the hepatic manifestation of metabolic syndrome. Despite the increasing incidence of MAFLD, no effective treatment is available. Recent research indicates a link between the intestinal microbiota and liver diseases such as MAFLD. The composition and characteristics of the intestinal microbiota and therapeutic perspectives of MAFLD are reviewed in the current study. An imbalance in the intestinal microbiota increases intestinal permeability and exposure of the liver to adipokines. Furthermore, we focused on reviewing the latest "gut-liver axis" targeted therapy.     

Diseases to differentiate from COPD, with emphasis on bronchial asthma

Differential diagnosis of chronic obstructive pulmonary disease (COPD) from asthma is not a difficult task for many clinicians. Patients with COPD have a history of heavy smoking and show a slowly progressive dyspnea on exertion and there is little variability in symptoms, and they show a poor response to bronchodilators and corticosteroids. Asthma usually begins in early childhood with atopy, shows episodic dyspnea with wheezing, especially during night and early morning. Some patients, however, show adult onset, irreversible airflow limitation, and neutrophilic airway inflammation. The airway remodeling in asthma may be the cause of confusing pathophysiology. Other diseases showing airway hyperresponsiveness, such as allergic bronchopulmonary aspergillosis, Churg-Strauss syndrome, and left heart failure presenting cardiac asthma, may sometimes show similar clinical pictures to COPD. Chronic airway diseases are also possible candidates for differential diagnosis of COPD. Bronchiectasis, sinobronchial syndrome, diffuse panbronchiolitis, obliterative bronchiolitis, and other chronic airway diseases should be considered. Some interstitial lung diseases, such as smoking-related interstitial lung diseases and lymphangioleiomyomatosis, often show obstructive ventilatory impairment, and therefore should be considered in differential diagnosis of COPD.     

A panel of multiple markers associated with chronic systemic inflammation and the risk of atherogenesis is detectable in asthma and chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease (COPD) are both lung diseases involving chronic inflammation of the airway. The injury is reversible in asthma whereas it is mostly irreversible in COPD. Both patients of asthma and COPD are known at risk for cardiovascular disease (CVD) and type 2 diabetes (T2DM), nephropathy, and cancer. We measured multiple risk markers for atherogenesis in 55 patients with asthma and 62 patients with COPD. We wanted to know whether risk markers for atherogenesis corresponding to sequence of events of chronic inflammation were also detectable in the airway inflammatory diseases. Elevation of almost all markers involving inflammation of the endothelial cells in the coronary artery were detectable in asthma and COPD involving the inflammation of the epithelial cell lining of the airway. Both the level and % elevation of all markers were found mostly higher in COPD, the more severe form of the lung disease. We believe that these markers are useful for predicting risk of developing clinical complications such as CVD.     

Inhaled adrenergics and anticholinergics in obstructive lung disease: do they enhance mucociliary clearance?

Pulmonary mucociliary clearance is an essential defense mechanism against bacteria and particulate matter. Mucociliary dysfunction is an important feature of obstructive lung diseases such as chronic obstructive pulmonary disease, asthma, cystic fibrosis, and bronchiectasis. This dysfunction in airway clearance is associated with accelerated loss of lung function in patients with obstructive lung disease. The involvement of the cholinergic and adrenergic neural pathways in the pathophysiology of mucus hypersecretion suggests the potential therapeutic role of bronchodilators as mucoactive agents. Although anticholinergics and adrenergic agonist bronchodilators have been routinely used, alone or in combination, to enhance mucociliary clearance in patients with obstructive lung disease, the existing evidence does not consistently show clinical effectiveness.     

The cytokine network in asthma and chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease (COPD) are very common inflammatory diseases of the airways. They both cause airway narrowing and are increasing in incidence throughout the world, imposing enormous burdens on health care. Cytokines play a key role in orchestrating the chronic inflammation and structural changes of the respiratory tract in both asthma and COPD and have become important targets for the development of new therapeutic strategies in these diseases.     

Brain-derived neurotrophic factor in the airways

In addition to their well-known roles in the nervous system, there is increasing recognition that neurotrophins such as brain derived neurotrophic factor (BDNF) as well as their receptors are expressed in peripheral tissues including the lung, and can thus potentially contribute to both normal physiology and pathophysiology of several diseases. The relevance of this family of growth factors lies in emerging clinical data indicating altered neurotrophin levels and function in a range of diseases including neonatal and adult asthma, sinusitis, influenza, and lung cancer. The current review focuses on 1) the importance of BDNF expression and signaling mechanisms in early airway and lung development, critical to both normal neonatal lung function and also its disruption in prematurity and insults such as inflammation and infection; 2) how BDNF, potentially derived from airway nerves modulate neurogenic control of airway tone, a key aspect of airway reflexes as well as dysfunctional responses to allergic inflammation; 3) the emerging idea that local BDNF production by resident airway cells such as epithelium and airway smooth muscle can contribute to normal airway structure and function, and to airway hyperreactivity and remodeling in diseases such as asthma. Furthermore, given its pleiotropic effects in the airway, BDNF may be a novel and appealing therapeutic target.     

Remission of asthma: The next therapeutic frontier?

Asthma treatment goals focus on disease control rather than remission as a therapeutic aim. This is in contrast to diseases where remission is frequently discussed and has well-defined criteria. In this review, we consider the similarities and differences between remission in asthma and another chronic inflammatory disease, rheumatoid arthritis, where new therapies have made remission a realistic treatment goal. Clinical remission of asthma is often defined as prolonged absence of asthma symptoms without requirement for medication while others insist on the demonstration of normal lung function and airway responsiveness. Even in those who develop a symptomatic remission of asthma, persistent physiological abnormalities and airway inflammation are common. There is a clear need to develop a precise, internationally accepted, definition of asthma remission that can be used as a therapeutic endpoint in studies of new asthma treatments. Spontaneous remission of asthma symptoms is relatively common, especially during adolescence. It is more likely in males, those with mild symptoms and normal lung function and in those who quit smoking, and may be linked to normalisation of immune function. Remission is less likely in severe asthma, atopy, eosinophilia, airflow obstruction, continued smoking and weight gain. Studies of spontaneous remissions may provide insight into how remission might be induced with therapy. Remission is not identical to cure, there remains a risk of subsequent symptomatic relapse of asthma and there is little evidence that current asthma treatments can induce remission. Long-term remission should be regarded as the next therapeutic frontier in asthma management.     

肠道菌群与炎症性肠病

炎症性肠病(IBD)是发生于胃肠道的慢性复发性疾病,克罗恩病(CD)和溃疡性结肠炎(UC)为其两种主要表现形式,其致病因素及发病机制至今尚未完全阐明,但目前普遍认为IBD是由遗传因素、免疫功能紊乱、肠道屏障功能障碍和肠道菌群改变等多因素所致。随着16S rRNA基因检测技术的应用及肠道微生物宏基因组学计划的开展,人们对肠道微生物——"被遗忘的器官"有了更深刻的认识,其在IBD中的重要作用也逐渐被重视。研究认为IBD患者中宿主与肠道微生物之间精确的平衡关系被打破,从而触发了基因易感个体的免疫炎症反应。因此,调节肠道菌群紊乱,恢复宿主与肠道微生物之间的稳态成为治疗IBD的一个新方向。本文就IBD患者中存在的肠道菌群紊乱现象、其与IBD发病的关系以及微生态制剂在IBD治疗中的应用做一简要综述。     

Impact of Aspergillus fumigatus in allergic airway diseases

ABSTRACT: For decades, fungi have been recognized as associated with asthma and other reactive airway diseases. In contrast to type I-mediated allergies caused by pollen, fungi cause a large number of allergic diseases such as allergic bronchopulmonary mycoses, rhinitis, allergic sinusitis and hypersensitivity pneumonitis. Amongst the fungi, Aspergillus fumigatus is the most prevalent cause of severe pulmonary allergic disease, including allergic bronchopulmonary aspergillosis (ABPA), known to be associated with chronic lung injury and deterioration in pulmonary function in people with chronic asthma and cystic fibrosis (CF). The goal of this review is to discuss new understandings of host-pathogen interactions in the genesis of allergic airway diseases caused by A. fumigatus. Host and pathogen related factors that participate in triggering the inflammatory cycle leading to pulmonary exacerbations in ABPA are discussed.     

Bronchial hyperresponsiveness and bacterial respiratory infections.

Some studies suggest a potential role for bacterial respiratory tract infections in the development of bronchospasm and the progression of chronic obstructive pulmonary disease (COPD). Patients with bronchiectasis or cystic fibrosis have exaggerated airway reactivity; croup in children can also cause exaggerated upper and lower airway responsiveness. Bronchial obstruction after inhalation of Haemophilus influenzae and other bacteria has been reported. Between January 1989 and June 1990 we and two other centers studied 193 patients suffering from acute exacerbation of asthma. Fifty-two (27%) of these patients had bacteria in their sputum. Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Moraxella catarrhalis, and H influenzae were the most commonly isolated bacterial species. Antibiotics may be of value in the treatment of infective lung disease, not only by killing bacteria but also by preventing increases in bacterial histamine levels within the lung airways. Moreover, an antibiotic of proven efficacy can reduce airway reactivity in patients with bacterial exacerbations of COPD or bronchial asthma. In 12 patients with acute bacterial exacerbation of asthma and high airway reactivity to methacholine, a ten-day course of treatment with cefaclor and existing bronchodilators induced microbiologic cure and a slight but nonsignificant change in airway reactivity in nine patients. Antibiotic therapy has a minor but clear role in the control of acquired bronchial hyperreactivity during bacterial respiratory infections in asthmatic patients; however, because of airway inflammation, an antibiotic's efficacy is evident only when the inflammatory process subsides. Approaches designed to minimize airway reactivity may contribute to the prevention or reversal of respiratory failure during exacerbation of COPD and bronchial asthma.     

Clues to asthma pathogenesis from microarray expression studies

Asthma is a chronic inflammatory disease characterized by airway hyperresponsiveness (AHR), tissue remodeling, and airflow obstruction. The pathogenesis of asthma is only partly understood, and there is an urgent need for improved therapeutic strategies for this disease. Microarray technology has considerable promise as a tool for discovery of novel asthma therapeutic targets, although the field is still in its infancy. A number of studies have described expression profiles derived from human asthmatic lung tissue, mouse airway tissue, or from key cell types associated with asthma, but to date relatively few studies have exploited these findings to discover new pathways involved in the pathogenesis of asthma. Among the genes to have been identified by array studies and validated by further studies are monokine induced by interferon (IFN)-gamma, fatty acid binding proteins (FABP), and complement factor 5 (C5). Here we provide examples of microarray approaches to the discovery of new molecules associated with asthma. We anticipate that these types of analyses will provide considerable insight into asthma pathogenesis and will provide a wealth of new molecules for downstream analyses such as gene deficient mouse studies, or monoclonal antibody production.     

Asthma as a chronic disease of the innate and adaptive immune systems responding to viruses and allergens

Research on the pathogenesis of asthma has traditionally concentrated on environmental stimuli, genetic susceptibilities, adaptive immune responses, and end-organ alterations (particularly in airway mucous cells and smooth muscle) as critical steps leading to disease. The focus of this cascade has been the response to allergic stimuli. An alternative scheme suggests that respiratory viruses and the consequent response of the innate immune system also drives the development of asthma as well as related inflammatory diseases. This conceptual shift raises the possibility that sentinel cells such as airway epithelial cells, DCs, NKT cells, innate lymphoid cells, and macrophages also represent critical components of asthma pathogenesis as well as new targets for therapeutic discovery. A particular challenge will be to understand and balance the innate as well as the adaptive immune responses to defend the host against acute infection as well as chronic inflammatory disease.     

The honey bee gut microbiota: strategies for study and characterization

Gut microbiota research is an emerging field that improves our understanding of the ecological and functional dynamics of gut environments. The honey bee gut microbiota is a highly rewarding community to study, as honey bees are critical pollinators of many crops for human consumption and produce valuable commodities such as honey and wax. Most significantly, unique characteristics of the Apis mellifera gut habitat make it a valuable model system. This review discusses methods and pipelines used in the study of the gut microbiota of Ap. mellifera and closely related species for four main purposes: identifying microbiota taxonomy, characterizing microbiota genomes (microbiome), characterizing microbiota–microbiota interactions and identifying functions of the microbial community in the gut. The purpose of this contribution is to increase understanding of honey bee gut microbiota, to facilitate bee microbiota and microbiome research in general and to aid design of future experiments in this growing field.     

Influence of gut microbiota on eye diseases: an overview

The microbiota is a dynamic ecosystem that plays a major role in the host health. Numerous studies have reported that alterations in the intestinal microbiota (dysbiosis) may contribute to the pathogenesis of various common diseases such as diabetes, neuropsychiatric diseases, and cancer. However, emerging findings also suggest the existence of a gut-eye axis, wherein gut dysbiosis may be a crucial factor influencing the onset and progression of multiple ocular diseases, including uveitis, dry eye, macular degeneration, and glaucoma. Currently, supplementation with pre- and probiotics appears is the most feasible and cost-effective approach to restore the gut microbiota to a eubiotic state and prevent eye pathologies. In this review, we discuss the current knowledge on how gut microbiota may be linked to the pathogenesis of common eye diseases, providing therapeutic perspectives for future translational investigations within this promising research field.     

The lung microbiome: progress and promise

The healthy lung was long thought of as sterile, but recent advances using molecular sequencing approaches have detected bacteria at low levels. Healthy lung bacteria largely reflect communities present in the upper respiratory tract that enter the lung via microaspiration, which is balanced by mechanical and immune clearance and likely involves limited local replication. The nature and dynamics of the lung microbiome, therefore, differ from those of ecological niches with robust self-sustaining microbial communities. Aberrant populations (dysbiosis) have been demonstrated in many pulmonary diseases not traditionally considered microbial in origin, and potential pathways of microbe-host crosstalk are emerging. The question now is whether and how dysbiotic microbiota contribute to initiation or perpetuation of injury. The fungal microbiome and virome are less well studied. This Review highlights features of the lung microbiome, unique considerations in studying it, examples of dysbiosis in selected disease, emerging concepts in lung microbiome–host interactions, and critical areas for investigation.     

Asthma: 2015 and beyond

Asthma is a multifactorial, chronic inflammatory disease of the airways. The knowledge that asthma is an inflammatory disorder has become a core fundamental in the definition of asthma. Asthma's chief features include a variable degree of air-flow obstruction and bronchial hyper-responsiveness, in addition to the underlying chronic airways inflammation. This underlying chronic airway inflammation substantially contributes to airway hyper-responsiveness, air-flow limitation, respiratory symptoms, and disease chronicity. However, this underlying chronic airway inflammation has implications for the diagnosis, management, and potential prevention of the disease. This review for the respiratory therapy community summarizes these developments as well as providing an update on asthma epidemiology, natural history, cause, and pathogenesis. This paper also provides an overview on appropriate diagnostic and monitoring strategies for asthma, pharmacology, and newer therapies for the future as well as relevant management of acute and ambulatory asthma, and a brief review of educational approaches.     

Evaluation of the patient with chronic cough

Initial evaluation of the patient with chronic cough (i.e., of more than eight weeks' duration) should include a focused history and physical examination, and in most patients, chest radiography. Patients who are taking an angiotensin-converting enzyme inhibitor should switch to a medication from another drug class. The most common causes of chronic cough in adults are upper airway cough syndrome, asthma, and gastroesophageal reflux disease, alone or in combination. If upper airway cough syndrome is suspected, a trial of a decongestant and a first-generation antihistamine is warranted. The diagnosis of asthma should be confirmed based on clinical response to empiric therapy with inhaled bronchodilators or corticosteroids. Empiric treatment for gastroesophageal reflux disease should be initiated in lieu of testing for patients with chronic cough and reflux symptoms. Patients should avoid exposure to cough-evoking irritants, such as cigarette smoke. Further testing, such as high-resolution computed tomography, and referral to a pulmonologist may be indicated if the cause of chronic cough is not identified. In children, a cough lasting longer than four weeks is considered chronic. The most common causes in children are respiratory tract infections, asthma, and gastroesophageal reflux disease. Evaluation of children with chronic cough should include chest radiography and spirometry.     

Targeting the NF-kappaB pathway in asthma and chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease are inflammatory lung disorders responsible for significant morbidity and mortality worldwide. While the importance of allergic responses in asthma is well known, respiratory viral and bacterial infections and pollutants especially cigarette smoke are important factors in the pathogenesis of both diseases. Corticosteroid treatment remains the first preference of treatment in either disease, however these therapies are not always completely effective, and are associated with side effects and steroid resistance. Due to such limitations, development of new treatments represents a major goal for both the pharmaceutical industry and academic researchers. There are now excellent reasons to promote NF-kappaB signalling intermediates and Rel family proteins as potential therapeutic targets for both asthma and chronic obstructive pulmonary disease. This notion is supported by the fact that much of the underlying inflammation of both diseases independent of stimuli, is mediated at least in part, by NF-kappaB mediated signalling events in several cell types. Also, a range of inhibitors of NF-kappaB signalling intermediates are now available, including DNA oligonucleotides and DNA-peptide molecules that act as NF-kappaB decoy sequences, small molecule inhibitors such as IKK-beta inhibitors, and proteasome inhibitors affecting NF-kappaB signalling, that have either shown promise in animal models or have begun clinical trials in other disorders. This review will focus on the role of NF-kappaB in both diseases, will discuss its suitability as a target, and will highlight recent key studies that support the potential of NF-kappaB as a therapeutic target in these two important inflammatory lung diseases.