Respirology

Abstract:  The major function of the respiratory epithelium was once thought to be that of a physical barrier. However, it constitutes the interface between the internal milieu and the external environment as well as being a primary target for inhaled respiratory drugs. It also responds to changes in the external environment by secreting a large number of molecules and mediators that signal to cells of the immune system and underlying mesenchyme. Thus, the epithelium is in a unique position to translate gene–environment interactions. Normally, the epithelium has a tremendous capacity to repair itself following injury. However, evidence is rapidly accumulating to show that the airway epithelium of asthmatics is abnormal and has increased susceptibility to injury compared to normal epithelium. Areas of detachment and fragility are a characteristic feature not observed in other inflammatory diseases such as COPD. In addition to being more susceptible to damage, normal repair processes are also compromised. Failure of appropriate growth and differentiation of airway epithelial cells will cause persistent mucosal injury. The response to traditional therapy such as glucocorticoids may also be compromised. However, whether the differences observed in asthmatic epithelium are a cause of or secondary to the development of the disease remains unanswered. Strategies to address this question include careful examination of the ontogeny of the disease in children and use of gene array technology should provide some important answers, as well as allow a better understanding of the critical role that the epithelium plays under normal conditions and in diseases such as asthma.

Abstract:  Smoking prevalence is lower among women than men in most countries, yet there are about 200 million women in the world who smoke, and in addition, there are millions more who chew tobacco. Approximately 22% of women in developed countries and 9% of women in developing countries smoke, but because most women live in developing countries, there are numerically more women smokers in developing countries. Unless effective, comprehensive and sustained initiatives are implemented to reduce smoking uptake among young women and increase cessation rates among women, the prevalence of female smoking in developed and developing countries is likely to rise to 20% by 2025. This would mean that by 2025 there could be 532 million women smokers. Even if prevalence levels do not rise, the number of women who smoke will increase because the population of women in the world is predicted to rise from the current 3.1 billion to 4.2 billion by 2025. Thus, while the epidemic of tobacco use among men is in slow decline, the epidemic among women will not reach its peak until well into the 21st century. This will have enormous consequences not only for women's health and economic wellbeing but also for that of their families. The health effects of smoking for women are more serious than for men. In addition to the general health problems common to both genders, women face additional hazards in pregnancy, female‐specific cancers such as cancer of the cervix, and exposure to passive smoking. In Asia, although there are currently lower levels of tobacco use among women, smoking among girls is already on the rise in some areas. The spending power of girls and women is increasing so that cigarettes are becoming more affordable. The social and cultural constraints that previously prevented many women from smoking are weakening; and women‐specific health education and quitting programmes are rare. Furthermore, evidence suggests that women find it harder to quit smoking. The tobacco companies are targeting women by marketing light, mild, and menthol cigarettes, and introducing advertising directed at women. The greatest challenge and opportunity in primary preventive health in Asia and in other developing areas is to avert the predicted rise in smoking among women.

Despite silica dust exposure being one of the earliest recognized causes of lung disease, Australia, USA, Israel, Turkey and other countries around the world have recently experienced significant outbreaks of silicosis. These outbreaks have occurred in modern industries such as denim jean production, domestic benchtop fabrication and jewellery polishing, where silica has been introduced without recognition and control of the hazard. Much of our understanding of silica‐related lung disease is derived from traditional occupations such as mining, whereby workers may develop slowly progressive chronic silicosis. However, workers in modern industries are developing acute and accelerated silicosis over a short period of time, due to high‐intensity silica concentrations, oxidative stress from freshly fractured silica and a rapid pro‐inflammatory and pro‐fibrotic response. Appropriate methods of screening and diagnosis remain unclear in these workers, and a significant proportion may go on to develop respiratory failure and death. There are no current effective treatments for silicosis. For those with near fatal respiratory failure, lung transplantation remains the only option. Strategies to reduce high‐intensity silica dust exposure, enforced screening programmes and the identification of new treatments are urgently required.

OSA is the result of structural and functional abnormalities that promote the repetitive collapse of the upper airway during sleep. This common disorder is estimated to occur in approximately 4% of men and 2% of women, with prevalence studies from North America, Australia, Europe and Asia indicating that occurrence is relatively similar across the globe. Anatomical factors, such as obesity and craniofacial morphology, are key determinants of the predisposition to airway collapse; however, their relative importance for OSA risk likely varies between ethnicities. Direct inter‐ethnic studies comparing craniofacial phenotypes in OSA are limited. However, available data suggest that Asian OSA populations primarily display features of craniofacial skeletal restriction, African Americans display more obesity and enlarged upper airway soft tissues, while Caucasians show evidence of both bony and soft tissue abnormalities. Our recent comparison of Chinese and Caucasian OSA patients found for the same degree of OSA severity. Caucasians were more obese, and Chinese had more skeletal restriction. However, the ratio of obesity to craniofacial bony size (or anatomical balance, an important determinant of upper airway volume and OSA risk) was similar between Caucasians and Chinese OSA patients. Ethnicity appears to influence OSA craniofacial phenotype but furthermore the relative contribution of the anatomical factors underlying OSA risk. The skeletal restriction craniofacial phenotype may be particularly vulnerable to increasing obesity rates. Better understanding of craniofacial phenotypes encompassing ethnicity may help improve OSA recognition and treatment; however, further studies are needed to elucidate ethnic differences in OSA anatomical risk factors.

Tuberculosis (TB) is an international public health priority and kills almost two million people annually. TB is out of control in Africa due to increasing poverty and HIV coinfection, and drug‐resistant TB threatens to destabilize TB control efforts in several regions of the world. Existing diagnostic tools and therapeutic interventions for TB are suboptimal. Thus, new vaccines, immunotherapeutic interventions and diagnostic tools are urgently required to facilitate TB control efforts. An improved understanding of the immunopathogenesis of TB can facilitate the identification of correlates of immune protection, the design of effective vaccines, the rational selection of immunotherapeutic agents, the evaluation of new drug candidates, and drive the development of new immunodiagnostic tools. Here we review the immunology of TB with a focus on aspects that are clinically and therapeutically relevant. An immunologically orientated approach to tackling TB can only succeed with concurrent efforts to alleviate poverty and reduce the global burden of HIV.

The primary function of the bronchial epithelium is to act as a defensive barrier aiding the maintenance of normal airway function. Bronchial epithelial cells (BEC) form the interface between the external environment and the internal milieu, making it a major target of inhaled insults. However, BEC can also serve as effectors to initiate and orchestrate immune and inflammatory responses by releasing chemokines and cytokines, which recruit and activate inflammatory cells. They also produce excess reactive oxygen species as a result of an oxidant/antioxidant imbalance that contributes to chronic pulmonary inflammation and lung tissue damage. Accumulated mucus from hyperplastic BEC obstructs the lumen of small airways, whereas impaired cell repair, squamous metaplasia and increased extracellular matrix deposition underlying the epithelium is associated with airway remodelling particularly fibrosis and thickening of the airway wall. These alterations in small airway structure lead to airflow limitation, which is critical in the clinical diagnosis of chronic obstructive pulmonary disease (COPD). In this review, we discuss the abnormal function of BEC within a disturbed immune homeostatic environment consisting of ongoing inflammation, oxidative stress and small airway obstruction. We provide an overview of recent insights into the function of the bronchial epithelium in the pathogenesis of COPD and how this may provide novel therapeutic approaches for a number of chronic lung diseases.

Background and objective:  Asthma and allergic rhinitis are significant, increasing causes of morbidity worldwide. Pollen, a major cause of seasonal rhinitis/conjunctivitis, carries proteolytic enzymes on its surface. We showed previously that peptidase allergens from house dust mites compromise epithelial barrier function by degrading the extracellular domains of the tight junction proteins, occludin and claudin, thus facilitating allergen delivery across epithelial layers. In this study, we aimed to determine whether peptidases from allergenic pollens should similarly be considered to have a role in disrupting tight junctions.

Methods:  Diffusates from stored pollen of Giant Ragweed, White Birch and Kentucky Blue Grass, and fresh pollen from Easter Lily were applied to confluent monolayers of Madin‐Darby canine kidney (MDCK) and Calu‐3 cells in serum‐free medium. Immunofluorescence was performed for the tight junction proteins, occludin, claudin‐1 and ZO‐1. The effect of pollen diffusate on occludin was studied by Western blotting, and enzymatic activity in the diffusates was demonstrated by zymography. The ability of protease inhibitors to block the action of the diffusate on tight junctions was investigated.

Results:  Diffusates from all four allergenic pollens caused loss of immunofluorescence labelling for tight junction proteins on MDCK and Calu‐3 cells. The effect was blocked by inhibitors of serine and cysteine proteases. Degradation of occludin was demonstrated by Western blotting and zymography indicated that diffusates contain proteolytic activity.

Conclusions:  Pollen peptidases directly or indirectly disrupt epithelial tight junctions, and this activity should be considered as a possible mechanism for facilitating allergen delivery across epithelia.

OSA is increasingly recognized as a major health problem in developed countries. Obesity is the most common risk factor in OSA and hence, the prevalence of OSA is undoubtedly rising given the epidemic of obesity. Recent data also suggest that OSA is highly associated with the metabolic syndrome, and it is postulated that OSA contributes to cardiometabolic dysfunction, and subsequently vasculopathy.

Current evidence regarding the magnitude of impact on ultimate cardiovascular morbidity or mortality attributable to OSA‐induced metabolic dysregulation is scarce. Given the known pathophysiological triggers of intermittent hypoxia and sleep fragmentation in OSA, the potential mechanisms of OSA–obesity–metabolic syndrome interaction involve sympathetic activation, oxidative stress, inflammation and neurohumoral changes. There is accumulating evidence from human and animal/cell models of intermittent hypoxia to map out these mechanistic pathways.

In spite of support for an independent role of OSA in the contribution towards metabolic dysfunction, a healthy diet and appropriate lifestyle modifications towards better control of metabolic function are equally important as CPAP treatment in the holistic management of OSA.

COPD is a major global concern, increasingly so in the context of ageing populations. The role of infections in disease pathogenesis and progression is known to be important, yet the mechanisms involved remain to be fully elucidated. While COPD pathogens such as Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae are strongly associated with acute exacerbations of COPD (AECOPD), the clinical relevance of these pathogens in stable COPD patients remains unclear. Immune responses in stable and colonized COPD patients are comparable to those detected in AECOPD, supporting a role for chronic colonization in COPD pathogenesis through perpetuation of deleterious immune responses. Advances in molecular diagnostics and metagenomics now allow the assessment of microbe–COPD interactions with unprecedented personalization and precision, revealing changes in microbiota associated with the COPD disease state. As microbial changes associated with AECOPD, disease severity and therapeutic intervention become apparent, a renewed focus has been placed on the microbiology of COPD and the characterization of the lung microbiome in both its acute and chronic states. Characterization of bacterial, viral and fungal microbiota as part of the lung microbiome has the potential to reveal previously unrecognized prognostic markers of COPD that predict disease outcome or infection susceptibility. Addressing such knowledge gaps will ultimately lead to a more complete understanding of the microbe–host interplay in COPD. This will permit clearer distinctions between acute and chronic infections and more granular patient stratification that will enable better management of these features and of COPD.