Epigenetics of asthma

Asthma is caused by both heritable and environmental factors. It has become clear that genetic studies do not adequately explain the heritability and susceptibility to asthma. The study of epigenetics, heritable non-coding changes to DNA may help to explain the heritable component of asthma. Additionally, epigenetic modifications can be influenced by the environment, including pollution and cigarette smoking, which are known asthma risk factors. These environmental trigger-induced epigenetic changes may be involved in skewing the immune system towards a Th2 phenotype following in utero exposure and thereby enhancing the risk of asthma. Alternatively, they may directly or indirectly modulate the immune and inflammatory processes in asthmatics via effects on treatment responsiveness. The study of epigenetics may therefore play an important role in our understanding and possible treatment of asthma and other allergic diseases. This article is part of a Special Issue entitled: Biochemistry of Asthma.     

Epigenetics of asthma

Asthma is caused by both heritable and environmental factors. It has become clear that genetic studies do not adequately explain the heritability and susceptibility to asthma. The study of epigenetics, heritable non-coding changes to DNA may help to explain the heritable component of asthma. Additionally, epigenetic modifications can be influenced by the environment, including pollution and cigarette smoking, which are known asthma risk factors. These environmental trigger-induced epigenetic changes may be involved in skewing the immune system towards a Th2 phenotype following in utero exposure and thereby enhancing the risk of asthma. Alternatively, they may directly or indirectly modulate the immune and inflammatory processes in asthmatics via effects on treatment responsiveness. The study of epigenetics may therefore play an important role in our understanding and possible treatment of asthma and other allergic diseases. This article is part of a Special Issue entitled: Biochemistry of Asthma.     

The pathophysiology of asthma

Because postmortem studies of humans provide little information on the initial pathophysiologic events in asthma, animal models have been developed. Recently the Ascaris-allergic rhesus monkey has provided an opportunity to examine the onset of pathophysiologic changes following challenge and to correlate them with airway structure. These studies have suggested that the initial interaction between antigen and mast cells may occur in the bronchial lumen or in the epithelium superficial to the tight junctions, where a small but significant percentage of airway mast cells exist. It also appears that this initial antigen-antibody interaction results in the release of mediators that both stimulate the rapidly adapting stretch receptors in the mucosa and alter the mucosal barrier so that proteins of large molecular weight can penetrate. The fact that antigen challenge results in hyperresponsiveness to a subsequent dose of inhaled histamine and increased systemic absorption of histamine suggests that the airway hyperresponsiveness could be related to increased penetration of histamine into the bronchial wall. These observations suggest that the initial event in an acute asthmatic attack is the release of mediators from superficial mast cells, and that this amplifies the allergic response by altering the mucosal permeability so that more antigen reaches the submucosal mast cells. This altered permeability may also help explain the hyperreactivity of the airways to nonspecific airway stimulants in persons with asthma.     

The biochemistry of asthma

Background

Asthma is not one disease. Different patients have biochemically distinct phenotypes.

Scope of review

Biomarker analysis was developed to identify inflammation in the asthmatic airway. It has led to a renewed interest in biochemical abnormalities in the asthmatic airway. The biochemical determinants of asthma heterogeneity are many. Examples include decreased activity of superoxide dismutases; increased activity of eosinophil peroxidase, S-nitrosoglutathione reductase, and arginases; decreased airway pH; and increased levels of asymmetric dimethyl arginine.

Major conclusions

New discoveries suggest that biomarkers such as exhaled nitric oxide reflect complex airway biochemistry. This biochemistry can be informative and therapeutically relevant.

General significance

Improved understanding of airway biochemistry will lead to new tests to identify biochemically unique subpopulations of patients with asthma. It will also likely lead to new, targeted treatments for these specific asthma subpopulations. This article is part of a Special Issue entitled Biochemistry of Asthma.     

Pharmacogenomics of pediatric asthma

CONTEXT:

Asthma is a complex disease with multiple genetic and environmental factors contributing to it. A component of this complexity is a highly variable response to pharmacological therapy. Pharmacogenomics is the study of the role of genetic determinants in the variable response to therapy. A number of examples of possible pharmacogenomic approaches that may prove of value in the management of asthma are discussed below.

EVIDENCE ACQUISITION:

A search of PubMed, Google scholar, E-Medicine, BMJ and Mbase was done using the key words “pharmacogenomics of asthma”, “pharmacogenomics of β-agonist, glucocorticoids, leukotriene modifiers, theophylline, muscarinic antagonists in asthma”.

RESULTS:

Presently, there are limited examples of gene polymorphism that can influence response to asthma therapy. Polymorphisms that alter response to asthma therapy include Arg16Gly, Gln27Glu, Thr164Ile for β-agonist receptor, polymorphism of glucocorticoid receptor gene, CRHR1 variants and polymorphism of LTC4S, ALOX5. Polymorphic variants of muscarinic receptors, PDE4 and CYP450 gene variants.

CONCLUSION:

It was concluded that genetic variation can improve the response to asthma therapy. However, no gene polymorphism has been associated with consistent results in different populations. Therefore, asthma pharmacogenomic studies in different populations with a large number of subjects are required to make possible tailoring the asthma therapy according to the genetic characteristic of individual patient.     

Control of asthma.

Developments of the past decade have greatly improved the likelihood that patients can control their asthma. Inhaled medications are basic to a regimen that may include bronchodilators only, or bronchodilators along with cromoglycate and steroid to the extent required to achieve and maintain control. The regimen is modified for the individual and designed to control symptoms while avoiding an overdose of any one agent and overuse of inhaled bronchodilators (a sign of their lessening effectiveness). The regimen outlined emphasizes controlling asthma day to day and providing effective intervention early to prevent attacks from becoming severe.     

The microbiology of asthma

Asthma remains an important human disease that is responsible for substantial worldwide morbidity and mortality. The causes of asthma are multifactorial and include a complex mix of environmental, immunological and host genetic factors. In addition, epidemiological studies show strong associations between asthma and infection with respiratory pathogens, including common respiratory viruses such as rhinoviruses, human respiratory syncytial virus, adenoviruses, coronaviruses and influenza viruses, as well as bacteria (including atypical bacteria) and fungi. In this Review, we describe the many roles of microorganisms in the risk of developing asthma and in the pathogenesis of and protection against the disease, and we discuss the mechanisms by which infections affect the severity and prevalence of asthma.     

Biochemistry of asthma.

Asthma is a chronic condition of the airways that involves many types of inflammatory cell and the release of many mediators and neurotransmitters that have multiple effects on the various target cells in the airway. There have been important advances in understanding the biochemical events involved in signal transduction in inflammatory cells, in mediator synthesis and release, in contraction and relaxation of airway smooth muscle and in neural mechanisms. This may lead to more effective and specific therapies for this common but complex disease.     

Viruses and asthma

Background

Viral respiratory infection has long been known to influence the occurrence of asthma exacerbations. Over the last 20 years much effort has been put into clarifying the role that viral respiratory infections play in the eventual development of asthma.

Scope of review

In this review we give a general background of the role of viruses in the processes of asthma exacerbation and asthma induction. We review recent additions to the literature in the last 3 years with particular focus on clinical and epidemiologic investigations of influenza, rhinovirus, bocavirus, respiratory syncytial virus, and metapneumovirus.

Major conclusions

The development of asthma emerges from a complex interaction of genetic predisposition and environmental factors with viral infection likely playing a significant role in the effect of environment on asthma inception. This article is part of a Special Issue entitled: Biochemistry of Asthma.

General significance

Further understanding of the role that viruses play in asthma exacerbation and inception will contribute to decreased asthma morbidity in the future. This article is part of a Special Issue entitled: Biochemistry of Asthma.