Asthma is a heterogenous inflammatory disorder of the airways characterized by chronic inflammation, airway hyper responsiveness, and by symptoms of recurrent wheezing, coughing, and shortness of breath. Asthma is a major public health problem affecting 300 million people worldwide, and has increased considerably in prevalence over the past three decades, particularly in the western world. The mechanisms of pathogenesis however, remain elusive. Steroids and combination therapies with long-acting β-agonists are the mainstay of asthma treatment. These therapies effectively suppress acute inflammatory symptoms and cytokine release but there are no preventions or cure of disease to date.
Mild to moderate allergic asthma is generally characterized by acute or chronic airway inflammation consisting of activated Th2 lymphocytes and eosinophil infiltrates in association with IgE production, mucus secreting cells, hyperplasia and metaplasia, remodeling of the airway wall and airway hyper responsiveness (AHR). The AHR is characterized by enhanced responsiveness and constriction of the airways to non-specific spasmogenic stimuli, such as methacholine. Th2 cells, through the secretion of their cytokines IL-3, IL-4, IL-5, IL-9, IL-13, amongst others, contribute to various pathological features of the disease.
Severe, neutrophilic or steroid refractory asthma has different pathological features to mild to moderate allergic asthma and is characterized by a mixed Th2/Th1 phenotype with a possible contribution of Th17 cells. Tumor necrosis factor (TNF)-α, Interferon (IFN)-γ, IL-17 and IL-27 are elevated and may induce the influx of neutrophils (rather than eosinophils) or a mixed granulocytic airway infiltrate that is characteristic for this subtype of asthma. Patients with this subtype of asthma are refractory to glucocorticoid treatment and both bacterial and viral infections are implicated in the induction and progression of disease. Also, asthmatic patients and patients with atopic dermatitis are more likely to develop infections e.g. pneumonia compared with non-atopic individuals.
The concept of treating asthma by targeting a single cytokine e.g. anti IL-4; anti IL-5; anti TNF-α has had limited success. Indeed, steroid therapy, which is currently the mainstay therapy, is thought to act by suppressing a range of pro-inflammatory pathways.
Chronic obstructive pulmonary disease (COPD). COPD is a major public health problem projected to be the fourth leading cause of death worldwide by 2020. Although persistent inhalation of toxic particles and gases are the major risk factors, with tobacco smoking being the best example of this type of risk, only 15 % of smokers develop COPD. Although smokers have a dysfunctional immune system, the development and increasing disease severity of COPD progressively worsens the inflammatory cell burden.
Microbiome. Infant microbiota is initially uniform across various body sites, differing in subsequent days and weeks into site-specific communities. The lung microbiome of healthy adults is dominated by the phylae Bacteroidetes, Firmicutes, and Proteobacteria with the core microbiota consisting of Pseudomonas, Streptococcus, Prevotella, Fusobacteria, Veillonella, Haemophilus, Neisseria and Porphyromonas. Among asthmatics an increased frequency of Proteobacteria (in particular Haemophilus, Moraxella and Neisseria) and Firmicutes (in particular Lactobacillus spp.) and decreased frequency of Bacteroidetes (in particular Prevotella) compared with controls has been observed. Similarly epidemiological data show that gut microbiota differs between asthmatic and non-asthmatic infants.