The Airway Epithelium In Asthma Biology Essay

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The airway epithelium, while playing an important role as a physical barrier, is now known to be fundamental to asthma pathogenesis. Bronchial biopsies in anything but the mildest forms of asthma show areas of epithelial metaplasia and damage, thickening of the subepithelial basal lamina, increased number of myofibroblasts, and other evidence of airway remodeling such as hypertrophy and hyperplasia of airway smooth muscle, mucous gland hyperplasia, angiogenesis and an altered deposition and composition of extracellular matrix proteins and proteoglycans (Holgate et al. 2004). While these pathologic features have been commonly reported in asthma deaths and in bronchial biopsies from patients with asthma of varying severity, more recently similar findings have been found in the airways of children in relation to the onset of asthma (Barbato et al. 2006). Evidence of epithelial damage with upregulation of epidermal growth factor receptors (EG FRs) and features of imp aired proliferation, e.g., reduced expression of proliferative markers such as Ki6 7 and proliferating cell nuclear antigen (PCNA) and upregulation of the cell cyclin inhibitor, nuclear p21, suggest that, as in adult asthma (Puddicombe et al. 2003), the epithelium is chronically injured and unable to repair properly (Kicic et al . 2006). One important feature of the asthmatic epithelium is its capacity to defend itself against oxidant injury, a feature that may partly explain why asthmatic subjects are so sensitive to oxidant pollutants such as ozone, environmental tobacco smoke and ambient air particulates (Truong-Tra n et al . 2003).

1.10. HETEROGENITY OF ASTHMA

Asthma is a heterogeneous disorder (Wenzel 2006). Although different types of asthma have long been recognized, such as that triggered by exposure to allergens, occupational chemicals, non steroidal anti inflammatory drugs (NSAIDs) and non allergic ''intrinsic'' asthma, there has never been a cellular or molecular basis for these different manifestations of intermittent airflow obstruction other than exposure to a particular environmental stimulus. With the advent of fiberoptic bronchoscopy and the ability to biopsy different parts of the bronchial tree, non invasive lung imaging such as HRCT and the development of therapeutics that target single cells or pathways, it is now clear that asthma is not a single disease but a wide rang e of different disorder s that share some common phenotypes such as reversible airflow obstruction and associated symptoms. Using noninvasive markers of airway inflammation suggests the presence of at least four distinct ''phenotypes'': eosinophilic, neutrophilic, mixed inflammatory, and paucigranulocytic asthma (Wenzel 2006).

1.10.1. Eosinophilic asthma

Bronchial biopsy studies of patients with mild asthma have shown that eosinophilic airway inflammation is highly characteristic regardless of whether patients were atopic, non atopic, aspirin-sensitive, or had occupational asthma (Bochner & Busse 2005). when eosinophils appear to be activated. With the advent of sputum induction it appears that there is a complex relationship between eosinophilic inflammation and other markers of asthma, including lung function and airway hyper responsiveness. In contrast eosinophilic airway inflammation appears to be much more closely related to the risk of severe asthma exacerbation (Green et al. 2002).

1.10.2. Neutrophilic asthma

The use of induced sputum as well as lavage and fiberoptic bronchoscopy has revealed that some patients with asthma have a sputum neutrophilia in the absence of eosinophils (Tsoumakidou et a l. 2006). Other studies have noted neutrophilic inflammation in some patients with severe asthma and during virus induced exacerbations. In addition, patients with severe asthma treated with oral (but not inhaled) corticosteroids also exhibit a predominantly neutrophilic airway inflammation and absence of eosinophils. Intense neutrophilic inflammation has also been reported in patients ventilated for acute severe asthma and in those who died suddenly of asthma (Carroll et al. 1996). In general, asthma associated with neutrophils tends to be a more aggressive disease possibly with more tissue destruction and airway remodeling (Holgate & Polosa 2006). Tobacco smoking is also associated with a greater neutrophil component and, importantly, corticosteroid refractoriness in both the air ways and systemically.

1.10.3. Mixed eosinophilic and neutrophilic asthma

Mixed eosinophilic and neutrophilic asthma has also been associated with Mycoplasma pneumoniae and/or Chlamydia pneumonia infection, with a beneficial response to macrolide antimicrobials (John-ston et al. 2006; Kraft & Hamid 2006)

1.10.4. Paucigranulocytic asthma

Although sudden asthma death has been recorded in the absence of airway inflammation, this is highly unusual. Asthma in the absence of either neutrophils or eosinophils (paucigranulocytic asthma) has been described in which MMP-9 levels in sputum disease were normal as opposed to elevated levels in patients with eosinophilic asthma; (Simpson et al. 2005), suggesting that an abnormal epithelium or underlying mesenchyme and /or smooth muscle may itself lead to an asthma phenotype without the presence of obvious inflammation.

1.11. ASTHMA characteristics

Asthma may be chronic or acute (Rang et al., 2006).

In chronic asthma, the individual has intermittent attacks of dyspnoea disorder of breathing), wheezing, and cough, the dyspnoea consisting of difficulty in breathing out. Note that the term reversible as applied to chronic asthma needs to be qualified since it is only the acute attack of dyspnoea that is reversible-the underlying pathological change may not be reversible and indeed can progress.

Acute severe asthma (also known as status asthmaticus) is not easily reversed. It can be fatal and requires prompt and energetic treatment. Hospitalization may be necessary.

It is currently recognized that the characteristic features of most cases of asthma are:

inflammatory changes in the airways

bronchial hyper-reactivity

In allergic asthma, these are related to, and follow from, prior sensitisation.

The term bronchial hyper-reactivity (or hyper-responsiveness) refers to abnormal sensitivity to a wide range of stimuli such as irritant chemicals, cold air, stimulant drugs etc., all of which can result in bronchoconstriction. Stimuli that cause the actual asthma attacks are many and varied and include allergens (in sensitized individuals), exercise (in which the stimulus may be cold air), respiratory infections and atmospheric pollutants (such as sulfur dioxide. The non-steroidal anti-inflammatory drugs NSAIDs), especially aspirin can precipitate asthma in sensitive individuals.

1.12. THE DEVELOPMENT OF ALLERGIC ASTHMA

In allergic asthma, there is predominant activation of the T helper (Th2) type 2 cell. Sensitization involves exposure of genetically predisposed individuals to allergens such as pollen or proteins of the house dust mite; environmental factors (e.g. atmospheric pollutants may contribute to asthma). The allergens interact with dendritic cells and helper lymphocytes giving rise to a clone of Th2 lymphocytes, which then:

Generate a cytokine environment that switches β cells/plasma cells to the production and release of IgE

Generate cytokines such as interleukin-5 (IL-5), which promote differentiation and activation of eosinophils.

1.13. Chronic obstructive pulmonary disease (COPD)

This is a disease characterized by a progressive airflow limitation caused by the abnormal inflammatory reaction to the chronic inhalation of particles. COPD currently ranks as the fourth leading cause of death in developing countries. One of the most troubling aspects of COPD is that is Under recognized by the patients and physicians and confused with that of asthma and lead to arguably undertreated. (Kelly Sequeira et al 2007).

1.13.1. General characters of COPD

The pathophysiology is mainly characterized by inflammation throughout the central and peripheral airways, lung parenchyma, and pulmonary vasculature. The usual cause of COPD is smoking.( Hargreave FE et al- 2006)

In the central airways the inflammation caused by activation of sensory nerve endings by inhaled irritants results in increased mucus production and impaired mucociliary clearance. It has been found that the mucous glands become enlarged and the number of globet cells increases, leading to mucus hypersecretion.(Rodriguez-Roisin R et al- 2005 ). Bacterial growth will occur in this area and things become more risky.

Repeated cycles of inflammation and repair lead to structural narrowing of the airways. This will lead to airway remodeling, including collagen deposition and scar tissue formation in the airway wall that narrow the airway lumen and leads to airway obstruction. Obstruction of the airways leads to reduction in inspiratory capacity,results in dyspnea and decreased exercise tolerance. Chronic bronchitis and emphysema are often present in COPD patients (Rodriguez-Roisin R et al- 2005).

1.13.1.1. Chronic bronchitis

In COPD patients, chronic bronchitis is depicted by inflammation with mucus production, and narrowing of the central airways. This will result in impaired muco-ciliary clearance and increased connective tissue deposition. (Hogg J et al. 2004)

1.13.1.2. Emphysema

Emphysema is the permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis.

1.13.2. Comparison with COPD and ASTHMA

ASTHMA

COPD

All airways

Peripheral airways

Hyperresponsiveness ↑↑↑

Hyperresponsiveness ↑

Inflammatory

Epithelial shedding

Epithelial mataplasia

Effects

Fibrosis ↑↑↑

Fibrosis ↑

No paranchymal change

Paranchymal destruction

Mucus secretion↑

Mucus secretion↑↑↑

Inflammatory cells

Mastcells, Eosinophils, , CD4+Lymphocytes,

Macrophages etc

Neutrophils, CD8+Lymphocytes,

Macrophages etc

Inflammatory mediators

Histamine, IL-4, IL-5, IL-13

Eotaxin, Rantes, oxidative

Stress.

IL-8, IL-6, TNFα

GRO-α, MCP-1,

Oxidative stress.

Table.1. defferance between Asthma & COPD

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