Pathophysiology of Asthma & COPD

Pathophysiology of Asthma

1. Broncho-spasm
2. Mucous Secretion
3. Oedema

Airway Inflammation (related to mucous secretion)

Immune system components:

1. Antibodies: specific proteins created by the immune system to identify and bind to foreign and potentially invading substances (IgE for allergens)
2. Inflammatory cells circulate in the bloodstream and can "sense" the body's surroundings or exposures to create immune responses directed against those exposures (mast cells, eosinophils, activated T-lymphocytes)
3. Inflammatory mediators: chemical substances that are secreted by immune cells to induce (or respond to) an ongoing immune response generated against a specific exposure to the body (cytokines)

Infectious agents constantly enter the body via the respiratory system. The bronchi have several protective methods against these invaders. These include:

• recruitment of inflammatory cells from the bloodstream into the bronchial wall, where they directly attack the invading organisms and secrete inflammatory chemicals that are toxic to the organisms
• swelling of the bronchial wall
• mucus secretion
• constriction of the airway

The fundamental defect in asthma is that, for reasons that are unclear, these inflammatory actions occur in the bronchi when no serious infection, toxin, or other inhaled threat to the body exists.

Airway inflammation in asthma is:

• a direct response of the immune system to a trigger
• a cascade of immunologic events that includes inflammatory cells and mediators
• an immune-mediated process that leads to inflammatory changes in the airway, including eosinophil recruitment and airway edema.

Normal airway	Inflamed airway
Epithelial cells lines and protects bronchial wall	Bronchial wall edema (due to plasma leakage from blood vessels) à thickening of wall
Mucous gland – protective layer of mucus	Enlarged mucous glands secrete excess mucus
Lumen free of mucus	Lumen has mucus
Few eosinophils in bronchial wall	Eosinophils migrate from bloodstream into bronchial wall & lumen à release eosinophil cationic protein & leukotrienes

Airway walls thicken --> (smooth muscle in) bronchial walls contract --> greater airway narrowing, coz’ the walls are already thickened --> greater airway resistance.

Bronchial Hyper-reactivity/responsiveness (related to broncho-spasm)

Hyper-reactivity of the airways to several stimuli is a hallmark of clinical asthma, and it appears bronchial hyper-reactivity (BHR) is caused by airway inflammation.

The presence of airway hyper-responsiveness or bronchial hyper-reactivity in asthma is an exaggerated response to numerous exogenous and endogenous stimuli. The mechanisms involved include direct stimulation of airway smooth muscle and indirect stimulation by pharmacologically active substances from mediator-secreting cells such as mast cells or non-myelinated sensory neurons. The degree of airway hyper-responsiveness generally correlates with the clinical severity of asthma.

Intermittent Airflow Obstruction (related to oedema)

Airflow obstruction can be caused by a variety of changes, including acute broncho-constriction, airway edema, chronic mucous plug formation, and airway remodeling.

Acute broncho-constriction is the consequence of immunoglobulin E–dependent mediator release upon exposure to aeroallergens and is the primary component of the early asthmatic response.

Airway edema occurs 6-24 hours following an allergen challenge and is referred to as the late asthmatic response.

Chronic mucous plug formation consists of an exudate of serum proteins and cell debris that may take weeks to resolve.

Airway remodeling is associated with structural changes due to long-standing inflammation. Airway remodeling and fibrosis may be the cause of "fixed" airflow obstruction in asthma that is not reversible with steroids, bronchodilators, or both.

Sources:

http://www.emedicine.com/med/topic177.htm
http://www.merckmedicus.com/pp/us/hcp/diseasemodules/asthma/pathophysiology.jsp

Pathophysiology of COPD

The pathophysiology of COPD is not completely understood; it is progressive with time.

1. Airway obstruction
2. Airflow limitation

Airway obstruction

Prominent inflammatory cells: neutrophils, macrophages, CD8+ T-lymphocytes
Inflammatory mediators: Leukotriene B4, Interleukin 8, and Tumor Necrosis Factor

Smoking and, occasionally, other inhaled irritants, perpetuates an ongoing inflammatory response. Oxidative stress caused by free radicals in cigarette smoke activate neutrophils. Activated neutrophils release proteases as part of the inflammatory process. Neutrophil influx also causes the secretion of MMPs (macrophage-derived matrix metalloproteinases) from macrophages.

Protease activity exceeds antiprotease activity, and tissue destruction and mucus hypersecretion result.

Neutrophil and macrophage activation also leads to accumulation of free radicals, superoxide anions, and hydrogen peroxide, which inhibit antiproteases and cause broncho-constriction, mucosal edema, and mucous hypersecretion. Neutrophil-induced oxidative damage, release of profibrotic neuropeptides (eg, bombesin), and reduced levels of vascular endothelial growth factor may also play a role, as does infection (we learnt about acute exacerbations of COPD in Thursday’s lecture, so I will not repeat. Go look at your lecture notes for that). :)

Physically, airways become edematous, excess mucus production occurs and cilia function poorly. With disease progression, patients have increasing difficulty clearing secretions.

Incr. airway resistance --> Incr. work of respiration (breathing) --> Incr. alveolar hypoventilation with hypoxia and hypercapnia --> Incr. pulmonary vascular tone --> pulmonary hypertension and cor pulmonale.

O₂ administration may then worsen hypercapnia in some patients by decreasing hypoxic ventilatory drive, leading to alveolar hypoventilation.

In order to understand the mechanisms, we need to study Chronic Bronchitis and Emphysema:

Chronic bronchitis

Mucous gland enlargement is the histologic hallmark of chronic bronchitis.

The structural changes described in the airways include atrophy, focal squamous metaplasia, ciliary abnormalities, variable amounts of airway smooth muscle hyperplasia, inflammation, and bronchial wall thickening.

Neutrophilia develops in the airway lumen, and neutrophilic infiltrates accumulate in the submucosa. The respiratory bronchioles display a mononuclear inflammatory process, lumen occlusion by mucous plugging, goblet cell metaplasia, smooth muscle hyperplasia, and distortion due to fibrosis (this is a repeat of inflammatory process as mentioned above).

These changes, combined with loss of supporting alveolar attachments, cause airflow limitation by allowing airway walls to deform and narrow the airway lumen.

Airflow Limitation

Emphysema

1. Centriacinar: limited to the respiratory bronchioles; assoc. with cigarette smoking; severe in upper lobes
2. Panacinar: entire alveolus distal to the terminal bronchiole; alpha1-antitrypsin deficiency; severe in lower lung
3. Distal acinar/paraseptal: distal airway structures, alveolar ducts, sacs; least common

Both emphysematous destruction and small airway inflammation often are found in combination in individual patients.

When emphysema is moderate or severe, loss of elastic recoil, rather than bronchiolar disease, is the mechanism of airflow limitation.

By contrast, when emphysema is mild, bronchiolar abnormalities are most responsible for the deficit in lung function. Although airflow obstruction in emphysema is virtually irreversible, broncho-constriction due to inflammation accounts for a limited amount of reversibility.

Sources:

http://www.emedicine.com/med/topic373.htm
http://www.merckmedicus.com/pp/us/hcp/framemm.jsp?pg=www.merck.com/mmpe/sec05/ch049/ch049a.html
http://www.aafp.org/afp/20010815/603.html
http://www.clevelandclinicmeded.com/diseasemanagement/pulmonary/copd/copd.htm
http://www.medicinenet.com/chronic_obstructive_pulmonary_disease_copd/page2.htm