Chronic obstructive pulmonary disease pathophysiology

Chronic obstructive pulmonary disease Microchapters
Home
Patient Information
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Differentiating Chronic obstructive pulmonary disease from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
Diagnostic Study of Choice
History and Symptoms
Physical Examination
Laboratory Findings
Electrocardiogram
X Ray
Echocardiography or Ultrasound
CT scan
MRI
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Future or Investigational Therapies
Case Studies
Case #1
Chronic obstructive pulmonary disease pathophysiology On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Chronic obstructive pulmonary disease pathophysiology All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Chronic obstructive pulmonary disease pathophysiology
CDC on Chronic obstructive pulmonary disease pathophysiology
Chronic obstructive pulmonary disease pathophysiology in the news
Blogs on Chronic obstructive pulmonary disease pathophysiology
Directions to Hospitals Treating Chronic obstructive pulmonary disease
Risk calculators and risk factors for Chronic obstructive pulmonary disease pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Cafer Zorkun, M.D., Ph.D. [2], Priyamvada Singh, MBBS [3]

Overview

Pathologic changes in chronic obstructive pulmonary disease (COPD) occur in the large (central) airways, the bronchioles, and the lung parenchyma. Increased numbers of activated polymorphonuclear leukocytes and macrophages release elastases, proteinase-3 and macrophage-derived matrix metalloproteinases (MMPs), cysteine proteinases, and a plasminogen activator resulting in lung destruction. The antiprotease in the body cannot counteract effectively these elastases. Additionally, increased oxidative stress caused by free radicals in cigarette smoke, phagocytes, and polymorphonuclear leukocytes all may lead to apoptosis. In addition to macrophages, T lymphocytes, particularly CD8+, play an important role in the pathogenesis of smoking-induced airflow limitation.

Pathophysiology

• Narrowing of the airways reduces the rate at which air can flow to and from the air sacs (alveoli) and limits the effectiveness of the lungs.
• In COPD, the greatest reduction in air flow occurs when breathing out (during expiration) because the pressure in the chest tends to compress rather than expand the airways.
• In theory, air flow could be increased by breathing more forcefully, increasing the pressure in the chest during expiration. In COPD, there is often a limit to how much this can actually increase air flow, a situation known as expiratory flow limitation.
• If the rate of airflow is too low, a person with COPD may not be able to completely finish breathing out (expiration) before he or she needs to take another breath. This is particularly common during exercise, when breathing has to be faster. A little of the air of the previous breath remains within the lungs when the next breath is started, resulting in an increase in the volume of air in the lungs, a process called dynamic hyperinflation.
• Dynamic hyperinflation is closely linked to dyspnea in COPD.
• It is less comfortable to breathe with hyperinflation because it takes more effort to move the lungs and chest wall when they are already stretched by hyperinflation.
• Another factor contributing to shortness of breath in COPD is the loss of the surface area available for the exchange of oxygen and carbon dioxide with emphysema. This reduces the rate of transfer of these gases between the body and the atmosphere and can lead to low oxygen and high carbon dioxide levels in the body.
• A person with emphysema may have to breathe faster or more deeply to compensate, which can be difficult to do if there is also flow limitation or hyperinflation.
• Some people with advanced COPD do manage to breathe fast to compensate, but usually have dyspnea as a result. Others, who may be less short of breath, tolerate low oxygen and high carbon dioxide levels in their bodies, but this can eventually lead to headaches, drowsiness and heart failure.
• It is not fully understood how tobacco smoke and other inhaled particles damage the lungs to cause COPD. The most important processes causing lung damage are:
  • Oxidative stress produced by the high concentrations of free radicals in tobacco smoke
  • Cytokine release due to inflammation as the body responds to irritant particles such as tobacco smoke in the airway
  • Tobacco smoke and free radicals impair the activity of antiprotease enzymes such as alpha 1-antitrypsin, allowing protease enzymes to damage the lung

• Several molecular signatures associated to lung function decline and corollaries of disease severity have been proposed, a majority of which are characterized in easily accessible surrogate tissue, including blood derivatives such as serum and plasma. A recent 2010 clinical study proposes alpha 1B-glycoprotein precursor/A1BG, alpha 2-antiplasmin, apolipoprotein A-IV precursor/APOA4, and complement component 3 precursor, among other coagulation and complement system proteins as corollaries of lung function decline, although ambiguity between cause and effect is unresolved.

Pathogenesis

• Hallmark features include: hyperplasia (increased number) and hypertrophy (increased size) of the goblet cells (mucous gland) of the airway, resulting in an increase in secretion of mucus, which contributes to the airway obstruction.
• Narrowing of the airways reduces the rate at which air can flow to and from the air sacs (alveoli) and limits the effectiveness of the lungs.

Microscopy

• On microscopic histopathological analysis, there is infiltration of the airway walls with inflammatory cells, particularly CD8+ T-lymphocytes and neutrophils. Inflammation is followed by scarring and remodeling that thickens the walls resulting in narrowing of the small airways.

Emphysema

Emphysema is caused by loss of elasticity (increased compliance) of the lung tissue, from destruction of structures supporting the alveoli, and destruction of capillaries feeding the alveoli. The result is that the small airways collapse during exhalation (although alveolar collapsability has increased), leading to an obstructive form of lung disease (airflow is impeded and air is generally "trapped" in the lungs in obstructive lung diseases).

• When toxins such as smoke are breathed into the lungs, the particles are trapped and cause a localized inflammatory response. Chemicals released during the inflammatory response (e.g., elastase) can break down the walls of alveoli (alveolar septum). This leads to fewer but larger alveoli, with a decreased surface area and a decreased ability to absorb oxygen and exude carbon dioxide by diffusion. The activity of another molecule called alpha 1-antitrypsin normally neutralizes the destructive action of one of these damaging molecules.
• After a prolonged period, hyperventilation becomes inadequate to maintain high enough oxygen levels in the blood. The body compensates by vasoconstricting appropriate vessels. This leads to pulmonary hypertension, which places increased strain on the right side of the heart, the one that pumps unoxygenated blood to the lungs, fails. The failure causes the heart muscle to thicken to pump more blood. Eventually, as the heart continues to fail, it becomes larger and blood backs up in the liver.
• Emphysema occurs in a higher proportion in patients with decreased alpha 1-antitrypsin (A1AT) levels (alpha 1-antitrypsin deficiency, A1AD). In A1AD, inflammatory enzymes (such as elastase) are able to destroy the alveolar tissue (the elastin fibre, for example). Most A1AD patients do not develop clinically significant emphysema, but smoking and severely decreased A1AT levels (10-15%) can cause emphysema at a young age. In all, A1AD causes about 2% of all emphysema. However, smokers with A1AD are in the highest risk category for emphysema.
• While A1AD provides some insight into the pathogenesis of the disease, hereditary A1AT deficiency only accounts for a small proportion of the disease. Studies for the better part of the past century have focused mainly upon the putative role of leukocyte elastase (also neutrophil elastase), a serine protease found in neutrophils, as a primary contributor to the connective tissue damage seen in the disease. This hypothesis, a result of the observation that NE is the primary substrate for A1AT, and A1AT is the primary inhibitor of NE, together have been known as the "protease-antiprotease" theory, implicating neutrophils as an important mediator of the disease. However, more recent studies have brought into light the possibility that one of the many other numerous proteases, especially matrix metalloproteases might be equally or more relevant than NE in the development of non-hereditary emphysema.

• The better part of the past few decades of research into the pathogenesis of emphysema involved animal experiments where various proteases were instilled into the trachea of various species of animals. These animals developed connective tissue damage, which was taken as support for the protease-antiprotease theory. However, just because these substances can destroy connective tissue in the lung, as anyone would be able to predict, doesn't establish causality. More recent experiments have focused on more technologically advanced approaches, such as ones involving genetic manipulation. Perhaps the most interesting development with respect to our understanding of the disease involves the production of protease "knock-out" animals, which are genetically deficient in one or more proteases, and the assessment of whether they would be less susceptible to the development of the disease

Gross Pathology

Pathology of lung showing centrilobular emphysema characteristic of smoking. Closeup of fixed, cut surface shows multiple cavities lined by heavy black carbon deposits. (CDC/Dr. Edwin P. Ewing, Jr., 1973)

Microscopic Pathology

H&E (haematoxylin and eosin) stained lung tissue sample from an end-stage emphysema patient. RBCs are red, nuclei are blue-purple, other cellular and extracellular material is pink, and air spaces are white.

Acute Exacerbations of COPD

An acute exacerbation of COPD is a sudden worsening of COPD symptoms (shortness of breath, quantity and color of phlegm) that typically lasts for several days. Airway inflammation is increased during the exacerbation, resulting in increased hyperinflation, reduced expiratory air flow and worsening of gas transfer. This can also lead to hypoventilation and eventually hypoxia, insufficient tissue perfusion, and then cell necrosis.

References

Template:WikiDoc Sources