Pathophysiology

Function and Structure of the Respiratory System

The main function of the respiratory system is to move air into the lungs so that oxygen can enter the body and carbon dioxide can be exhaled. During breathing, air passes from the nose and mouth into the pharynx (see figure below) and through the larynx into the trachea. The trachea bifurcates to carry air into each lung. These two tubes are the main stem bronchi; there is a single left main stem bronchus and a single right main stem bronchus for the left and right lungs, respectively.

Organs of the Respiratory System

From Shier et al. [1996]; with permission.
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All bronchial branching occurs as bifurcations (see following figures). This pattern is repeated as air moves down the bronchi and into the periphery of the lungs. With each branching, the tubes become smaller in diameter and eventually microscopic, until they end in the alveolar chambers that are, themselves, microscopic in size.

Bronchial Tree Consisting of the Passageways that Connect the Trachea and Alveoli (the alveoli are enlarged to show their location)

From Shier et al. [1996]; with permission.
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A Plastic Cast of the Bronchial Tree

From Shier et al. [1996]; with permission.
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Gas exchange occurs within about 300 million alveoli. The alveoli have very thin walls to allow oxygen and carbon dioxide to cross between the lung capillaries and the alveolar spaces. The central function of respiration — gas exchange — takes place in the alveoli. Besides conducting air to and from the alveoli, the bronchi also serve to protect the alveoli. The bronchi warm and moisten the air before it enters the alveoli. The alveolar structures are delicate and can easily be damaged by cold, dry air.

Clearing airborne particles

Air passages have a self-cleaning mechanism to remove small, inhaled airborne particles. Among the cells that line the inside of the respiratory passages, from the nasal lining through the trachea and bronchi, are those that secrete mucus and others with cilia.

The purpose of mucus is to coat the lining of the airway to create a sticky surface that can collect foreign particles from inhaled air. Mucus-secreting cells are present on the airway surface and in specialized mucus glands found deep within the bronchial wall. However, most cells that line the airway have cilia on their surface that constantly move in a regular, sweeping fashion. Fine airborne particles land on the airway lining and are trapped in mucus, which is then swept upward by the movement of these cilia. Eventually, the mucus is brought far enough up in the respiratory system to be coughed out of the respiratory system or — more commonly — swallowed. This self-cleaning mechanism is called mucociliary clearance. Minute foreign particles that are not removed by the airway lining can reach the alveoli, where they are phagocytosed by large scavenging cells called alveolar macrophages for removal from the airway.

Controlling airway caliber

Smooth muscle in the bronchial wall can contract or relax, without conscious control, to result in constriction or dilation of the airway (see following figure). The airway smooth muscle allows the body to change airway diameter for different environmental conditions. The body may respond to an inhaled noxious stimulus — such as smoke or another toxic irritant — by causing the airways to constrict. This "clamp down" of the airway smooth muscle, sometimes termed bronchospasm, can serve to protect the delicate alveoli from toxic damage.

Cross-section of Bronchial Wall

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The Action of Breathing

Muscles

The diaphragm and the intercostal muscles are the principal muscles involved in breathing. During normal breathing, inspiration is an active process that involves contraction of the diaphragm (to expand the chest cavity downward) and the intercostal muscles (to expand the chest cavity up and outward). Expiration is largely passive, during which time the diaphragm and intercostal muscles relax.

Neural control

The respiratory center controls the rate and depth of breathing. During inspiration, motor impulses travel from the respiratory center to the diaphragm and external intercostal muscles, which contract and cause the lungs to expand. This expansion stimulates stretch receptors in the lungs to send inhibiting impulses to the respiratory center, thus preventing overinflation.

An increase in carbon dioxide levels will stimulate an increase in the rate or depth (or both) of breathing. A decrease in oxygen levels will cause an increase in the rate of breathing. In the control of the airways, different autonomic nerve systems are also involved.

Parasympathetic nerves

Parasympathetic nerves are characterized by their use of the neurotransmitter acetylcholine. The vagus nerve sends motor fibers from the brain to smooth muscle cells in the bronchial walls. Stimulation of the vagus nerve releases acetylcholine, which binds to specific "cholinergic" receptors on smooth muscle cells within the bronchial walls and, thus, constricts the airways. Simply stated, cholinergic stimulation causes bronchoconstriction through airway smooth muscle contraction [Murray and Nadel, 2000].

Sympathetic nerves

Sympathetic nerves are characterized by the use of catecholamine neurotransmitters. Also produced by the adrenal glands, catecholamines act by binding to "adrenergic" receptors. The sympathetic system sends nerves to blood vessels and glands in the lungs, but not to the bronchial smooth muscle. Thus, sympathetic nerves cannot directly control airway diameter. Instead, sympathetic nervous effects (such as bronchodilation) are caused when catecholamines, such as epinephrine, are released into the bloodstream by the adrenal glands [Murray and Nadel, 2000].

The Immune System

The three main components of the immune system are antibodies, inflammatory cells, and inflammatory mediators. Antibodies are the specific proteins created by the immune system to identify and bind to foreign and potentially invading substances. Inflammatory cells circulate in the bloodstream and can "sense" the body's surroundings or exposures to create immune responses directed against those exposures. Inflammatory mediators are 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.

Antibodies

An antibody, or an immunoglobulin (Ig), is a small protein molecule created by the immune system to have a close structural "fit" to the surface of a foreign substance. The foreign substance is an antigen. The primary job of antibodies is to bind to an infectious agent (a virus, bacteria, or parasite) and, in so doing, to notify and trigger the rest of the immune system to fight off this invader. The aspect of the immune system that depends on antibodies to identify a foreign substance is sometimes termed the humoral immune system. The so-called "humoral response" refers to the creation, by the immune system, of antibodies that can be the first step for the body to detect — and subsequently eliminate — a foreign substance.

Antibodies are created and secreted by B cells. Each individual B cell responds to a unique antigenic structure by secreting an antibody that corresponds to that structure. Once a foreign antigen interacts by binding to the B cell bearing the antibody with the best "fit," that B cell is activated to divide repeatedly (termed B cell proliferation).

The body manufactures five classes of antibodies, namely IgM, IgG, IgA, IgD, and IgE. For certain infections, generating antibodies of the IgM and IgG classes is essential for the body to fight off the infection quickly and successfully. Nonetheless, each class of antibody is specialized to perform particular functions in the immune response [Murray and Nadel, 2000].

Immunoglobulin E

The antibody class of allergic diseases, including allergic asthma, is IgE. It is fundamental to the allergic immune response. Any true allergic reaction occurs because IgE antibodies are binding specifically to the substance that is stimulating the allergic reaction.

Although the usual antibody response to an antigen is to generate IgM or IgG antibodies (or both), it is unclear why some antigens in some patients lead to generation of a specific IgE antibody response. An antigen that stimulates an IgE antibody response is more specifically termed an allergen. These IgE antibodies are generally directed against substances that are not harmful to the body, including pollens; fur from cats; certain mold spores; certain foods; certain drugs; and (most commonly) droppings from microscopic dust mites. Only certain people have apparently inherited a tendency to generate IgE antibodies to innocuous allergens. This is also known as atopy [Murray and Nadel, 2000].

IgE usually occurs in very minute concentration in serum, amounting only to nanograms per milliliter — for total serum IgE, in contrast to milligrams per milliliter — for serum IgM or IgG. More important than the level of circulating IgE is the level of IgE that is bound to the surface of certain inflammatory cells that are central to an allergic reaction. The most important of these cells in an immediate hypersensitivity reaction is the mast cell. After initial exposure of the patient to an allergen, the primary immune response is to generate unique IgE antibodies that become bound to the surface of mast cells. These mast cells live within various tissues of the body, including in the bronchi.

If the patient is later re-exposed to an allergen by inhalation, the allergen binds to the surface-bound IgE on mast cells in the bronchi. Binding of at least two IgE molecules, bridged by a single allergen molecule, is termed cross-linking. Cross-linking of IgE by allergen on the surface of the mast cell is the initial biologic event of an allergic reaction [Murray and Nadel, 2000].

An allergic reaction can be technically referred to as an "immediate hypersensitivity" reaction; this term derives from the two key aspects of an allergic reaction:

• The reaction occurs very quickly after exposure to the substance that stimulates the reaction (allergen). The reaction may occur (and may be life-threatening) 5-10 minutes or less after exposure to the allergen and, thus, is termed immediate.
• The person having the allergic reaction is more sensitive (i.e., shows hypersensitivity) to the offending substance than one who is not allergic. A person without allergies would be expected to have absolutely no discernible reaction to the very same substance that could be fatal to one who has exquisite allergic sensitivity to that substance.

Inflammatory cells

Participants in the immune system include several types of cells. Two classes of cells include granulocytes and lymphocytes (see figure below). Granulocytes include a number of cell types that are all characterized by containing many granules. The most important granulocytes in asthma are mast cells and eosinophils. Lymphocytes lack granules and manufacture other kinds of proteins that are involved in the inflammatory process.

Inflammatory Cells and Mediators

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Mast cells

A mast cell becomes "sensitized" to an allergen when the IgE specific for that allergen circulates in the bloodstream and eventually lands on the surface of the mast cell; the latter is fixed in a particular tissue location (e.g., a bronchial wall). Cross-linking of surface IgE by an allergen molecule triggers a rapid activation (<15 minutes) of the mast cell, which then releases numerous inflammatory mediators into the tissue surrounding the cell (see figure above).

Eosinophils

The eosinophil is the inflammatory cell most closely associated with asthma [Murray and Nadel, 2000]. Unlike mast cells that are fixed in various tissues throughout the body, eosinophil are very mobile. In association with asthma, elevated numbers of eosinophils have been identified in various tissue compartments, including:

• circulating in the peripheral blood. The increase in peripheral blood eosinophils in asthma is probably due to inflammatory cells or mediators coming from the lungs to cause increased production of eosinophils by the bone marrow.
• in biopsies of lung tissue, particularly in the bronchial wall of patients with asthma.
• in fluid specimens obtained from the lung using a bronchoscope. With this method, fluid that "washes out" the bronchi and alveoli — termed bronchoalveolar lavage (BAL) fluid — is obtained by inserting a fiberoptic scope down the air passages and into the lungs.
• in secretions or sputum of patients with asthma. A sputum specimen is basically a coughed-up sample of the mucus that is coating the airway lining.

The mobility of eosinophils indicates that they can be stimulated to leave the bloodstream and enter the tissues. In asthma, eosinophils move from the blood into the bronchi (as documented in bronchial biopsies and in BAL fluid) and onto the surface of the airway lining (as documented in sputum). Importantly, the levels of eosinophils in each of these compartments demonstrate a rough correlation with the disease state of asthma and even with the clinical severity of asthma. When activated, eosinophils release several pre-formed mediators from within their granules. These granules contain several proteins, among which is eosinophilic cationic protein.

Eosinophils appear to play a role in virtually all types and severities of asthma. Although mast cells play a central role in allergic asthma, the activity of eosinophils is evident in both allergic and nonallergic asthma. Also, there is clear documentation of increased eosinophil numbers (sometimes termed eosinophilia) and increased eosinophil activation in the blood, lungs, and sputum of asthmatics.

Lymphocytes

Lymphocytes lack granules and manufacture other kinds of proteins that are involved in the inflammatory process. B lymphocytes have the important function of manufacturing antibodies. T lymphocytes play an essential role in events that lead to airway inflammation by orchestrating the entire inflammatory process. T cells release a variety of cytokines that communicate with most other cells in the inflammatory process. Cytokines from T cells can, for instance, activate B cells to make antibodies (even controlling the choice between making IgM, IgG, or IgE) or activate eosinophils versus neutrophils.

T cells thus initiate and orchestrate a cascade of cytokine-mediated airways inflammation. T cells and their cytokines provide a common pathway for allergic (i.e., IgE-mediated) and nonallergic asthma. They are, however, not a source of mediators of immediate hypersensitivity reactions and thus do not participate in the acute (<15 minutes) response to allergen that can cause an acute asthma attack.

Inflammatory mediators

The immunologic cascade and the ensuing inflammatory reaction comprise activation of specific inflammatory cells that also release various inflammatory mediators, such as histamine, mast cell tryptase, leukotrienes, prostaglandins, eosinophil cationic protein, and cytokines. However, these represent a small subset of the several inflammatory mediators that have been identified and studied worldwide (see figure above).

Development of Asthma

Airway Inflammation

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.

Pathophysiology of the Airway in Asthma

A cross-section of a normal airway is shown in the figure below. The lumen is free of significant mucus. The single layer of ciliated epithelial cells lines and protects the bronchial wall. The mucous gland provides a protective layer of mucus above the epithelial cells. There are few eosinophils in the bronchial wall.

Histologic Findings of a Normal Airway

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The following figure depicts some of the histologic features of airway inflammation. Plasma leakage from blood vessels contributes to bronchial wall edema, which results in thickening of the bronchial wall. Eosinophils migrate from the bloodstream into the bronchial wall and the airway lumen and can release eosinophil cationic protein and leukotrienes. Enlarged mucus glands secrete excess mucus that can plug the airway lumen.

Histologic Findings of an Inflamed Airway

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Moreover, as the airway walls thicken due to these inflammatory reactions, the amount of airway narrowing produced by a given amount of smooth muscle contraction in asthma is much greater than that in a normal airway. Thus, even a small contraction of bronchial smooth muscle can lead to dramatic increases in airway resistance when the bronchial walls are already thickened from the actions of inflammatory cells and airway edema.

Bronchial hyperreactivity

Hyperreactivity of the airways to several stimuli is a hallmark of clinical asthma, and it appears bronchial hyperreactivity (BHR) is caused by airway inflammation. Studies have shown that the degree of BHR correlates, for instance, with the number of inflammatory cells recovered in BAL fluid from the airways of asthmatic patients [Murray and Nadel, 2000].

Clinically, the degree of BHR (measured in research studies by methacholine challenge) has been shown to correlate with general asthma severity, with morning peak expiratory flow rate (PEFR), with the degree of diurnal variation of PEFR, and with the frequency of inhaled beta-agonist use (when taken by patients as needed for symptoms). The degree of BHR appears to decrease when asthma is well controlled with medication. The ultimate result and significance of BHR is the airflow obstruction that occurs when an asthmatic is exposed to a trigger.

Bronchoconstriction

Inhalation of an allergen solution by a patient with allergic asthma causes prompt and significant bronchoconstriction. After this bronchial allergen challenge, there is a rapid decline in forced expiratory volume in 1 second (FEV1) that begins within 15 minutes and generally subsides within the first hour (see figure below). This bronchial manifestation of immediate hypersensitivity has been termed an early asthmatic reaction (EAR), or the early phase response. After this phase resolves (spontaneously or with a beta-agonist, if needed), the FEV1 reaches a level that is at or close to the pre-challenge baseline.

The Early and Late Asthmatic Response following Allergen Challenge

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In about 50% of patients, there can be a spontaneous return of bronchoconstriction that occurs several hours after the allergen challenge (and after the EAR has resolved) (see figure above). This late phase response usually occurs 6-24 hours after exposure to the allergen and is termed the late asthmatic response (LAR). This late decline in FEV1 may be less severe than during the EAR but is generally more prolonged, lasting several hours (see figure above).

The EAR results from binding of inhaled allergen to mast cell membrane-bound IgE with subsequent release of mediators (e.g., histamine, leukotrienes, and prostaglandins). Among these mediators, the cysteinyl leukotrienes appear to account for a significant part of the early bronchoconstrictor response (see figure below).

Inflammatory and Bronchoconstriction Events of the Early Phase of an Acute Asthmatic Response to Allergen Exposure

Adapted from Barnes et al. [1998]; with permission.
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The LAR to an allergen is typified not only by a decline in FEV1 but also by the influx of inflammatory cells, most notably eosinophils, and airway edema. The intensity of LAR inflammation correlates with the degree of airflow obstruction that occurs during the LAR. Note that the airflow obstruction of the LAR usually lasts longer, as much as several hours or more (see figure below).

Inflammatory and Bronchoconstriction Events of the Late Phase of an Acute Asthmatic Response to Allergen Exposure

Adapted from Barnes et al. [1998]; with permission.
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The LAR often resembles asthma, which is a chronic inflammatory disease. It is possible that repeated or prolonged episodes of LAR may approximate the events in the airways in both chronic allergic and nonallergic asthma.

"Airway remodeling"

The term airway remodeling is widely used to refer to the development of specific structural changes in the airway wall in asthma accompanying long-standing and severe airway inflammation [Murray and Nadel, 2000]. Airway remodeling and fibrosis may be the cause of "fixed" airflow obstruction in asthma that is not reversible with steroids, bronchodilators, or both. Interest has especially been focused on subepithelial collagen deposition, myofibroblast accumulation, airway smooth muscle hyperplasia and hypertrophy, mucous gland and goblet cell hyperplasia, and epithelial disruption (see figure below).

Processes in Airway Remodeling

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Although the presence of these features is accepted, further studies are required to define the changes that occur at the pathologic and ultrastructural levels and to determine whether these changes occur in small airways. The natural history of the response has not been well described. Remodeling occurs in the airways of asthmatic children and adults with newly diagnosed asthma, and studies that have attempted to relate the extent of remodeling to disease severity have produced conflicting findings. The role of remodeling in the progressive decline in lung function that leads to fixed airflow obstruction in some patients is also unclear.

Epidemiologic studies are currently hindered by the lack of a useful noninvasive marker of remodeling. Airway remodeling is frequently assumed to be a consequence of chronic inflammation, although the relationship between the remodeling and inflammatory components in asthma is unclear. The cellular and molecular events underlying the remodeling process are also poorly understood. The ability of antasthmatic therapies to prevent or reverse airway remodeling is uncertain.

References

Barnes PJ, Rodger IW, Thomson NC, eds. Asthma: Basic Mechanisms and Clinical Management. 3rd ed. San Diego, Calif.: Academic Press; 1998.

Murray JF, Nadel JA, eds. Textbook of Respiratory Medicine. Vol. 1, 3rd ed. Philadelphia, Pa.: W.B. Saunders; 2000.

Shier D, Butler J, Lewis R. Hole's Human Anatomy and Physiology. 7th ed. Dubuque, Iowa: William C Brown Publishers; 1996.

Copyright ©2001-2008 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved.

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