Asthma Pathophysiology Pathway Notes and Explanation with video Lecture

Asthma is a chronic inflammatory disorder of the airways. This feature of asthma has
implications for the diagnosis, management, and potential prevention of the disease.
 The immunohistopathologic features of asthma include inflammatory cell infiltration:
— Neutrophils (especially in sudden-onset, fatal asthma exacerbations; occupational
asthma, and patients who smoke)
— Eosinophils
— Lymphocytes
— Mast cell activation
— Epithelial cell injury
 Airway inflammation contributes to airway hyperresponsiveness, airflow limitation,
respiratory symptoms, and disease chronicity.
 In some patients, persistent changes in airway structure occur, including sub-basement
fibrosis, mucus hypersecretion, injury to epithelial cells, smooth muscle hypertrophy, and
angiogenesis.
 Gene-by-environment interactions are important to the expression of asthma.
 Atopy, the genetic predisposition for the development of an immunoglobulin E
(IgE)-mediated response to common aeroallergens, is the strongest identifiable
predisposing factor for developing asthma.
— Viral respiratory infections are one of the most important causes of asthma exacerbation
and may also contribute to the development of asthma.

Bronchoconstriction. In asthma, the dominant physiological event leading to clinical
symptoms is airway narrowing and a subsequent interference with airflow. In acute
exacerbations of asthma, bronchial smooth muscle contraction (bronchoconstriction) occurs
quickly to narrow the airways in response to exposure to a variety of stimuli including
allergens or irritants. Allergen-induced acute bronchoconstriction results from an
IgE-dependent release of mediators from mast cells that includes histamine, tryptase,
leukotrienes, and prostaglandins that directly contract airway smooth muscle (Busse and
Lemanske 2001). Aspirin and other nonsteroidal anti-inflammatory drugs (see section 3,
component 3) can also cause acute airflow obstruction in some patients, and evidence
indicates that this non-IgE-dependent response also involves mediator release from airway
cells (Stevenson and Szczeklik 2006). In addition, other stimuli (including exercise, cold air,
and irritants) can cause acute airflow obstruction. The mechanisms regulating the airway
response to these factors are less well defined, but the intensity of the response appears
related to underlying airway inflammation. Stress may also play a role in precipitating
asthma exacerbations. The mechanisms involved have yet to be established and may
include enhanced generation of pro-inflammatory cytokines.
 Airway edema. As the disease becomes more persistent and inflammation more
progressive, other factors further limit airflow (figure 2–2). These include edema,
inflammation, mucus hypersecretion and the formation of inspissated mucus plugs, as well
as structural changes including hypertrophy and hyperplasia of the airway smooth muscle.
These latter changes may not respond to usual treatment.

Airway hyperresponsiveness. Airway hyperresponsiveness—an exaggerated
bronchoconstrictor response to a wide variety of stimuli—is a major, but not necessarily
unique, feature of asthma. The degree to which airway hyperresponsiveness can be
defined by contractile responses to challenges with methacholine correlates with the clinical
severity of asthma. The mechanisms influencing airway hyperresponsiveness are multiple
and include inflammation, dysfunctional neuroregulation, and structural changes;
inflammation appears to be a major factor in determining the degree of airway
hyperresponsiveness. Treatment directed toward reducing inflammation can reduce airway
hyperresponsiveness and improve asthma control.
 Airway remodeling. In some persons who have asthma, airflow limitation may be only
partially reversible. Permanent structural changes can occur in the airway (figure 2–2);
these are associated with a progressive loss of lung function that is not prevented by or fully reversible by current therapy. Airway remodeling involves
an activation of many of the structural cells, with consequent permanent changes in the airway that increase
airflow obstruction and airway responsiveness and render
the patient less responsive to therapy (Holgate and Polosa
2006). These structural changes can include thickening of
the sub-basement membrane, subepithelial fibrosis, airway
smooth muscle hypertrophy and hyperplasia, blood vessel
proliferation and dilation, and mucous gland hyperplasia
and hypersecretion (box 2–2). Regulation of the repair and
remodeling process is not well established, but both the
process of repair and its regulation are likely to be key
events in explaining the persistent nature of the disease and
limitations to a therapeutic response

Mast cells. Activation of mucosal mast cells releases bronchoconstrictor mediators (histamine,
cysteinyl-leukotrienes, prostaglandin D2) (Boyce 2003; Galli et al. 2005; Robinson 2004).
Although allergen activation occurs through high-affinity IgE receptors and is likely the most
relevant reaction, sensitized mast cells also may be activated by osmotic stimuli to account for
exercise-induced bronchospasm (EIB). Increased numbers of mast cells in airway smooth
muscle may be linked to airway hyperresponsiveness (Brightling et al. 2002). Mast cells also can release a large number of cytokines to change the airway environment and promote
inflammation even though exposure to allergens is limited.
Eosinophils. Increased numbers of eosinophils exist in the airways of most, but not all,
persons who have asthma (Chu and Martin 2001; Sampson 2000; Williams 2004). These cells
contain inflammatory enzymes, generate leukotrienes, and express a wide variety of
pro-inflammatory cytokines. Increases in eosinophils often correlate with greater asthma
severity. In addition, numerous studies show that treating asthma with corticosteroids reduces
circulating and airway eosinophils in parallel with clinical improvement. However, the role and
contribution of eosinophils to asthma is undergoing a reevaluation based on studies with an
anti-IL-5 treatment that has significantly reduced eosinophils but did not affect asthma control
(Leckie et al. 2000). Therefore, although the eosinophil may not be the only primary effector cell
in asthma, it likely has a distinct role in different phases of the disease.
Neutrophils. Neutrophils are increased in the airways and sputum of persons who have severe
asthma, during acute exacerbations, and in the presence of smoking. Their pathophysiological
role remains uncertain; they may be a determinant of a lack of response to corticosteroid
treatment (Fahy et al. 1995). The regulation of neutrophil recruitment, activation, and alteration
in lung function is still under study, but leukotriene B4 may contribute to these processes
(Jatakanon et al. 1999; Wenzel et al. 1997; Wenzel 2006).
Dendritic cells. These cells function as key antigen-presenting cells that interact with allergens
from the airway surface and then migrate to regional lymph nodes to interact with regulatory
cells and ultimately to stimulate Th2 cell production from naïve T cells (Kuipers and Lambrecht
2004).
Macrophages. Macrophages are the most numerous cells in the airways and also can be
activated by allergens through low-affinity IgE receptors to release inflammatory mediators and
cytokines that amplify the inflammatory response (Peters-Golden 2004).
Resident cells of the airway. Airway smooth muscle is not only a target of the asthma
response (by undergoing contraction to produce airflow obstruction) but also contributes to it
(via the production of its own family of pro-inflammatory mediators). As a consequence of
airway inflammation and the generation of growth factors, the airway smooth muscle cell can
undergo proliferation, activation, contraction, and hypertrophy—events that can influence airway
dysfunction of asthma.
Epithelial cells. Airway epithelium is another airway lining cell critically involved in asthma
(Polito and Proud 1998). The generation of inflammatory mediators, recruitment and activation
of inflammatory cells, and infection by respiratory viruses can cause epithelial cells to produce
more inflammatory mediators or to injure the epithelium itself. The repair process, following
injury to the epithelium, may be abnormal in asthma, thus furthering the obstructive lesions that
occur in asthma.
Inflammatory Mediators
Chemokines are important in recruitment of inflammatory cells into the airways and are mainly
expressed in airway epithelial cells (Zimmermann et al. 2003). Eotaxin is relatively selective for
eosinophils, whereas thymus and activation-regulated chemokines (TARCs) and
macrophage-derived chemokines (MDCs) recruit Th2 cells.

Cytokines direct and modify the inflammatory response in asthma and likely determine its
severity. Th2-derived cytokines include IL-5, which is needed for eosinophil differentiation and
survival, and IL-4 which is important for Th2 cell differentiation and with IL-13 is important for
IgE formation. Key cytokines include IL-1β and tumor necrosis factor-α (TNF-α), which amplify
the inflammatory response, and granulocyte-macrophage colony-stimulating factor (GM-CSF),
which prolongs eosinophil survival in airways. Recent studies of treatments directed toward
single cytokines (e.g., monoclonal antibodies against IL-5 or soluble IL-4 receptor) have not
shown benefits in improving asthma outcomes.
Cysteinyl-leukotrienes are potent bronchoconstrictors derived mainly from mast cells. They
are the only mediator whose inhibition has been specifically associated with an improvement in
lung function and asthma symptoms (Busse 1996; Leff 2001). Recent studies have also shown
leukotriene B4 can contribute to the inflammatory process by recruitment of neutrophils (Gelfand
and Dakhama 2006).
Nitric oxide (NO) is produced predominantly from the action of inducible NO synthase in airway
epithelial cells; it is a potent vasodilator (Deykin et al. 2002; Strunk et al. 2003). Measurements
of fractional exhaled NO (FeNO) may be useful for monitoring response to asthma treatment
because of the purported association between FeNO and the presence of inflammation in
asthma (Green et al. 2002).
Immunoglobulin E
IgE is the antibody responsible for activation of allergic reactions and is important to the
pathogenesis of allergic diseases and the development and persistence of inflammation. IgE
attaches to cell surfaces via a specific high-affinity receptor. The mast cell has large numbers of
IgE receptors; these, when activated by interaction with antigen, release a wide variety of
mediators to initiate acute bronchospasm and also to release pro-inflammatory cytokines to
perpetuate underlying airway inflammation (Boyce 2003; Sporik et al. 1995). Other cells,
basophils, dendritic cells, and lymphocytes also have high-affinity IgE receptors.
The development of monoclonal antibodies against IgE has shown that the reduction of IgE is
effective in asthma treatment (Busse et al. 2001; Holgate et al. 2005). These clinical
observations further support the importance of IgE to asthma.