Asthma

• Asthma is a chronic inflammatory disease characterized by episodic airway

obstruction and airway hyperresponsiveness usually accompanied by airway
inflammation
• Most of the times the airway obstruction is reversible, but in a subset of
asthmatics, a component of the obstruction may become irreversible
• Asthma most frequently presents as episodic shortness of breath, wheezing,
and cough, these symptoms can occur in combination or separately, which
can occur in relation to triggers but may also occur spontaneously. Other
symptoms can include chest tightness and/or mucus production.
• These symptoms can resolve spontaneously or with therapy. In some
patients, wheezing and/or dyspnoea can be persistent.
• Episodes of acute bronchospasm, known as exacerbations, may be severe
enough to require emergency medical care or hospitalization and may result
in death.
• Asthma is the one of the most common chronic disease with ∼241
million people affected globally.
• Cross-sectional studies suggest that 7.9% of the population in the
United States suffers from asthma as compared to ∼4.3% prevalence
worldwide.
• Prevalence continues to increase (starting at 7.3% in 2001 in the
United States) and is associated with transition from rural to urban
living.
• Asthma is more prevalent among children (8.4%) than adults (7.7%).
In children, the prevalence is greatest among boys (2:1 male-to-
female ratio), with a trend toward greater prevalence in women in
adulthood.
• Asthma Development Pathway
Pathophysiology
• Asthma is associated with a specific chronic inflammation of the mucosa of the
lower airways. One of the main aims of treatment is to reduce this inflammation.
• Airway Inflammation
• There is inflammation in the respiratory mucosa from the trachea to terminal
bronchioles, but with a predominance in the bronchi (cartilaginous airways).
• The pattern of inflammation in asthma is characteristic of allergic diseases, with
similar inflammatory cells seen in the nasal mucosa in rhinitis.
• However, an indistinguishable pattern of inflammation is found in non allergic
asthma, and this may reflect local rather than systemic IgE production.
• the common pattern of inflammation in asthma is characterized by eosinophil
infiltration, some patients with severe asthma show a neutrophilic pattern of
inflammation that is less sensitive to corticosteroids. However, many
inflammatory cells are involved in asthma with no key cell that is predominant
• MAST CELLS
• Mast cells are important in initiating the acute bronchoconstrictor responses to
allergens and several other indirectly acting stimuli, such as exercise, fog etc.
• Activated mucosal mast cells are found at the airway surface in asthma patients
and also in the airway smooth-muscle layer.
• Mast cells are activated by allergens through an IgE-dependent mechanism, and
binding of specific IgE to mast cells makes them more sensitive to be activated by
physical stimuli such as osmolality.
• The importance of IgE in the pathophysiology of asthma has been found with
humanized anti-IgE antibodies, which inhibit IgE mediated effects, reduce
asthma symptoms, and reduce exacerbations.
• There are uncertainties about the role of mast cells in more chronic allergic
inflammatory events.
• Mast cells release several bronchoconstrictor mediators, including histamine,
prostaglandin D2, and cysteinyl-leukotrienes, but also several cytokines,
chemokines, growth factors, and neurotrophins.
• EOSINOPHILS
• Eosinophil infiltration is a characteristic feature of asthmatic airways.
• Allergen inhalation results in a marked increase in activated eosinophils in the
airways at the time of the late reaction.
• Eosinophils are linked to the development of AHR through the release of basic
proteins and oxygen-derived free radicals.
• Eosinophil recruitment involves adhesion of eosinophils to vascular endothelial
cells in the airway circulation due to interaction between adhesion molecules,
migration into the submucosa under the direction of chemokines, and their
subsequent activation and prolonged survival
• Blocking antibodies to IL-5 causes a profound and prolonged reduction in
circulating and sputum eosinophils, but is not associated with reduced AHR or
asthma symptoms.
• Eosinophils may be important in release of growth factors involved in airway
remodeling and in exacerbations but probably not in AHR.
• MACROPHAGES AND DENDRITIC CELLS
• Macrophages, which are derived from blood monocytes, may available in high number into
the airways in asthma and may be activated by allergens via low-affinity IgE receptors.
• Macrophages have the capacity to initiate a type of inflammatory response via release of a
certain pattern of cytokines, they also release anti-inflammatory mediators like IL-10, so,
their roles in asthma are uncertain.
• Dendritic cells are specialized macrophage-like cells in the airway epithelium, which are the
major antigen-presenting cells.
• Dendritic cells take up allergens, process them to peptides, and migrate to local lymph
nodes where they present the allergenic peptides to uncommitted T lymphocytes to
program the production of allergen-specific T cells.
• Immature dendritic cells in the respiratory tract promote T helper cell differentiation, and
require cytokines such as IL-12 and tumor necrosis factor a to promote the dominate
response of T helper cells.
• The cytokine thymic stromal lymphopoietin (TSLP) released from epithelial cells in asthmatic
patients instructs dendritic cells to release chemokines that attract T helper cells into the
airways.
 Pathophysiological changes
• Airway Hyperresponsiveness: It is a hallmark of asthma
• It is defined as an acute narrowing response of the airways in reaction to agents that
do not elicit airway responses in nonaffected individuals or an excess narrowing
response to inhaled agents as compared to that which would occur in nonaffected
individuals.
• It may be due to indirect activation of airway narrowing mechanisms because of
stimulation of inflammatory cells which release direct bronchoconstrictors and
mediators that cause airway edema and/or mucus secretion and/or stimulation of
sensory nerves that can act on the smooth muscle or inflammatory cells.
• Airway wall thickness is associated with disease severity and duration, this may result
from a combination of smooth-muscle hypertrophy and hyperplasia, subepithelial
collagen deposition, airway edema, and mucosal inflammation etc.
• A major therapeutic objective in asthma is to decrease the degree of airway
hyperresponsiveness.
• Inflammatory Cells
• While airway inflammation can be precipitated by acute exposure to inhalants
but many patients have evidence of chronic inflammation in the airways.
• Most commonly, this inflammation is eosinophilic in nature. In some patients,
neutrophilic inflammation may be predominant, especially in those with more
severe asthma, mast cells are also more frequent .

• Airway Smooth Muscle

• Airway smooth muscle can contribute to asthma in three ways:
• First, it can be hyperresponsive to stimuli, Second, hypertrophy and hyperplasia
can lead to airway wall thickening with consequences for hyperresponsiveness,
and Third, airway smooth-muscle cells can produce chemokines and cytokines
that promote airway inflammation and promote the survival of inflammatory
cells, particularly mast cells.
• Subepithelial collagen deposition and Matrix deposition
• Thickening of the subepithelial basement membrane occurs as a result of deposition
of repair-type collagens and tenascin, periostin, fibronectin, and osteopontin,
primarily from myofibroblasts under the epithelium.
• The deposition of collagen and matrix stiffens the airway and can result in
exaggerated responses to increased circumferential tension exerted by the smooth
muscle.
• Such deposition can also narrow the airway lumen and decrease its ability to relax
and thus can contribute to chronic airway obstruction.
• Airway Epithelium
• Airway epithelium disruption takes where columnar cells get separated from the
basal cells.
• The damaged epithelium is believed to form a unit with the underlying mesenchyme.
This unit elaborates multiple growth factors thought to contribute to airway
remodeling as well as multiple cytokines and mediators that promote asthmatic
airway inflammation
• Vascular Proliferation
• There is a significant degree of angiogenesis believed to be secondary to elaboration of angiogenic
factors in the context of airway inflammation.
• Inflammatory mediators can result in leakage from postcapillary venules, which can contribute to the
acute and chronic edema of the airways.

• Airway Edema
• Submucosal edema can be present as an acute response in asthma and as a chronic contributor to
airway wall thickening.

• Epithelial Goblet Cell Metaplasia and Mucus Hypersecretion

• Chronic inflammation can result in the appearance and proliferation of mucus cells. Increased mucus
production can reduce the effective airway luminal area. Mucus plugs can obstruct medium-size
airways and can extend into the small airways.

• Neuronal Proliferation
• Neurotrophins, which can lead to neuronal proliferation, are elaborated by smooth-muscle cells,
epithelial cells, and inflammatory cells. Neuronal inputs can regulate smooth-muscle tone and mucus
production, which may mediate acute bronchospasm and potentially chronically increased airway
Airway Inflammation
• Most asthma is accompanied by airway inflammation.
• In the past, asthma had been divided into atopic and nonatopic (or
intrinsic) asthma.
• Atopic identified as relating to allergen sensitivity and exposure, with
production of IgE, and occurring more commonly in children.
• Nonatopic (or intrinsic) identified as occurring in individuals with later
onset asthma, with or without allergies, but frequently with eosinophilia.
• Now a days these inflammations are divided in type 2 or non–type 2
inflammation.
• This immunologic classification is driven by a developing understanding of
the underlying immune processes and by the development of therapeutic
approaches that target type 2 inflammation
• Type 2 Inflammation :
• It is called type 2 because it is associated with the type 2 subset of CD4+ T-helper
cells
• It is an immune response involving the innate and adaptive arms of the immune
system to promote barrier immunity on mucosal surfaces.
• CD4+ T-helpers produce the cytokines interleukin (IL) 4, IL-5, and IL-13, which are
capable to produce multiple effects.
• IL-4 induces B-cell isotype switching to production of IgE, through its binding to
basophils and mast cells, results in environmental sensitivity to allergens as a result
of cross-linking of IgE on the surface of these mast cells and basophils, the products
released from these cells include type 2 cytokines as well as direct activators of
smooth-muscle constriction and edema.
• IL-5 has a critical role in regulating eosinophils, it controls formation, recruitment,
and survival of these cells.
• IL-13 induces airway hyperresponsiveness, mucus hypersecretion, and goblet cell
metaplasia.
• While allergen exposure in allergic individuals can elicit a cascade of
activation of type 2 inflammation.
• These cells can produce IL-5 and IL-13. ILC2s can be activated by epithelial
cytokines known as alarmins, which are produced in response to
“nonallergic” epithelial exposures such as irritants, pollutants, oxidative
agents, fungi, or viruses. Thus, these “nonallergic” stimuli can be
associated with eosinophilia.
• The development of anti–IL-5 drugs that dramatically reduce eosinophils,
that has determined that, in many asthmatics, eosinophils play a major
role in asthma pathobiology.
• They may induce hyperresponsiveness through release of oxidative radicals
and major basic protein, which can disrupt the epithelium.