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Stachler
Inflammatory mechanisms
Local inflammation occurs when an inhaled antigen causes
an IgE-mediated type 1 hypersensitivity reaction. This ini-
tiates an inflammatory cascade, characterized by mast cell
degranulation. Preformed mediators including histamine,
kinins, and proteases are released, which causes chemotaxis
and migration of other sensitized mast cells, neutrophils,
basophils, eosinophils, T lymphocytes, and macrophages
across a mucosal endothelium into the local area (nose or
bronchial mucosa) and submucosa. Vascular leakage and
interstitial edema occur, causing pruritis, rhinorrhea, nasal
congestion, and sneezing.
46
This response is linked by up-
regulated systemwide inflammatory mediators at distal sites
in the respiratory tract (lined by pseudostratified colum-
nar epithelium).
41,47–49
Braunstal et al.
41,48,49
and Geor-
gopoulos et al.
47
noted in a series of studies that antigens
placed in the nose resulted in upregulation of inflamma-
tory mediators in the distal bronchi. Similarly, they noted
that antigen placement into the bronchi with a broncho-
scope resulted in upregulation of inflammatory mediators
in the nose. Interactions between inflammatory cells, mast
cells, alveolar macrophages, eosinophils, lymphocytes, neu-
trophils, basophils and associated mediators, histamine,
leukotrienes, prostaglandin D
2
, and platelet-activating fac-
tor cause bronchial smooth muscle contraction.
7,50
This
late-phase response will occur several hours after an initial
response because it requires an influx of inflammatory cells
and can lead to chronic changes. The eosinophils seem to
have the greatest increase in proportion to other inflamma-
tory cells in this timeframe.
50,51
These reactions show that
allergic changes in one area can effect the whole unified
airway. This links the allergic reactions to distal locations
in the unified airway.
Eosinophils and their release of their cationic pro-
teins (major basic protein [MBP], eosinophil cationic
protein [ECP], peroxidase, and eosinophil-derived
neurotoxin [EDN]) is the cardinal feature of allergic
pathophysiology.
52–54
The eosinophil is drawn to the
inflammatory reaction by the T helper 2 (TH2) cy-
tokine interleukin 5 (IL-5).
55
IL-5 mediates eosinophil
expansion, priming, recruitment, and prolonged tissue
survival in allergic reactions.
55
IL-5, IL-4, IL-13, and
eotaxins (eosinophil-specific chemokines) are responsible
for promoting the eosinophil-mediated inflammatory
responses.
55
Endothelial adhesion proteins, intercellular
adhesion molecule-1 (ICAM-1), and vascular cell ad-
hesion molecule-1 (VCAM1) assist in the migration of
neutrophils, lymphocytes, and eosinophils from the in-
travascular space into the airway.
50,56–59
Other cells in the
inflammatory process, mast cells, release their mediators
and histamine causing leukotrienes to be created, which
cause bronchoconstriction. The eosinophil release of the
toxic proteins causes endothelial cell damage and airflow
obstruction.
50
Histologically, these processes create the
mucosal edema, submucosal gland and bronchial smooth
muscle hypertrophy, mucous hypersecretion, basement
membrane thickening, and fibrosis classically seen in
asthma.
50,60–62
Systemic, neurogenic mechanisms
Neuronal stimulation in the nose can result in the re-
lease of cholinergic neurotransmitters and contraction of
the bronchial smooth muscle.
63,64
This reaction links a lo-
cal response to a systemic, distal location. Furthermore,
there is strong evidence that links the distribution of in-
flammatory mediators from an initial inflammatory site
to lymphoid tissue
65
and marrow, amplifying the inflam-
matory responses across the nasal passages, sinuses, and
lower airways. Increased blood eosinophil and IL-5 levels
in the upper and lower airways were shown when a single
antigen challenge was administered to nonasthmatic sub-
jects with seasonal allergy.
66
Bronchial hyperresponsive-
ness was noted when atopic patients with AR and asthma
were given a nasal challenge.
67
Nasal challenges in aller-
gic patients without asthma resulted in increased bronchial
expression of adhesion molecules (VCAM-1, ICAM-1, and
endothelial-leukocyte adhesion molecule 1). As discussed
previously in the inflammatory mechanisms section, these
molecules are responsible for assisting in the transport of
the eosinophil from the circulation into the airway, reduc-
ing the peak expiratory airflow
41
as the numbers of the cells
in the area increase and the inflammation from the reaction
begins to augment.
Bronchial challenge with antigens, in nonasthmatic, al-
lergic patients, resulted in an intense nasal inflammatory
reaction causing immune cell degranulation, and increased
IL-5 levels in peripheral blood.
49
This suggests that stimu-
lation can occur anywhere within the unified airway.
Neuroregulatory mechanisms from vagal nerve acti-
vation may cause bronchoconstriction of the bronchial
smooth muscle. Neuromediators, substance P and calci-
tonin gene–related peptide, modulate the release of his-
tamine and bradykinin, which cause unrestricted passage
of proteins and fluid through the vascular epithelium. Di-
rect cholinergic neurotransmitter release may cause stimu-
lation of the bronchial smooth muscle.
68–70
The results is
bronchoconstriction, which is a defining characteristic of
asthma.
Chronicity of asthma
Asthma is a chronic disease of the lower airways that has
3 defining characteristics: (1) airway inflammation; (2) re-
versible airway obstruction, in most cases; and (3) increased
airway responsiveness to extrinsic stimuli.
71
The inflamma-
tion that is the hallmark of asthma may be present for many
years and is undetectable until the symptoms of asthma be-
gin to appear. As described previously, in the prior two
sections, the eosinophil appears to be the key inflamma-
tory cell in the destructive process at the cellular level.
The chronic inflammation that develops causes airway
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