PATHOGENESIS

Asthma is state as an inflammatory condition of the airways. The acute attack of asthma
induced by aspirin an other NSAIDs which is similar to the immediate hypersensitivity
reaction which might to be mediated by IgE-dependent mechanisms. However, the skin
test responses with ASA lysine and IgE antibodies against either aspirin or NSAIDs are
negative in patients receiving aspirin-induced asthma (AIA). So, the reactions could be
termed as anaphylactoid because of the hypersensitivity reaction might be mediated by
IgE-independent mechanisms. The biochemical pathways involved in aspirin-sensitive
asthma are not fully established. However, aspirin hypersensitivity is likely to be mediated
by a deviation of the arachidonic acid metabolic pathway toward excessive leukotriene
(LT) production. Overproduction of cysteinyl-leukotrienes (cys-LTs) in the bronchial tree
and inhibition of prostaglandin synthesis by COX inhibitors appear to be main factors in
the pathogenesis.
The Cyclo-Oxygenase Pathway
The cyclo-oxygenase (COX) pathway converts arachidonic acid to prostaglandins,
prostacyclin and thromboxane A2. There are two isoforms of COX, namely COX-1 which
is constitutively expressed in most tissues and blood platelets and involved in cellular
housekeeping functions and COX-2 which is induced by inflammatory stimuli such as
growth factors, cytokines and mitogens in fibroblasts and by bacterial lipopolysaccharide
in monocytes and macrophages. 1
The evidence, which supports the COX theory, is as follows: (1) NSAIDs with anti-COX
activity precipitate bronchoconstriction in aspirin-sensitive patients, while NSAIDs
deprived of this activity are well-tolerated; (2) there is a positive correlation between the
potency of NSAIDs to inhibit COX in vitro and their potency to induce asthma attacks in
the sensitive patients; (3) after aspirin desensitization, cross-desensitization to other
NSAIDs which inhibit COX also occurs.2
There are two major pathway of arachidonic acid cascade: cyclooxygenase (COX) and
leukotriene pathways. Both of them play an important role in the production of
inflammatory and anti-inflammatory mediators.
Aspirin like drugs are precipitated the asthma attack due to the inhibition of COX in
airways of the sensitive patients. Airway lavage fluid after ASA-lysine challenge showed
significant decrease in PGE2 and thromboxane B2 (TXB2) level in AIA and asthmatics
tolerant to aspirin (ATA) groups. It was suggested that asthmatic bronchospasm may be
due to overproduction of the bronchoconstrictor PGF at the expense of the bronchodilator
PGE2 due to altered COX response. There was no difference between AIA and ATA groups
with relation to COX 1 and COX 2 expression. Prostaglandin E2 inhibits of inflammatory
mediator release from mast cells, eosinophils and macrophages. It slows down leukotriene
synthesis and inhibits LTB4 and superoxide release from polymorphonuclear leukocytes.
There is depression of basal generation of PGE2 by epithelial cells from nasal polyps.
Thus, aspirin/NSAIDs induced defective synthesis of PGE2 might be one of molecular
disturbances observed in AIA and leading to the precipitation of asthmatic attacks. In the
presence of aspirin, COX-2 is modified enzymatically to form 5-hydroxyeicosatetraenoic
acid, especially prostaglandin E2 (PGE2) that inhibits leukotriene biosynthesis. 5-
hydroxyeicosatetraenoic acid stimulates 5-lipoxygenase (5-LO) that generate 5-LO
products and could count for the effects of AIA.1

The Leukotriene Pathway

Of primary importance in AIA is the chronic overproduction of cys-LTs, even in the
absence of aspirin challenge. Cys-LTs are potent bronchoconstrictors, cause mucosal
edema, vasoconstriction and mucus hypersecretion, and are important chemoattractants for
eosinophils in human airways. Their biologic activities are mediated through interaction
with cys-LT receptors. Cys-LT1 receptor is expressed in human lung smooth-muscle cells
and macrophages, in peripheral blood eosinophils and CD34+ cells, monocytes, basophils
and B-lymphocytes.2
1. Aspirin Induced Asthma- a Review
2. Diagnosis, Prevention and Treatment of Aspirin-Induced Asthma and Rhinitis