Aspirin and Asthma

K. Suresh Babu, MD, DNB; and Sundeep S. Salvi, MD, DNB, PhD, From the Department of Respiratory Cell and Molecular Biology, University of Southampton, Southampton General Hospital, Southampton, UK.

Disclosures

CHEST. 2000;118(5) 

In This Article

The COX Pathway

The metabolism of arachidonic acid via the COX pathway leads to the generation of prostanoids, which are important signaling molecules that are produced both in normal physiologic as well as in inflammatory conditions. The airway inflammatory cells produce both proinflammatory prostanoids like PGD2 and PGF2alpha and anti-inflammatory PGs like PGE2.[14,15]

The notion that asthma exacerbations might result from the specific inhibition of a single enzyme (namely, COX) has gained both experimental and clinical support. The COX enzymes exist in two isoforms, COX-1 and COX-2. COX-1 is the housekeeping enzyme expressed in cells at baseline, while COX-2 is induced during inflammation and mainly enhances synthesis of inflammatory prostanoids. The results of bronchial biopsy studies show no difference in expression of COX-1 or COX-2 between subjects with and without AIA. [16] In addition, airway lavage fluid after ASA-lysine does not show any alteration in the levels of COX-1 and COX-2 in patients with AIA. [9] The results of segmental bronchial challenge with aspirin in patients with AIA and ATA have revealed no changes in the levels of PGD2, PGF2alpha, and PGF2 in the AIA group, but have demonstrated significantly decreased levels in the ATA group, who acted as control subjects. The levels of PGE2 and thromboxane B2 were decreased in the AIA and the ATA groups. [17] The normal levels of PGD2,PGF2alpha, and PGF2 in the AIA group, in contrast to the decreased levels of proinflammatory eicosanoids and the decreased levels of PGE2, produce a characteristic disturbance leading to the precipitation of an asthmatic attack. Hence, the altered synthesis of some PGs after interaction with ASA/NSAIDs and COX enzymes seems crucial in the pathogenesis of AIA.

The initial event in AIA appears to be the interruption of the synthesis of PGE2. PGE2 has profound regulatory effects on other inflammatory systems. It reduces LT synthesis by inhibiting 5-LO, inhibits cholinergic transmission, prevents mediator release from mast cells, and prevents ASA-precipitated bronchoconstriction. [12] Hence, it is possible that PGE2 may act as a brake for the inflammatory responses. Alterations in the COX pathway by NSAIDs in patients with AIA might suggest an anomaly of COX-1 or COX-2, but no evidence of genetic polymorphism or mutation has been reported in AIA patients. Alternatively, in the presence of aspirin, COX-2 is modified enzymatically to form 5-hydroxyeicosatetraenoic acid instead of PGs. [18] This putative pathway could generate 5-LO products and could account for the effects of AIA.

The evidence that supports the role of COX in the pathogenesis of AIA includes the following: (1) precipitation of bronchoconstriction by NSAIDs with anti-COX activity, while NSAIDs deprived of this activity are well-tolerated; (2) a positive correlation with the potency of NSAIDs to inhibit COX and their potency to induce asthmatic attacks; and (3) cross-desensitization to other NSAIDs after desensitization to aspirin.

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