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.


CHEST. 2000;118(5) 

In This Article

The Lipoxygenase Pathway

Cysteinyl LTs are derived from arachidonic acid via the 5-lipoxygenase (LO) pathway (Fig 1). The cellular biosynthesis of LTs involves 5-LO activating protein, which transports arachidonic acid into the cytosol to be acted on by the enzyme 5-LO. The sequential catalytic action of 5-LO on arachidonic acid yields LTA4, which is further hydroxylated to LTB4 or is converted into the first of the cysteinyl LTs, LTC4,by LTC4 synthase. LTC4 is exported to the extracellular space where it forms LTD4, which in turn is cleaved to form the 6-cysteinyl analog of LTC4 known as LTE4. The cysteinyl LTs exert their biological action by binding to two types of G-protein-coupled 7-transmembrane receptors, CysLT1 and CysLT2.

Figure 1.

Aspirin inhibits the COX pathway and consequently diverts arachidonic acid metabolites to the LO pathway. This also leads to a decrease in the levels of PGE2, the anti-inflammatory PG. LTC4 synthase overexpression further increases the number of cysteinyl LTs, tilting the balance toward inflammation.

Aspirin-induced bronchoconstriction is thought to be caused by the shunting of the arachidonic acid metabolism away from the cyclooxygenase (COX) pathway toward the LO pathway. This results in the increased production of LTs with the resultant bronchoconstriction. Consistent with this finding, bronchoconstriction in patients with AIA can be inhibited by LT receptor antagonists. [6]

Provocation with aspirin in AIA patients produces airflow obstruction accompanied by the release of cysteinyl LTs into the urine and BAL fluid. [7,8] LTC4 synthase is the rate-limiting enzyme for the synthesis of cysteinyl LTs. Bronchial biopsy studies have revealed an overexpression of LTC4 synthase in patients with AIA as compared to aspirin-tolerant asthma (ATA) patients. [9] The gene for LTC4 synthase has been localized to chromosome 5q, telomeric to other candidate genes, including interleukin (IL)-3, IL-4, IL-5, and granulocyte macrophage colony-stimulating factor, which also have been implicated in asthma pathogenesis. [10] A genetic variant of LTC4 synthase gene promoter has been described, which is overexpressed in the AIA population. [11] However, 30% of patients with AIA do not have a predisposing variant of the LTC4 synthase gene, whereas 25% of the control subjects do have it without any consequence to their health. [12] Although this will not explain the pathophysiology of AIA in all patients in the population, such a finding is common in conditions with multifactorial inheritance and is predictable on the basis of nonmendelian low inheritance of AIA. The normal expression of 5-LO in patients with AIA precludes 5-LO as a contributing factor in the pathogenesis of AIA. [13]

Overexpression of the LTC4 synthase in the bronchial wall may be the single most important determinant of acute respiratory reactions to aspirin in subjects with AIA. In addition, the removal of the prostaglandin (PG) E2 brake in all subjects by NSAIDs, as described later, leads to exaggerated cysteinyl LT synthesis only in AIA patients due to the altered threshold activity of LTC4 synthase in their bronchial wall.


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