Primary and Secondary Effector Cells in the Pathogenesis of Bronchial Asthma

Abstract

The immediate and late asthmatic reactions provoked by inhaled allergens have provided useful models enabling the dissection of individual inflammatory cells and their mediators that may contribute to the pathogenesis of asthma. The immediate reaction is considered to be mast cell-mediated on the basis that about 50% of the response is inhibitable by potent and selective H₁-receptor antagonists such as terfenadine and astemizole. Additional inhibition (∼30%) by the potent cyclooxygenase inhibitor flurbiprofen implies an important role for prostanoids in the immediate response, the most likely mast cell-derived product being prostaglandin (PG) D₂. In man, PGD2 is selectively metabolised to 9α1 1β-PGF₂, a unique prostaglandin which shares with PGD₂ contractile properties on guinea-pig and human airways smooth muscle. The inability of piriprost, a potent leukotriene synthesis inhibitor, to influence the allergen-provoked immediate reaction raises the possibility that sulphidopeptide leukotrienes play a minor role in this response. The late asthmatic reaction is considered to resemble clinical asthma since it is accompanied by increased responsiveness of the airways to a wide range of stimuli. The late reaction in man is inhibited by nedocromil sodium (4 mg) but only marginally attenuated by salbutamol (200 μg) if both drugs are administered prior to allergen challenge. Since salbutamol, in the dose administered, is a potent mast cell-stabilising agent, these findings must question the obligatory role of mast cell mediator release in the pathogenesis of the late response. A model of the late reaction in conscious guinea-pigs demonstrates a selective influx of neutrophils followed by eosinophils 6–12 h after challenge in relation to the late reaction, suggesting a role for these secondary effector cells in mediating this response and possibly the acquisition of increased bronchial responsiveness. These human and animal studies demonstrate a complex interaction of primary and secondary effector cells in the pathogenesis of bronchoconstrictor responses to allergen and should help to clarify the contribution of ‘inflammation’ to clinical asthma.

Interleukin-8 plays a significant role in IgE-mediated lung inflammation

“…Sensitized asthmatics exposed to allergen exhibit dramatic lung inflammatory responses [23,24]. The stimuli that induce inflammatory responses likely involve a myriad of cells and mediators.…”

Cytokines induce selective granulocyte chemotactic responses

“…Sensitized asthmatics exposed to allergen exhibit dramatic lung inflammatory responses [24,25]. Neutrophils and eosinophils are key immune effector cells in allergic inflammatory responses in the airways [24,25].…”

“…Neutrophils and eosinophils are key immune effector cells in allergic inflammatory responses in the airways [24,25]. The stimuli that induce granulocytes to migrate to sites of inflammation in the airway are not definitively known.…”

Aspirin‐induced asthma as a viral disease

“…The cytotoxic reaction can be amplified by leukotriene B4 [37], generation of which becomes enhanced in the absence of inhibitory action of PGE2 [19]. Furthermore, eosinophils and neutrophils, present in the bronchial tissue of asthmatic patients [38], might add to the irritating and toxic effects of lymphocyte cytolysis through superoxide anions generation, facilitated greatly by the inhibition of production of PGE2 [39].…”