Abstract
BackgroundMast cells play a critical role in allergic and inflammatory diseases, including exercise-induced bronchoconstriction (EIB) in asthma. The mechanism underlying EIB is probably related to increased airway fluid osmolarity that activates mast cells to the release inflammatory mediators. These mediators then act on bronchial smooth muscle to cause bronchoconstriction. In parallel, protective substances such as prostaglandin E2 (PGE2) are probably also released and could explain the refractory period observed in patients with EIB.ObjectiveThis study aimed to evaluate the protective effect of PGE2 on osmotically activated mast cells, as a model of exercise-induced bronchoconstriction.MethodsWe used LAD2, HMC-1, CD34-positive, and human lung mast cell lines. Cells underwent a mannitol challenge, and the effects of PGE2 and prostanoid receptor (EP) antagonists for EP1–4 were assayed on the activated mast cells. Beta-hexosaminidase release, protein phosphorylation, and calcium mobilization were assessed.ResultsMannitol both induced mast cell degranulation and activated phosphatidyl inositide 3-kinase and mitogen-activated protein kinase (MAPK) pathways, thereby causing de novo eicosanoid and cytokine synthesis. The addition of PGE2 significantly reduced mannitol-induced degranulation through EP2 and EP4 receptors, as measured by beta-hexosaminidase release, and consequently calcium influx. Extracellular-signal-regulated kinase 1/2, c-Jun N-terminal kinase, and p38 phosphorylation were diminished when compared with mannitol activation alone.ConclusionsOur data show a protective role for the PGE2 receptors EP2 and EP4 following osmotic changes, through the reduction of human mast cell activity caused by calcium influx impairment and MAP kinase inhibition.
Highlights
Asthma is a complex chronic inflammatory disease of the airways that involves the activation of many inflammatory and structural cells
Our data show a protective role for the prostaglandin E2 (PGE2) receptors EP2 and EP4 following osmotic changes, through the reduction of human mast cell activity caused by calcium influx impairment and MAP kinase inhibition
MO); anti-p38 Thr180/Tyr182, anti–p-ERK Thr202/Tyr204, and anti–p-JNK (i.e., c-Jun N-terminal kinase) Thr183/Tyr185 (Cell Signaling Technology, Danvers, MAs); pAKT antibody was from Santa Cruz Biotechnology, Santa Cruz, CA); PGE2 and antibodies against the EP (Prostaglandin E2) receptors were from Cayman Chemical (Ann Arbor, MI), except for EP-4 (Abcam, Cambridge, UK); EP1/EP2 antagonist receptor AH6809 and EP4 antagonist receptor AH23848 (Sigma); and EP3 antagonist receptor L-826266 (Merck, Darmstadt, Germany)
Summary
Asthma is a complex chronic inflammatory disease of the airways that involves the activation of many inflammatory and structural cells. The osmotic theory proposes that the primary effect of airway water loss is the induction of an increased osmolality in the airway surface liquid [4] that stimulates the release of various mediators via mast cell mechanisms. Both the epithelium and eosinophils may be involved in the generation of EIB-related mediators [5,6]. The mechanism underlying EIB is probably related to increased airway fluid osmolarity that activates mast cells to the release inflammatory mediators These mediators act on bronchial smooth muscle to cause bronchoconstriction. Protective substances such as prostaglandin E2 (PGE2) are probably released and could explain the refractory period observed in patients with EIB
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