Adenosine A₁ and Prostaglandin E Receptor 3 Receptors Mediate Global Airway Contraction after Local Epithelial Injury

Abstract

Epithelial injury and airway hyperresponsiveness are prominent features of asthma. We have previously demonstrated that laser ablation of single epithelial cells immediately induces global airway constriction through Ca(2+)-dependent smooth muscle shortening. The response is mediated by soluble mediators released from wounded single epithelial cells; however, the soluble mediators and signaling mechanisms have not been identified. In this study, we investigated the nature of the epithelial-derived soluble mediators and the associated signaling pathways that lead to the L-type voltage-dependent Ca(2+) channel (VGCC)-mediated Ca(2+) influx. We found that inhibition of adenosine A1 receptors (or removal of adenosine with adenosine deaminase), cyclooxygenase (COX)-2 or prostaglandin E receptor 3 (EP3) receptors, epidermal growth factor receptor (EGFR), or platelet-derived growth factor receptor (PDGFR) all significantly blocked Ca(2+) oscillations in smooth muscle cells and airway contraction induced by local epithelial injury. Using selective agonists to activate the receptors in the presence and absence of selective receptor antagonists, we found that adenosine activated the signaling pathway A1R→EGFR/PDGFR→COX-2→EP3→VGCCs→calcium-induced calcium release, leading to intracellular Ca(2+) oscillations in airway smooth muscle cells and airway constriction.

Sputum microRNA‐screening reveals Prostaglandin EP3 receptor as selective target in allergen‐specific immunotherapy

“…PTGER3, the prostaglandin EP 3 receptor (EP 3 ), is one of four receptors for prostaglandin E 2 (PGE 2 ) and is involved in bronchoconstriction. 37,38 PTGER3 showed a counter regulation to miR-3935 as expected (Figure 4F, Figure S1E-F), which was underlined by the inverse correlation between miR-3935 and its predicted target PTGER3 (Figure 4G; r = −0.57; p = .0294).…”

“…On the other hand, 661 genes were predicted as targets of the upregulated miRs (Figure 4E, Table ; Figure ; Table ), of which only one gene (PTGER3) was also significantly downregulated on the mRNA level in the same samples. PTGER3, the prostaglandin EP 3 receptor (EP 3 ), is one of four receptors for prostaglandin E 2 (PGE 2 ) and is involved in bronchoconstriction 37,38 . PTGER3 showed a counter regulation to miR‐3935 as expected (Figure 4F, Figure E‐F), which was underlined by the inverse correlation between miR‐3935 and its predicted target PTGER3 (Figure 4G; r = −0.57; p = .0294).…”

“…72 Previous studies have mainly focussed on the effect of PGE 2 in inflammatory processes exerted through the EP 2 and EP 4 receptors; however, its effect via the EP 3 receptor is not well understood and remains to be elucidated in further detail. Studies in human and guinea pig systems suggest a broncho-constrictive effect of PGE 2 -EP 3 signalling, 37,38 thus suggesting that miR-mediated downregulation of EP 3 expression upon AIT may have beneficial effects on lung function in asthmatic patients.…”

A microphysiological model of the bronchial airways reveals the interplay of mechanical and biochemical signals in bronchospasm

“…Similar rapid responses have been observed in recent studies using ex vivo lung-tissue slices from rats, where local injury to a single epithelial cell triggered an instantaneous Ca 2+ wave throughout the epithelium and induced ASM contraction within several seconds that lasted for tens of seconds (54). It was observed that epithelial injury triggered the release of ATP, and airway contraction was completely blocked by selective inhibition of COX2 (55). While, in these studies, the ASM contraction was triggered by an injury to the epithelium, our study suggests that mechanically stimulating the epithelium can be sufficient to obtain similar results.…”

Selective Inhibition of NF-κB and Surfactant Therapy in Experimental Meconium-Induced Lung Injury

“…Recently, it has been shown that COX-2 induction in airway smooth muscle cells and COX-2-derived lung inflammation may be triggered also via PI3K/Akt/NF-κB pathway after activation of EGFR/PDGFR ). These receptors can be rapidly activated by adenosine released from injured epithelial cells, leading to immediate COX-2-mediated airway constriction (Zhou et al 2013). Taken together, in meconium-polluted airways where multiple agents including phospholipase A2 can directly damage epithelial cells, inhibition of NF-κB-dependent COX-2 induction may prevent prostanoid bronchoconstriction and improve oxygenation.…”