FIGURE 1.

Possible mechanisms of synergistic actions of the LABA/LAMA combination against inflammation. (A) Synergistic inhibitory effect of LABA/LAMA against ACh release from airway epithelial cells. Signaling via β₂AR inhibits the function of OCT1, a transporter for the release of acetylcholine from airway epithelial cells, whereas signaling via M₃ possibly upregulates the function of OCT1. Therefore, the LABA/LAMA combination synergistically inhibits the release of ACh. (B) Synergistic inhibitory effect of LABA/LAMA against the production of inflammatory mediators. Signaling via β₂AR activates AC-cAMP-PKA signaling pathway. PKA inhibits ERK and p38MAPK pathways. In contrast, signaling via M₃ activates PKC, which results in the activation of NF-κB. The combination of LABA and LAMA therefore possibly inhibits the production of pro-inflammatory mediators synergistically via inhibiting both MAPK and NF-κB pathways. ACh, acetylcholine; AC, adenylate cyclase; β₂AR, beta-2 adrenergic receptor; cAMP, cyclic adenosine monophosphate; CHT1, high-affinity choline transporter 1; ERK, extracellular signal-regulated kinase; LABA, long-acting β₂ agonist; LAMA, long-acting muscarinic antagonist; MAPK, mitogen-activated protein kinase; M₃, acetylcholine muscarinic M3 receptor; NF-κB, nuclear factor-kappa B; OCT1, organic cationic transporter 1; PKA, protein kinase A; PKC, protein kinase C.