Inhibition of Phosphoinositide 3 ‐Kinase (PI3K) promotes dilation of human small airways in a Rho kinase‐dependent manner

Asthma manifests as a heterogeneous syndrome characterized by airway obstruction, inflammation and hyperresponsiveness (AHR). Although the molecular mechanisms remain unclear, activation of specific phosphoinositide 3‐kinase (PI3K) isoforms mediate inflammation and AHR (Lee et al., 2006; Nashed et al., 2007; Ali et al., 2008; Takeda et al., 2009). We aimed to determine whether inhibition of PI3Kδ evokes dilation of airways, and to elucidate potential mechanisms. Human precision cut lung slices (hPCLS) from non‐asthma donors, and primary human airway smooth muscle cells (HASM) from both non‐asthma and asthma donors, were utilized. Phosphorylation of protein kinase B (AKT), myosin phosphatase target subunit 1 (MYPT1), and myosin light chain (MLC) were assessed in HASM cells following either PI3K inhibitor or siRNA treatment. HASM relaxation was assessed by micro‐pattern deformation. Reversal of constriction of airways was assessed following stimulation with PI3K or ROCK inhibitors. Soluble inhibitors or PI3Kδ knockdown reversed carbachol‐induced constriction of human airways, relaxed agonist‐contracted HASM, and inhibited pAKT, pMYPT1, and pMLC in HASM. Similarly, inhibition of Rho kinase also dilated human PCLS airways and suppressed pMYPT1 and pMLC. Using PI3Kδ siRNA, carbachol‐induced pMYPT1 and pMLC were abrogated. Baseline pMYPT1 was significantly elevated in HASM cells derived from asthma donors in comparison to non‐asthma donors. After β2AR tachyphyla...
Source: British Journal of Pharmacology - Category: Drugs & Pharmacology Authors: Tags: RESEARCH PAPER Source Type: research