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Inhibition of PI3K promotes dilation of human small airways in a rho kinase‐dependent manner
Author(s) -
KoziolWhite Cynthia J,
Yoo Edwin J,
Cao Gaoyuan,
Zhang Jie,
Papanikolaou Eleni,
Pushkarsky Ivan,
Andrews Adam,
Himes Blanca E,
Damoiseaux Robert D,
Liggett Stephen B,
Di Carlo Dino,
Kurten Richard C,
Panettieri Reynold A
Publication year - 2016
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13542
Subject(s) - pi3k/akt/mtor pathway , medicine , asthma , rho associated protein kinase , myosin light chain kinase , inflammation , constriction , pharmacology , endocrinology , kinase , myosin , microbiology and biotechnology , signal transduction , biology
Background and Purpose Asthma manifests as a heterogeneous syndrome characterized by airway obstruction, inflammation and hyperresponsiveness (AHR). Although the molecular mechanisms remain unclear, activation of specific PI3K isoforms mediate inflammation and AHR. We aimed to determine whether inhibition of PI3Kδ evokes dilation of airways and to elucidate potential mechanisms. Experimental Approach Human precision cut lung slices from non‐asthma donors and primary human airway smooth muscle (HASM) cells from both non‐asthma and asthma donors were utilized. Phosphorylation of 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. Key Results 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. Baseline pMYPT1 was significantly elevated in HASM cells derived from asthma donors in comparison with non‐asthma donors. After desensitization of the β 2 ‐adrenoceptors, a PI3Kδ inhibitor remained an effective dilator. In the presence of IL‐13, dilation by a β agonist, but not PI3K inhibitor, was attenuated. Conclusion and Implications PI3Kδ inhibitors act as dilators of human small airways. Taken together, these findings provide alternative approaches to the clinical management of airway obstruction in asthma.