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Br J Pharmacol. 2016 Sep;173(18):2726-38. doi: 10.1111/bph.13542. Epub 2016 Aug 3.

Inhibition of PI3K promotes dilation of human small airways in a rho kinase-dependent manner.

Author information

1
Rutgers Institute for Translational Medicine and Science, Child Health Institute, Rutgers University, New Brunswick, NJ, USA.
2
Department of Bioengineering, University of California, Los Angeles, CA, USA.
3
Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA.
4
California NanoSystems Institute, University of California, Los Angeles, CA, USA.
5
Department of Molecular and Medicinal Pharmacology, University of California, Los Angeles, CA, USA.
6
University of South Florida, Tampa, FL, USA.
7
Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA.
8
Arkansas Children's Hospital Research Institute and Department of Physiology & Biophysics, University of Arkansas Medical Sciences, Little Rock, AR, USA.

Abstract

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 β2 -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.

PMID:
27352269
PMCID:
PMC4995285
DOI:
10.1111/bph.13542
[Indexed for MEDLINE]
Free PMC Article

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