title: Inhibition of PI3K promotes dilation of human small airways in a rho kinase-dependent manner.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Rutgers Institute for Translational Medicine and Science, Child Health Institute, Rutgers University, New Brunswick, NJ, USA.
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Koziol-White
authors.affiliation: Rutgers Institute for Translational Medicine and Science, Child Health Institute, Rutgers University, New Brunswick, NJ, USA.
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: Yoo
authors.affiliation: Rutgers Institute for Translational Medicine and Science, Child Health Institute, Rutgers University, New Brunswick, NJ, USA.
authors.forename: Gaoyuan
authors.initials: G
authors.lastname: Cao
authors.affiliation: Rutgers Institute for Translational Medicine and Science, Child Health Institute, Rutgers University, New Brunswick, NJ, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Rutgers Institute for Translational Medicine and Science, Child Health Institute, Rutgers University, New Brunswick, NJ, USA.
authors.forename: Eleni
authors.initials: E
authors.lastname: Papanikolaou
authors.affiliation: Department of Bioengineering, University of California, Los Angeles, CA, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Pushkarsky
authors.affiliation: Department of Bioengineering, University of California, Los Angeles, CA, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Andrews
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Blanca E
authors.initials: BE
authors.lastname: Himes
authors.affiliation: California NanoSystems Institute, University of California, Los Angeles, CA, USA.|Department of Molecular and Medicinal Pharmacology, University of California, Los Angeles, CA, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Damoiseaux
authors.affiliation: University of South Florida, Tampa, FL, USA.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Liggett
authors.affiliation: Department of Bioengineering, University of California, Los Angeles, CA, USA.|California NanoSystems Institute, University of California, Los Angeles, CA, USA.|Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA.
authors.forename: Dino
authors.initials: D
authors.lastname: Di Carlo
authors.affiliation: Arkansas Children's Hospital Research Institute and Department of Physiology & Biophysics, University of Arkansas Medical Sciences, Little Rock, AR, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Kurten
authors.affiliation: Rutgers Institute for Translational Medicine and Science, Child Health Institute, Rutgers University, New Brunswick, NJ, USA.
authors.forename: Reynold A
authors.initials: RA
authors.lastname: Panettieri
mesh_terms: D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering