Pharmacologically-induced mitotic synchrony in airway epithelial cells as a mechanism of action of anti-inflammatory drugs.
BACKGROUND
Mitotic synchrony is the synchronous progression of a population of cells through the cell cycle and is characteristic of non-diseased airway epithelial cells. However, we previously showed that asthmatic airway epithelial cells are characterized by mitotic asynchrony and are pro-inflammatory as a result. Glucocorticoids can induce mitotic synchrony that in turn suppresses the pro-inflammatory state of diseased cells, suggesting a novel anti-inflammatory mechanism of action. Herein, we benchmarked traditional glucocorticoids against the ability of a new clinical-stage dissociative steroidal drug, VBP15, for mitotic resynchronization and associated anti-inflammatory activity in asthmatic airway epithelial cells.


METHODS
Primary airway epithelial cells differentiated at air-liquid interface were exposed to VBP15, dexamethasone or vehicle following in vitro mechanical injury. Basolateral cytokine secretions (TGF-β1, IL-6, IL-10, IL-13, and IL-1β) were analyzed at different time points using cytometric bead assays and mitosis was examined by flow cytometry.


RESULTS
VBP15 improved mitotic synchrony of proliferating asthmatic cells in air-liquid interface cultures compared to vehicle-exposed cultures. VBP15 also significantly reduced the basolateral secretion of pro-inflammatory (i.e. IL-1β) and pro-fibrogenic cytokines (i.e. TGF-β1) in air-liquid interface-differentiated asthmatic epithelial cultures following mechanical injury.


CONCLUSIONS
VBP15 improves mitotic asynchrony and injury-induced pro-inflammatory and fibrogenic responses in asthmatic airway epithelial cultures with efficacy comparable to traditional glucocorticoids. As it is predicted to show superior side effect profiles compared to traditional glucocorticoids, VBP15 holds potential for treatment of asthma and other respiratory conditions.
Division of Emergency Medicine, Children's National Health System, Washington, DC, USA. rfreishtat@childrensnational.org.|Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC, USA. rfreishtat@childrensnational.org.|Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA. rfreishtat@childrensnational.org.
R J
RJ
Freishtat
Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC, USA. gnino@childrensnational.org.|Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA. gnino@childrensnational.org.|Division of Pulmonary and Sleep Medicine, Children's National Health System, Washington, DC, USA. gnino@childrensnational.org.
G
G
Nino
George Washington University School of Medicine and Health Sciences, Washington, DC, USA. ytsegaye@gwmail.gwu.edu.
Y
Y
Tsegaye
George Washington University School of Medicine and Health Sciences, Washington, DC, USA. sda@gwmail.gwu.edu.
S E
SE
Alcala
Children's National Health System, Washington, DC, USA. asbenton@gmail.com.
A S
AS
Benton
George Washington University School of Medicine and Health Sciences, Washington, DC, USA. augie95@gmail.com.
A M
AM
Watson
ReveraGen Biopharma, Inc., Silver Spring, MD, USA. Erica.Reeves@reveragen.com.
E K M
EK
Reeves
Division of Pulmonary and Sleep Medicine, Children's National Health System, Washington, DC, USA. suraiyakureshi@yahoo.com.
S K
SK
Haider
Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA. Jesse.Damsker@reveragen.com.|ReveraGen Biopharma, Inc., Silver Spring, MD, USA. Jesse.Damsker@reveragen.com.
J M
JM
Damsker
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects* / Q000473:pathology; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008938:Mitosis / Q000187:drug effects*; D011244:Pregnadienediols / Q000494:pharmacology*; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D013997:Time Factors
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D005938:Glucocorticoids; D018836:Inflammation Mediators; D011244:Pregnadienediols; C584811:VBP15 compound; D003907:Dexamethasone