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Bronchial Thermoplasty restores abnormal
PRMT1 high expression from asthma patients

Lei Fang, Michael Roth, Qingzhu Sun, Michael Tamm, Daiana Stolz
Respiratory Medicine & Pulmonary Cell Research
University and University Hospital of Basel

Sep.2017, Milan, Italy

lei.fang@unibas.ch
Statement of conflict interest:

 I have no, real or perceived, conflicts of interest that relate to this presentation.
Bronchial thermoplasty to treat severe asthma

• A minimal invasive procedure that


delivers radio frequency energy (65°C)
to the airways through bronchoscope
to reduce airway smooth muscle mass

• Approved by the FDA in 2010

• > 6’000 patients treated worldwide

University of Basel 4
How does thermoplasty work?

Decreased airway remodelling:


• Decrease basement membrane thickening
• Decrease submucosal & ASM-associated nerve fibres
• Decrease epithelial neuroendocrine cells
• Decrease ASMC area

University of Basel 5
Petrolani et al, JACI 2017; Bicknell et al, Breathe, 2014
Protein arginine methyltransferase family (PRMTs)

• Type I: arginine asymmetrical dimithylation (PRMT1, etc)


• Type II: arginine symmetrical dimethylantion (PRMT5, etc)
• Type III: arginine monomethylation (PRMT7)

University of Basel 6
Kyle K, et al, Nature Reviews, 2015
PRMTs in lung diseases

PRMT status Potential consequences of PRMT dysregulation PRMT status Potential consequences of PRMT dysregulation

• enhanced IL-4 induced PRMT1-driven • Impaired intracellular asymmatric


eosinophil infiltration into the lung. dimethylation and increased PASMIC
PRMT1 ↑ • Increased PRMT1-driven signaling and proliferation.
cytokine production followed by T-cell PRMT1 ↓ • Increased pulmonary ADMA levels in mouse
activation. PRMT2 ↑ model of hypoxia-induced pulmonary
hypertension, mainly due to enhanced
• increased pulmonary ADNA context due to
PRMT2 ↑ expression of PRMT2 in alveolar type II
PRMT2 up-regulation.
cells.
PRMT3 ↑
PRMT4 ↓ ? Pulmonary
PRMT6 ↑
hypertension
COPD and
asthma
Pulmonary
Lung
fibrosis
cancer
PRMT status Potential consequences of PRMT dysregulation PRMT status Potential consequences of PRMT dysregulation

• Efficient PRMT1 and PRMT6-dependent DNA • PRMT6-mediated regulation of histone 3


repair and increased DNA stability, inhibition PRMT6 ↓ function together with negative regulation of
PRMT1 ↑ of cell growth arrest followed by enhanced specific gene promoter activities.
PRMT6 ↑ cell proliferation.
• Increased migration and invasion of cancer
cells.

Courtesy of Prof. M. Roth University of Basel 7


PRMT1 is up-regulated in severe asthmatic lung

Sun, JACI, 2017 University of Basel 8


PRMT1 is upregulated in asthmatic ASMC

Sun, JACI, 2017 University of Basel 9


PRMT1 is regulated by ERK1/2 MAPK and STAT1 signaling

Sun, JACI, 2017 University of Basel 10


Constitutive high PRMT1 expression promotes airway remodeling

Sun, JACI, 2017 University of Basel 11


Hypothesis:
Does bronchial thermoplasty works through interfering PRMT1?

Mesenchymal cells miR-19a


BAL collection
Epithelial cells

BAL before BAL after C/EBPβ ERK


secretome
BT BT P

si-C/EBPβ
Asthmatic mesenchymal cells PRMT1

AMI-1
Outcomes PRMT1 expression
PGC-1α Proliferation
Erk1/2 MAPK signal activation

Expression of miR19a

Mitochondrial performance
Mitochondria performance

Fang, ERS, 2017 University of Basel 12


BT derived BAL reduces PRMT1 signaling in airway fibroblast

Control fibroblast Asthmatic fibroblast


* *

tErk1/2

pErk1/2

PRMT1

C/EBPβ
* *

GAPDH

BAL before BT - + - - + -

BAL after BT - - + - - +
n=3, *p<0.05

Fang, ERS, 2017 University of Basel 13


BT derived BAL restores miR-19a expression

Control fibroblast
Asthmatic BAL BAL after BT
miR19a expression Asthmatic fibroblast

*
miR-19a -- miR-19a ++
150.00
Relative gene expression (%)

100.00 * Erk1/2 ++ Erk1/2 --

50.00
PRMT1 ++ PRMT1 --

0.00
C/EBPβ ++ C/EBPβ --
++ --

n=3, *p<0.05
Mitochondrial performance
Fang, ERS, 2017 University of Basel 14
BT derived BAL inhibits mitochondrial activity

DAPI Phallodin Cytochrome c Merge

Control Medium
mitochondrial mass (%)

*
160.0

120.0
BAL before BT

80.0

40.0
BAL after BT

0.0

Blank

Before

After BT
BT
n=15, *p<0.05

Fang, ERS, 2017 University of Basel 15


BT decreases pERK1/2 and PRMT1 expression in human airways
pERK1/2 expression PRMT1 expression

Before BT

50μM 50μM
3 months After BT

50μM 50μM

Fang, ERS, 2017 University of Basel 16


Conclusion:
BT reduces abnormal PRMT1 high expression from asthmatic patients

miR-19a
epithelial cells

C/EBPβ ERK
secretome

mesenchymal
PRMT1 cells

Bronchial
thermoplasty proliferation
PGC-1α

mitochondria
performance

Fang, ERS, 2017 University of Basel 17


Thank you
for your attention.
Pulmonary Cell Research Team, Basel, Switzerland

Prof. Dr. Daiana Stolz Dr. Eleni Papakonstantinou


Prof. Dr. Michael Roth Dr. Ly Chu Phuong
Prof. Dr. Michael Tamm Dr. Qingzhu Sun
PD. Dr. Kathrin Hosttetler Dr. Spasenija Savic
Dr. Petra Kahn

Sep.2017, Milan, Italy