Airway Vista 2013 Asan Medical Center Seoul, Korea. March 30, Autophagy: Friend or foe in asthma and COPD?
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1 Airwy Vist 213 Asn Medicl Center Seoul, Kore Mrch 3, 213 Autophgy: Friend or foe in sth nd COPD? Augustine M.K. Choi, MD Prker B. Frncis Professor of Medicine Hrvrd Medicl School Pulonry nd Criticl Cre Medicine Brigh nd Woen s Hospitl Proterris Disclosures 1
2 Outline Introduction Autophgy: Regultion nd function in experientl nd hun lung disese (e.g. COPD) Selective Autophgy: Mitophgy nd ciliophgy in experientl nd hun lung disese (e.g. COPD) Trnsltionl/Clinicl Iplictions J. Cell Biol, 1962 J. Cell Biol,
3 Autophgy NEJM, 213 Autophgy NEJM, 213 3
4 Selective Autophgy NEJM, 213 Autophgy nd Hun Diseses Neurodegenertion Myopthies Cncer Aging Liver disese Infection nd iunity Hert disese Nture 28 4
5 Physiologic or Pthologic Roles of Autophgy Mizushi N et l., Cell, 211 NEJM, 213 5
6 Functionl Role of Autophgy in Lung Disese Ryter nd Choi, Annul Review of Physiology, 212 6
7 Autophgy in Soke Induced COPD HDAC Activity Histone cetyltion LC3B Atg4 LC3B-II Egr-1 E2F4 Autophgy Chen et l., PLoS ONE 28 Chen, et l. PNAS 21 Ki et l., Autophgy 28 Ryter et l., Autophgy 29 Ki et l., Methods Enzyol 29 COPD Lung cell poptosis 7
8 Chen & L et l. PNAS, 21 (Trck II) Autophgy in Soke Induced Ephyse Atg5 Cv-1 Atg12 Cv-1 LC3 LC3 Cv-1 Autophgy Apoptosis Ephyse LC3 LC3 Autophgy Less poptosis Less lung injury Chen & L et l. PNAS, 21 (Trck II) 8
9 Cigrette Soke Autophgy Mitochondril ROS COPD Blood biorker LC3B Cv-1 FAS FADD Cspse-8 Cv-1 LC3B LC3B secretion Bid t-bid Autophgy LC3B LC3B ROS Bx LC3B Apoptosis Autophgosoe Crdiolipin Ox-crdiolipin Cspse-3 Autophgic Flux Cyto-c Cspse-9 Chen & L et l. PNAS, 21 (Trck II) Nt Med 21 9
10 Events (% of x) Events (% of x) Reltive MFI Reltive MFI Cigrette soke cuses itochondril dysfunction. Control E c Unstined Control E 2h E 4h MitoSOX Control E2h E4h d MitoTrcker Deep Red MitoTrcker Green Unstined Control E 2h E 4h Control E 2h E 4h Control E 2h E4h Mitotrcker Deep Red Mitotrcker Green PINK1, itochondril ebrne protein is regulted in E treted cells nd in COPD lung tissues. PINK1 β-actin E (h) full length processed d. Never sokers Ptients with COPD (GOLD2) PINK1 LC3B b. PINK1 β-actin E (h) e. β-actin Never Sokers COPD 1
11 ψ (Reltive JC-1 uptke to roo ir control of WT) Events (% of x) Reltive MFI Cigrette Soke Extrct induces itophgy. Control E t-kei ex. 458 n t-kei ex. 543 n 2. t-kei rtio (543/458) b. E Control 2h 4h Blue: Hoechest33258 (nucleus) Green: To2 (itochondri) regultes PINK1 nd itochondril dysfunction in vivo. Mitochondril frction Cytosolic frction Mitochondril frction Cytosolic frction b. To2 β-actin Protein stining (ebrne) Cont E Cont E PINK1 Ubiqutin Cont E Cont E % of Mx PE-A MitoSOX 1.2 Isolted lveolr epithelil cells fro WT ice Isolted lveolr epithelil cells fro PINK1 KO ice c. 12% 1% # LC3B Air.2 WT PINK1 KO 8% 6% 4% 2% % (n=8) (n=6) WT (n=6) (n=6) PINK1 KO 11
12 Chord Length (μ) Resistnce (Ω/c 2 ) % 3h Clernce PINK1 deficient ice exhibit decresed -induced ephyse nd MCC dysfunction. b. # 35 Air d # Air (n=6) (n=4) (n=5) (n=5) WT PINK1 KO (n=5) (n=5) (n=3) (n=4) WT PINK1 KO The Model: Mouse trchel-bronchil epithelil cells (MTECs) grown t ir-liquid interfce (ALI) Seed (d) ALI (1d) Experient (24d) Cilited Cell ALI D ALI (1d) Tie (d) Bsl Cell 1h 4h 8h Non-cilited Cell v High Dose Low Dose 24h s n 12
13 (d) % Cilited Cells TER (Ω/c 2 ) % Cilited Cells ΔLC3B II (ng) ΔLC3B II (ng) disrupts intercellulr contcts nd induces cili loss in MTEC cultures 4h 24h LD HD LD HD Tie (h) LD HD Centrin 1 Mucin 5AC induces cili loss nd utophgy in MTEC cultures b c f 3 2 CT L C S β-ctin 1 d RA c α-tub F-ctin nuclei Tie (d) g Punct / 1 μ h CQ Tie (h) p62 p62 LC3B GFP-LC3B nuclei I II HMW p62 β-ctin e n 5 1 n i R A 1w 2 h RA 1w 2 24 h 13
14 Cilited Cells (norlized to ) Colocliztion of cili nd utophgic rkers following exposure c α-tub LC3B nuclei W C L Centrin 1 LC3B LAMP2 5 W C L 1 W C L IP:LC3B IB:Pericentrin IB:IFT88 IB:LC3B IN IgG IP E IN IgG IP 199 Autophgic degrdtion of cili coponents (ciliophgy) prootes -induced cili loss Becn1 +/+ Becn1 +/- n s g b Autophgososes/1μ Becn1 +/+ Becn1 +/- c Autophgosoes/1 μ RA Becn1 +/+ Becn1 +/- d ΔLC3B (ng).8 RA Becn1 +/+ Becn1 +/- e Becn1 +/+ f Becn1 +/+ Becn1 +/- Becn1 +/-.5 14
15 % 3h Clernce ΔLC3B (ng) % Activity Reining RA Cilited Cells (norlized to ) induced ciliophgy nd ggrephgy is edited by HDAC6 Autophgoses/1 μ RA b RA c IP: LC3B W IgG IP HDAC6 IB:LC3B E W IgG IP d Hdc6 +/Y n n Hdc6 -/Y e Ubiquitin Hdc6 +/Y Hdc6 -/Y MW (kd) Hdc6 +/ Y Hdc6 -/Y Hdc6 +/Y Hdc6 -/Y β-ctin f g Hdc6 +/Y Hdc6 -/Y h Hdc6 +/Y 1.5 Hdc6 +/Y Hdc6 -/Y 1. Hdc6 -/Y.5 PA nuclei Rescue of ucociliry clernce dysfunction by HDAC6 inhibition Sgittl L S 15 1 RA Coronl 95 L 9 L S Tie (h) 15 RA 1 5 WT Vehicle HDAC6 -/Y Tubsttin 15
16 % 3h Clernce Rescue of ucociliry clernce dysfunction in beclin or LC3 deficient ice 3 RA 2 1 WT PBA Becn +/- Mplc3b -/- Pthogenesis of COPD Infltion Autophgy Cell deth Oxidnt -Antioxidnt Protese -Antiprotese Vsculr Microbil pthogen Autoiunity 16
17 TEAM Zhihu Chen, PhD Hilire C. L, PhD cndidte Hong-Pyo Ki, PhD Stefn W. Ryter, PhD Jeffrey A. Hspel, MD, PhD Ts Doliny, MD, PhD Seon-Jin Lee, PhD Aky Sith, MD Young-S Ki, MD, PhD Kiichi Nkhir, MD, PhD Joshu Englert, MD Eek Ifeidgbo, MS Roberto Lndzury, Bsc 17
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