Upload
vanduong
View
236
Download
1
Embed Size (px)
Citation preview
Endometriosis and oxidative stress ?
Pietro Santulli MD, PhD Université Paris Descartes, Sorbonne Paris Cité, Faculté de médecine, AP-HP, Cochin Saint Vincent de Paul, Department of Gynecology Obstetrics II and Reproductive Medicine, Paris, France Inserm, Unité de recherche U1016 – équipe Pr Batteux, Institut Cochin, Paris, France
Presentation outline
• Pathogenesis of inflammation
• Clinical consequences: Pain and infertility
• Oxidative stress
• Targeted treatments of endometriosis
Implantation theory of endometriosis
SUP, superficial lesion; OMA, endometrioma; DIE, deep infiltrating endometriosis
Adenomyosis SUP OMA DIE
Glands Stroma
Ectopic implantation
Cycle of pathogenesis in endometriosis
Kobayashi H et al. Arch Gynecol Obstet 2014; 289(1): 13–21.
Invasion
Proliferation
Steroidogenesis
Angiogenesis
Adhesion
Glands Stroma
Ectopic implantation
Mechanisms of pathogenesis in endometriosis
Adapted from Kobayashi H et al. Arch Gynecol Obstet 2014; 289(1): 13–21.
Chronic inflammatory response ++++
Excess oxidative stress
Attenuated progesterone
action
Altered immune functions
Neuroangiogenesis
Invasion
Proliferation
Steroidogenesis
Angiogenesis
Adhesion
Cholesterol
Androstenedione
STAR
CYP11A1
CYP17
EstroneCYP19A1
NR5A1 Estradiol
PGE2 PTGS2
+
+
+
+
VEGF
+
MMP
INSL3
Proliferation
Inflammation
Steroidogenesis
Adhesion-Migration
Angiogenesis
Molecular pathways involved in endometriosis
VEGF, vascular endothelial growth factor; PGE2, prostaglandin E2; PTGS2, prostaglandin-endoperoxide synthase 2; PTGER, prostaglandin E receptor; MMP, matrix metalloproteinase; INSL3, insulin-like 3; STAR, steroidogenic acute regulatory protein; CYP, cytochrome P; NR, nuclear receptor. Adapted from Bulun SE. N Engl J Med 2009; 360(3): 268–279.
PTGER
Cholesterol
Androstenedione
STAR
CYP11A1
CYP17
EstroneCYP19A1
NR5A1 Estradiol
PGE2 PTGS2
+
+
+
+
VEGF
+
MMP
INSL3
Proliferation
Inflammation
Steroidogenesis
Adhesion-Migration
Angiogenesis
Molecular pathways involved in endometriosis
PTGER
VEGF, vascular endothelial growth factor; PGE2, prostaglandin E2; PTGS2, prostaglandin-endoperoxide synthase 2; PTGER, prostaglandin E receptor; MMP, matrix metalloproteinase; INSL3, insulin-like 3; STAR, steroidogenic acute regulatory protein; CYP, cytochrome P; NR, nuclear receptor. Adapted from Bulun SE. N Engl J Med 2009; 360(3): 268–279.
Inflammatory response pathway leads to tissue injury and chronic pain
IL, interleukin; TNF, tumor necrosis factor; PG, prostaglandin; CXCL, chemokine; NGF, nerve growth factor; NF-Kβ, nuclear factor kappa beta.
! Iron
Oxidative stress
Increased pro-inflammatory
factors
Decreased anti-inflammatory
factors
Tissue injury
ê CXCL 10 ê IL-19,22
é TNF-α é IL-1β é IL-6,8,33 é Rantes é PGs
é PGsExcessive sensory
innervationé NGF
Neuroangiogenesis
Pelvic Pain
! NF- Kβ
Inflammation Regurgitation
Inflammatory response can contribute to infertility
de Ziegler D et al. Lancet 2010; 376(9742): 730–738.
Ovaries: • Decreased ovarian response • Altered oocyte quality? • Iron overload (proinflammatory factors)
Uterus: • Increased synthesis of prostaglandin &
altered receptivity • Production of estrogens in situ and
resistance to progestogen
Pelvic cavity: • Proliferation of macrophages • Phagocytic dysfunction • Release of proinflammatory factors
Sphingosines
MAPK pathway
PTGS2
Inflammation
Inflammation in endometriosis: Molecular intermediates and pathways
PTGS2, prostaglandin-endoperoxide synthase 2
Invasion
Proliferation
Steroidogenesis
Angiogenesis
Adhesion
Oxidative Stress
Sphingosines
MAPK pathway
PTGS2
Inflammation
Inflammation in endometriosis: Molecular intermediates and pathways
PTGS2, prostaglandin-endoperoxide synthase 2
Invasion
Proliferation
Steroidogenesis
Angiogenesis
Adhesion
Oxidative StressOxidative Stress
Inflammatory response is linked to an altered balance of oxidative stress
IL, interleukin; CXCL, chemokine; GSH, glutathione; NADPH, nicotinamide adenine dinucleotide phosphate-oxidase; AOPP, advanced oxidation protein products; PGs, prostaglandins.
Pro-OxidantsAnti-OxidantsPersistent inflammation
N=85 N=55 N=31 N=64
Oxidative stress is increased in endometriosis, especially in DIE
DIE, deep infiltrating endometriosis; SUP, superficial lesion; OMA, endometrioma; AOPP, advanced oxidation protein products. Santulli P et al. Hum Reprod 2015; 30(1): 49–60.
N=36 N=28
N=150
Oxidative stress is increased further in intestinal DIE
Hydrogen Peroxide (H2O2)
Endometrioma1
Increased oxidative stress correlates with increased cellular proliferation
1. Ngô C et al. Am J Pathol 2009; 175(1): 225–234. 2. Leconte M et al. Am J Pathol 2011; 179(2): 880–889.
Superoxide Anion (O2--) Hydrogen Peroxide (H2O2)
Superoxide Anion (O2--)Deep infiltrating endometriosis2
Epithelial Ce, control endometrial Ee, eutopic endometrial De, deep infiltrating endometriotic Stromal Cs, control endometrial Es, eutopic endometrial Ds, deep infiltrating endometriotic
Increased oxidative stress correlates with increased cellular proliferation: Link to MAPK pathway
NAC, N-acetyl-cysteine; ERK, Extracellular signal-regulated kinases; pERK, phosphorylated-ERK. Ngô C et al. Am J Pathol 2009; 175(1): 225–234.
Cont
rols
Euto
pic
Ecto
pic
NAC
ERK
pERK
Prol
ifera
tion
Prol
ifera
tion
NACLevel of untreated cells
Level of untreated cells
Opt
ic D
ensi
ty p
ERK
/ER
K
H2O
2 Pro
duct
ion
Sphingosines PTGS2
Inflammation
Inflammation in endometriosis: Molecular intermediates and pathways
PTGS2, prostaglandin-endoperoxide synthase 2
Invasion
Proliferation
Steroidogenesis
Angiogenesis
Adhesion
Oxidative Stress MAPK pathway
Cell proliferationTranscriptional regulation
Angiogenesis
NADPH oxidase
GSH ROS
IL-33RPDGFR VEGFR
S1P
MAPK pathway links increased oxidative stress and inflammatory response in endometriosis
IL, interleukin; NADPH, nicotinamide adenine dinucleotide phosphate-oxidase; GSH, glutathione; PDGFR, platelet-derived growth factor receptors; VEGFR, vascular endothelial growth factor receptor; ROS, reactive oxidative species. Ngô C et al. J Pathol 2010; 222(2): 148–159. Santulli P et al. Fertil Steril 2012; 97(4): 904–911. Santulli P et al. Hum Reprod 2012; 27(7): 2001–2009.
MAPK pathway
Endometriosis and MAPK Vemurafenib - braf
Endometriosis and MAPK Sorafenib – raf1- braf - tkr
Endometriosis and inflammation Targeting MAP Kinase pathway
2015
LOCAL SYSTEMIC
Future trends Targeting inflammation in endometriosis: MAPK
Future trends Targeting inflammation in endometriosis: MAPK
à " " New non hormonal targeted tretments of endometriosis
MAPK
Conclusions
• Endometriosis is an • Enigmatic • Heterogeneous • Neurologic • Inflammatory
• New treatments could target inflammation and oxidative stress pathways
disease
Gynecology Surgical unit: C Chapron, B Borghese, L Marcellin, P Santulli, H Foulot, MC Lafay-Pillet, A Bourret, G Pierre, MC Lamau, P Marzouk, F Decuypere, L Campin Medical unit: A Gompel, G Plu-Bureau, L Maitrot; J Hugon Reproductive endocrinology unit: P Santulli, V Gayet, M Bourdon, C Maignien, F Kefelian, S Eskenazi, S Douard, B Boquet, A Marszalek, A Fubini Intestinal surgery B Dousset, S Gaujoux, M Leconte Radiology AE Millischer, L Maitrot
Laboratory: Genetic D Vaiman, F Mondon, S Barbaux Laboratory: Imunulogy F Batteux, S Chouzenoux, C Nicco, C Chéreau, B Weill Laboratory: Reproducive biology JP Wolf, C Patrat, K Pocate, V Lange, JM Kuntzman, C Chalas Statistical unit F Goffinet, PY Ancel
A Gompel, Professor and Head, Medical Gynecological unit, P Santulli, Doctor and Head, Reproductive ART and Infertility unit,
C Chapron, Professor and Chair, Gynecology Obstetrics II and Reproductive Medicine