ROLE OF HEME OXYGENASE-1 (HO) & CARBON MONOXIDE (CO) …

ROLE OF HEME OXYGENASE-1 (HO) & CARBON MONOXIDE (CO)

IN TRANSPLANTATION

Hun-Taeg Chung, M.D., Ph.D.Meta-inflammation Research Laboratory,

School of Biological Sciences,University of Ulsan, Ulsan 680-749, Korea

CONTENTS

A Introduction

B Gaseous Transmitters

C Physiological Function of HO system

D Therapeutic Effects of HO-1 System in Transplantation

E ConclusionD-1. HO-1 and transplantationD-2. CO and transplantationD-3. Br/Bv and transplantationD-4. HO-1 and IRI

CO

Fe2+

BiliverdinHeme Bilirubin

2NADPH3O2

2NADP+

3H2O

NADPHH+

NADP+

Heme Oxygenase

Biliverdin Reductase

Introduction

Introduction and COCO : Its Chemical Properties

:CO:- +

Carbon monoxide (CO) is an odorless,

tasteless and colorless gas composed

of one carbon atom and one oxygen

atom with a triple bonding.

Due to its formal charges, CO is more

reactive than oxygen molecule, but

not more than nitric oxide.

Degradation of Heme by HO-1and HO-2

Fe

CO

BILIRUBIN

HEME

HEMOGLOBIN

Bone marrowDestruction of maturing

erythroid cells

SpleenDestruction of senescent

erythrocytes

All tissuesTurnover of heme

& hemoprotein

HO-1or

HO-2

Introduction and HO-1 & HO-2

Heme

CO

Fe2+Bilirubin

Iron homeostasisAnti-apoptosisCytoprotection

AntioxidantAnti-apoptosisCytoprotection

Anti-apoptosisCytoprotection

Anti-inflammationAnti-proliferation

HO-1

AntioxidantsAnti-inflammatory cytokines

Heat shock proteins

NOSome drugs

HO-1 as a Therapeutic Funnel

CO/HO-1

Up-regulation

Down-regulation

ROS

Vascular permeability

Adhesion molecules

Cell proliferation

Apoptosis

cGMP

Cytoprotection

Angiogenesis

Tissue repair

Resolution

Trans-

plantation

?

HO-1/CO : Its Biochemical Roles

Introduction and HO-1/CO

Landscape View of Gas Biology

Gaseous Transmitters and General Properties

1. The gases are highly membrane-permeable and thus serve as a substance

conveying the signal from one site to another

Important Gaseous Transmitters in Mammalian Cells:

Nitric Oxide (NO), Carbon Monoxide (CO)

& Hydrogen Sulfide (H2S)

3. The gases could not only exert comparable biological actions but also compete

with and are antagonists with each other

2. The gases could exert their biological actions via interaction with proteins in

multiple ways

A unique class of biomaterials indispensable of maintaining the homeostasis of biological system

Criteria for Aerokines (Gaseous Transmitters)

(1) Small molecules of gas, like NO, CO and H2S.

(2) Freely permeable to membrane.

Their effect will not rely on cognate membrane receptors.

(3) Endogenously and enzymatically generated and their generation

is regulated.

(4) Well-defined specific functions at physiologically relevant concentrations.

(5) Mediated by second messengers, but should have specific cellular and

molecular targets.

Gaseous Transmitters and NO, CO and H2S

Synthesis & Significances

Enzyme SubstrateGaseous Mediator

Cystathionine -Synthase (CBS)

Cystathionine -Lyase (CSE)dHydrogen Sulfide (H2S)c L-Cysteine (L-Cys)

Nitric Oxide (NO)a

Carbon Monoxide (CO)b

NO Synthase (NOS)

[e.g. iNOSd, eNOS, nNOS]

Heme Oxygenase (HO)

[e.g. HO-1d, HO-2, HO-3]

L-Arginine (L-Arg)

Free Heme

Different gases that are synthesized by enzymes in the body could not only exertcomparable biological actions but often compete with and are antagonists witheach other

a Radical species with high reactivity, short half-life, colorless & odorlessb Gas with high binding affinity with hemoglobin, colorless & odorlessc Hydrophilic and flammable gas, colorless & characteristic smell of rotten eggsd Inducible

iNOS knockout

Immune deficiency

Endothelial dysfunction

HO-1 knockout

Chronic inflammation


CSE knockout

Hyperhomocysteinemia


Gaseous Transmitters and Enzymes and Substrates

Activation of Secondary Messenger

H2S

H3O+H2O +H2S

1. Activation of cAMP

2. Reaction with H2O

CO

Fe

Fe

CO

CO

O2

1. Activation of sGC

2. Inhibition of CYP 450NO

Fe

Fe

NO

NO

ONOO-O2-+NO

RS-ONRSH

NO

3. Modulation of thiol enzymes

1. Activation of sGC

2. Formation of peroxynitrite

CYP 450

Substrate

Product

CO

+ HS-

Adenyl cyclase

HS-

cAMP

AMP

PKA

CBS

CSE

L-Cys

NOS

L-Arg

HO

Biliverdin

HemeFe2+

Reducing cytotoxic homocycteineReducing pathological antigen Reducing inflammatory free heme

Gaseous Transmitters and Signaling Pathways

Hypothetical Interplay among CO, NO and H2S

NO/NOS

H2S/CBSCO/HO-1&CSE

InhibitionStimulation

Gaseous Transmitters and Interactions among Aerokines

Possible Mechanisms underlying HO-1 Inductionby NO and NO Derivatives in Eukaryotic Cells

HO-1 Induction by NO and Its Derivatives

antioxidant

antinitrosative

NO + O2- ONOO-

Transcriptional Activator ?

HO-1

decreased NOS

Protein levels

decreased NOS

activity

cell growth

vessel tone

OS =Oxidative stress

NS =Nitrosative stress

iNOS

induction

NO

donors

Bilirubin CO

cGMP

Thiol depletion

OS

NSOS

NS


CO Induces Nrf2 activation and HO-1 Expression

Nrf2/CF

Nrf2/NF

HO-1

Actin

-

-

-

-

5

-

-

-

10

-

-

-

20

-

-

-

-

+

-

-

5

+

-

-

10

+

-

-

-

-

5

-

RuCO (M)

Hb

RuCl2 (M)

CO gas

-

-

10

-

-

-

20

-

-

-

-

+

20

+

-

-

RuCO (M)

Hb

RuCl2 (M)

CO gas

5

-

-

-

1

2

0

10

-

-

-

20

-

-

-

-

+

-

-

10

+

-

-

20

+

-

-

-

-

5

-

-

-

10

-

-

-

-

+

-

-

-

-

5

+

-

-

Fold

in

du

ctio

n Nrf2/NF

Nrf2/CFHO-1

-

-

20

-

*

*

* *

*

**

*

*

*

*

*

CO

Nrf2

HO-1

In HUVECs, CO donor and CO gas induce Nrf2 nuclear translocation and HO-1

expression in a dose-dependent manner. However, in the presence of the CO

scavenger, Nrf2 activation and HO-1 expression are not observed.


Proved Interplay among CO, NO and H2S

H2S

CO

NO

CO

Hypothesized triangular

interactions among CO, H2S and

NO in vascular tissues. The solid

line ( ) indicates the stimulatory

input and the dashed line ( ), the

inhibitory input.

H.T. Chung et al. Current pharmaceutical design, 2008, 14(5):422-428


NO, CO & H2S ; Their Interplay in Biological System

CO

HO-1

NO

iNOS

H2S

CSE


Initial Signals of HO-1/CO

Bilban M, et. al. J. Mol. Med. 2008, 86:267-279.

Gaseous Transmitters and Physiological Roles of HO-1/CO

Anti-Apoptosis, -Inflammation, -Proliferation & -Thrombosis

Ryter S.W. et. al. Physiol. Rev. 2006, 86:583-650.


Anti-Inflammation/Up (IL-10) & Down (TNF-α, IL-1β & MIP-1β) Regulation

Otterbein L.E. et. al. Nat. Med. 2003, 6;422-428.


Anti-Proliferation/Up (EC) & Down (SMC) in Balloon Injury

HO-1/COControl

3 Days

2 Weeks

2 Weeks


Pro-Survival Effects on Tissues/Cells

Wang X et. al. J. Biol. Chem. 2007, 282(3):1718-1726.


CO Protects ECs from ER-Stress-Induced Apoptosis by Blocking CHOP via p38

p-JNK

p-p38

Actin

p-ERK1/2

- 1 5 10

RuCO (M)

p-p38

Actin

0 10 20 40 (min)

RuCO 10M

20

40

60

80

120

0

100

* *

TG

RuCO

SB203580

+

-

-

+

+

-

+

+

+

-

-

-

Via

bil

ity (

%)

-

-

+

*

CHOP

Actin

HO-1

+

+

+

TG

RuCO

SB203580

-

-

-

+

-

-

+

+

-

Nrf2/Keap 1eIF2

ATF4 Nrf2

PERK

HO-1CHOP siRNA

TG/HCysCO

Keap 1

Cell SurvivalCell Death

CHOP

p38 Nrf2/Keap 1eIF2

ATF4 Nrf2

PERK

HO-1CHOP siRNA

TG/HCysCO

Keap 1

Cell SurvivalCell Death

CHOP

p38

The p38 inhibitor SB reverses CO-induced inhibition of CHOP expression and apoptosis induced by ER stress.


Integrative Stress Response vs. Integrative Survival Response

PERK PKR GCN2 HRI

ER Stress dsRNA AA Starvation Carbon Monoxide

eIF2 kinase

Anti-apoptotic

Molecules

CHOP

eIF2-P

Heme Deficiency

PERK

eIF2 kinase

ATF4

CHOP

eIF2-P

ATF4

Apoptosis

Anti-apoptotic

Molecules

Apoptosis

Integrative Survival ResponseIntegrative Stress Response

Differential Points

Between

I. Str. R. and I. Sur. R.


HO-1 Expression in Regulatory T Cells

CD4+

CD4+CD25-

CD4+CD25+98.5%

0.5%

7.4%

CD4-FITC

CD

25

-PE

0 3 6 12 24 0 3 6 12 24

CD4+CD25- CD4+CD25+

CD

4+

CD

4+C

D2

5-

CD

4+C

D2

5+

Time (h)

HO-1

-actin

HO-1

-actin

Stimulated

Resting

Resting Stimulated

HO-1

CD4+

CD4+CD25-

CD4+CD25+

0

100

200

300

400

Pro

life

rati

on (

cpm

x 1

03)

Pae HO, et al. Differential expressions of heme oxygenase-1 gene in CD25- and CD25+ subsets

of human CD4+ T cells. Biochem Biophys Res Commun. 2003;306(3):701-705.

HO-1/CO in Immune System and Effects of HO-1/CO on Processing

- +

Actin

-

HO-1

+ CoPP

* *

0

20

40

60

80

100

--

+-

++

CD3/CD28CoPP

[H3]

TdR

Upta

ke

(cpm

/wel

l x

10

-3)

0

10

20

30

40

50

--

+-

* *

++

[H3]

TdR

Upta

ke

(cpm

/wel

l x

10

-3)

CD3/CD28CoPP

CD4+ T cellsPBMCs

(B)(A)

Jurk

at/

pcD

NA

Actin

HO-1

Jurk

at

Jurk

at/

HO

-1

Jurk

at/

pcD

NA

40

30

20

10

0

50

Jurk

at

Jurk

at/

HO

-1

[H3]

TdR

Up

take

(cpm

/wel

l x

10

-3)

*

(C)

Actin

HO-1

CoPP

1. Pae HO, et al. Carbon monoxide produced by heme oxygenase-1 suppresses T cell proliferation via inhibition

of IL-2 production. J Immunol. 2004;172(8):4744-4751.

2. Pae HO, et al. Roles of heme oxygenase-1 in the antiproliferative and antiapoptotic effects of nitric oxide on

Jurkat T cells. Mol Pharmacol. 2004;66(1):122-128.

Anti-proliferative Effect of HO-1 Expression on T Cells


Anti-proliferative Effect of CO on TCR-stimulated T Cells

1. Pae HO, et al. Carbon monoxide produced by heme oxygenase-1 suppresses T cell proliferation via inhibition

of IL-2 production. J Immunol. 2004;172(8):4744-4751.

2. Pae HO, et al. Roles of heme oxygenase-1 in the antiproliferative and antiapoptotic effects of nitric oxide on

Jurkat T cells. Mol Pharmacol. 2004;66(1):122-128.

*

0

20

40

60

80

100

[H3]

TdR

Upta

ke

(cpm

/wel

l x

10

-3)

CO gas

Fe2+

Bilirubin

-

-

-

+

-

-

-

+

-

-

-

+

(A) (B)

% I

nhib

itio

n

RuCO (M)

RuCO + HbRuCO

0

20

40

60

80

100

0 20 40 60 80

(C)

0

20

40

60

80

100

CD3/CD28

CoPP

Hb

+

-

-

+

+

-

+

+

+

* *

[H3]

TdR

Upta

ke

(cpm

/wel

l x

10

-3)


CO Blocks Early Signals of TCR-stimulated T Cells

0

12

3

4

5

6

7

0

1

2

34

56

7

0

12

3

0

CD3/CD28

RuCO After CD3/CD28

RuCOBefore CD3/CD28

Medium

Even

t

CFSE

(A) (B)Medium CD3/CD28

RuCO Before CD3/CD28

Cel

l N

um

ber

Relative DNA Content

G0/G1

G2/M

RuCO After CD3/CD28

1234567 0

HO

-1

CFSE

Division number

(C)

Pae HO, et al. Carbon monoxide produced by heme oxygenase-1 suppresses T cell proliferation

via inhibition of IL-2 production. J Immunol. 2004;172(8):4744-4751.


Transfer of Foxp3 Gene into Tres Mimics Treg Functions

Vec

tor/

Tre

s

Fre

sh T

reg

Fre

sh T

res

FO

Xp

3/T

res

Fre

sh T

reg

+ F

resh

Tre

s

FO

Xp

3/T

res

+F

resh

Tre

s

(Tra

nsw

ell)

FO

Xp

3/T

res

+ F

resh

Tre

s

FOXp3/Tres

Fresh Treg

Fresh Tres

(B)

(C)

(A)

SuppressionAnergy

Yagi H, et al. Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells.

Int Immunol. 2004;16(11):1643-1656.

HO-1/CO in Immune System and Effects of HO-1/CO on Regulation

Transfer of Foxp3 Gene Induces HO-1 Expression

0.00Rel

ati

ve

Cel

l P

roli

fera

tio

n

0.50

1.00

Jurk

at

1.25

Jurk

at/

pcD

NA

Jurk

at/

Fo

xp

3

*

0.75

0.25

C

B

Rel

ati

ve

Fo

ld A

ctiv

ity

1

0

Jurk

at

Jurk

at/

Fo

xp

3

Jurk

at/

pcD

NA

*

2

3

4

-actin

Jurk

at

Jurk

at/F

oxp

3

Jurk

at/p

cDN

A

HO-1

D

IL-2

(p

g/m

L)

50

0

Jurk

at

Jurk

at/

pcD

NA

Jurk

at/

Fo

xp

3

*

100

150

200

Foxp3

Jurk

at

Jurk

at/F

oxp

3

Jurk

at/p

cDN

A

-actin

A

IFN

- (p

g/m

L)

25

0

Jurk

at

Jurk

at/

pcD

NA

Jurk

at/

Fo

xp

3

50

100

75

*

Choi BM, et al. Critical role of heme oxygenase-1 in Foxp3-mediated immune suppression.

Biochem Biophys Res Commun. 2005;327(4):1066-71.


HO-1 Induced by Foxp3 Inhibits T Cell Proliferation

Rel

ati

ve

Cel

l P

roli

fera

tion

0.0

1.0

Jurk

at

1.5

Jurk

at/

pcD

NA

Jurk

at/

Fo

xp

3

NoneIL-2

*

0.5

C

Rel

ati

ve

Cel

l P

roli

fera

tion

0.0

1.0

Jurk

at

1.5Ju

rkat

/ p

cDN

A

Jurk

at/

Fo

xp

3

NoneZnPPSiRNA

**

0.5

A

*

0

IL-2

(p

g/m

L)

100

150

Jurk

at

200

Jurk

at/

pcD

NA

Jurk

at/

Fo

xp

3

NoneZnPPSiRNA

50

B

**

*

Anergy




HO-1 Induced by Foxp3 Suppresses T Cell Proliferation

Rel

ati

ve

Cel

l P

roli

fera

tion

0.0

1.0

Jurk

at

alo

ne

1.5

+Ju

rkat

/ F

oxp

3

NoneZnPPSiRNA

*0.5

**

A

Rel

ati

ve

Cel

l P

roli

fera

tion

0.0

1.0

1.5

0.5

*

NoneIL-2

B

Jurk

at

alo

ne

+Ju

rkat

/ F

oxp

3

Rel

ati

ve

Cel

l P

roli

fera

tion

0.0

1.0

1.5

0.5

C

Jurk

at

alo

ne

+Ju

rkat

/ F

oxp

3

+Ju

rkat

/ F

oxp

3

(tra

nsw

ell

)

Suppression




Tres Treg

APC

MHC

TCRB7

CD28

MHC

TCR B7

CTLA-4

Tryptophan

KynureninesIDO

HO-1

Heme

Fe2+

COBiliverdin

IL-2

IFN-

IL-10

TGF-

IL-2

HA

An Integral Role for HO-1/CO in Maintaining Peripheral Tolerance by CD4+CD25+ Regulatory T Cells

Brusko et. al. Journal of Immunology 2005, 174:5181-5186.


Involvement of HO-1/CO in Generation/Function of Treg Cells


T-Cell

APC

Monocyte

Th1

CO

CO

Cytokine

AICD

COCO

HO-1

Enhancing

Blocking

Treg

Tres

CO

CO

HO-1

NO H2S

IFN-

Tres

IL-10

Treg

As Inducer

As Inhibitor

Interactions of Gases, Cytokines & Cells in the Immune Response


Protective Effects of HO-1/CO on RA & Autoimmune Hepatitis

Co

llag

en

+ C

oP

P

Co

ntr

ol

Co

llag

en

SnPP + Con ACORM + Con A

Control Con A

HO-1/CO in Immune System and Effects of HO-1/CO on Disorders

HO-1

Nrf2

MAPKs

Inducers

Heme

DC

T Cell

MC

Eos

Sensitization

Th2 Cell Proliferation

Mediator Release

Inflammation & Oxidative Stress

Allergen

CO/Nrf2

Fe2+/Ferritin

BV,BR/NF-B Antioxidant/Anti-inflammatory

An

ti-a

lle

rgic

B Cell IgE Production

DC: Dendritic Cell

MC: Mast Cell

Eos: Eosinophil

Re-e

xp

os

ure

Multi-targeted Effects of HO-1 on Allergic Inflammation


Inhibitory Effects of HO-1/CO on Contact Hypersensitivity

Control

SnPP + DNFB

CoPP + DNFB

DNFB

0

5

10

15

20

25

E

ar-s

wel

lin

g r

esp

on

se (

1 x

10

-2m

m)

+-+

DNFBSnPP

CoPP/CO

---

-+-

-++

++-

+--

30

GAPDH

TNF-

IL-1

IL-4

IFN-

IL-5

IL-2

DNFBCoPP/CO

SnPP

---

+--

++-

+-+

Actin

HO-1

Veh

icle

Co

PP

Veh

icle

Co

PP

- DNFB + DNFB


Inducersor

DonorsSensors & Signals Biological Effects Tissue Protection

GasCORM

LPSTNF-α

HypoxiaNO & CO

COFromHeme

Oxygenase

Vasoregulation

Anti-inflammation

Anti-proliferation

Anti-thrombosis

Anti-apoptosis

IR-

injury

Endotoxemia

Asthma/COPD

Bleomycin-

and ventilator-

induced lung injury

Oxidative lung injury

Lung transplantation

Hemoprotein

sGC cGMP

MtROS MAPK (p38)

KCa

eNOS

HO-1/CO AS REHABILITATING MOLECULES

CO-induced Pathways of Potential Therapy in Lung Diseases

Potential Preventive Roles in Sepsis

In response to LPS, HO-1-deficient

mice, as compared with wild-type

mice, exhibit greater impairment in

renal hemodynamics.

Also, HO-1-deficient mice exhibit an

exaggerated induction of pro-

inflammatory cytokines in the kidney

in response to LPS.

HO-1 deficiency exaggerates

activation of NF-B, whereas HO-1

over-expression reduces NF-B

activation.

Tracz et. al. Am J Pathol. 2007;170(6):1820–1830.

LPSHO-1

CO/BR

Uncontrolled

Inflammation

NF-B?

HO-1

CORM

CO gas ?

Tissue

Damage

??

Endogenous

Exogenous


Rat lung transplantation increased HO-1 mRNA expression and protein level

A: Total RNA from the transplanted lung (day 4) was extracted and subjected to Northernblot hybridization with a 32P-labeled HO-1 cDNA Probe

B: Protein from the transplanted lung (day 4) was extracted and subjected to Western blothybridization with HO-1 antibody Am J Pathol 2003, 163:231–242

THERAPEUTIC EFFECTS OF HO-1 SYSTEM ON TRANSPLANTATION

Heme Oxygenase-1 and Transplantation

HO-1 induction in, or administering CO or bilirubin to, the donor, prolonged BALB/c isletssurvival in C57BL/6 recipients following transplantation FASEB J. 21, 3450–3457 (2007)



Combined treatments with CoPP, CO, and bilirubin led to long-term survival of isletallograft FASEB J. 21, 3450–3457 (2007)



Expression of Foxp3, TGF-,and IL-10 in spleens and isletgrafts from recipients carryinglong-term surviving grafts

FASEB J. 21, 3450–3457 (2007)



Detection of Foxp3 expression in islet grafts at 7 days following transplantationby staining with the anti-Foxp3 antibody FASEB J. 21, 3450–3457 (2007)



Diabetes 54:1400–1406, 2005

CO administration only to the donor (●, n = 6), the islet (■, n = 6), or the recipient (▲, n= 6) led to long-term survival of allogeneic islets. A high percentage of grafts survivedlong-term when both donor and recipient were exposed to CO (✖, n = 7) compared withthe controls (○, n = 9).

Carbon Monoxide and Transplantation


Gross anatomy of lungs from rats 6 days after transplantation (arrow in A, B),and lungs from rats 6 days after transplantation which received 500 ppm COover this time period (arrow in C, D) Am J Pathol 2003, 163:231–242



CO administration only to the donor suppresses macrophage infiltration to theislet grafts in the recipients Diabetes 54:1400–1406, 2005



Myeloperoxidase activity was decreased in the CO-treated lung fromtransplantation Am J Pathol 2003, 163:231–242



Effect of CO on transplantation-induced TUNEL staining. Markedly elevated TUNELstaining (A, arrow and blue staining in B) occurred in lungs from rats 6 days aftertransplantation compared to lungs (C and D) from transplantation which received 500ppm CO over an equivalent time period. Scale bar, 100 m. Am J Pathol 2003, 163:231–242



CO inhibited transplantation-induced IL-6 mRNA expression and serum IL-6

A: Total RNA from the transplanted lung was extracted and subjected to Northern blothybridization with a 32P-labeled IL-6 cDNA probe

B: Serum was collected 4 days after transplantation and analyzed for IL-6 levels by ELISAAm J Pathol 2003, 163:231–242



CO decreased protein levels of multiple chemokines/cytokines following lung transplantation Am J Pathol 2003, 163:231–242



Biliverdin IXa

Bilirubin IXa

Heme

Two steps of heme degradation

THERAPEUTIC EFFECTS OF HO-1 / Br & Bv and Transplantation

Biliverdin Bilirubin

Biliverdin

Mechanisms of bilirubin/biliverdin action on acute rejection


Exogenous biliverdin administration induces donor specific tolerance to cardiac allografts


Bilirubin induces long-term survival to allogeneic islet allografts


Potential mechanism of the beneficial effect of bilirubin on allogeneic transplanted -cell islets

Bilirubin

Bilirubin

Bilirubin


Bilirubin/biliverdin inhibits proliferation of VSMCs

Bilirubin/Biliverdin

Apoptosis


Bilirubin suppresses neointimal hyperplasia associated with balloon injury


Effects of bilirubin/biliverdin in various animal models of IRI

Liver Kidney

Heart Small bowel


Potential mechanisms of bilirubin/biliverdin improving organ function during/after IRI


Apoptosis

Inflammation


Br/Bv Inhibits Acute & Chronic Rejections and IRI

Transplantation



Schematic representation of HO-1→CO axis, which acts on the proliferative response tothe benefit of the cell type involved so as to best re-establish homeostasis.

[Cell Cycle 7:10, 1379-1384; 15 May 2008

Heme Oxygenase-1 and Ischemia Reperfusion Injury

THERAPEUTIC EFFECTS OF HO-1 / HO-1 and IRI

Balance between immune effectors and protective gene expression: a working paradigmto determine the fate of the graft. X, Y, Z refer to additional protective proteins. EC,endothelial cells; SMC, smooth muscle cells Transplantation 2006;82: S36–S40

HO-1 inhibits Transplant Arteriosclerosis


A mechanistic scheme how HO-1 may affect IRI in the transplantA: The mechanism of IRI can be attributed to local neutrophil accumulation, lymphocyte/macrophage

activation, and release of pro-inflammatory mediators (ROS, cytokines), which lead to cell injury,and culminate in the graft failure

B: HO enzyme activity degrades heme to biliverdin, CO, and Fe 2+ Annals of Transplantation 2004, 9:84–87

Heme Oxygenase-1 and Ischemia Reperfusion Injury


Transplantation. Vol 74, 905–912 (2002)

HO-1 system: mechanisms of cytoprotection

CONCLUSION

Transplantation. Vol 74, 905–912 (2002)

HO-1 dynamics: Local and Systemic Interactions

CONCLUSION

Protective Roles of HO-1, CO & Br/Bv in Transplantation

Decreased Immune Response

Increased Immune Response

Chemokines

Free Heme

Cytokines

Apoptosis

T cell infiltration

HO-1

Inactivation

HO-1

Activation

Graft Survival

Graft Rejection

Nonself

Antigen

I/R injuryCO

BR

HO-1 metabolizes the

pro-oxidant free heme.

CO/BR prevents I/R

injury and apoptosis.

Expression of

chemokines and

cytokines is reduced by

HO-1 expression and/or

CO/BR treatment.

CO/BR inhibits T cell

activation and

infiltrations into graft

tissue.

CONCLUSION

CO-NO-REsearch Group

Dr. PaeDr. Lee

Dr. Kim

Zheng

Thank you

Documents

ROLE OF HEME OXYGENASE-1 (HO) & CARBON MONOXIDE (CO) …