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	ADENOSINE RECEPTORS: Therapeutic Aspects for Inflammatory and Immune Diseases
		Preface
		Contributors
		Table of Contents
3999_c001.pdf
	ADENOSINE RECEPTORS: Therapeutic Aspects for Inflammatory and Immune Diseases
		Table of Contents
		Chapter 1: Adenosine Receptor Pharmacology
			1.1 INTRODUCTION
			1.2 ADENOSINE RECEPTOR SUBTYPES
				1.2.1 S IGNALING
				1.2.2 S TRUCTURE
			1.3 ADENOSINE RECEPTOR LIGANDS
				1.3.1 A GONISTS
				1.3.2 ANTAGONISTS
			1.4 PHYSIOLOGICAL FUNCTIONS OF ADENOSINE
				1.4.1 CARDIOVASCULAR ACTIONS
				1.4.2 ADENOSINE AND THE KIDNEY
				1.4.3 CNS ACTIONS OF ADENOSINE
				1.4.4 ADENOSINE RECEPTORS AND CANCER
			1.5 CONCLUSION
			REFERENCES
3999_c002.pdf
	ADENOSINE RECEPTORS: Therapeutic Aspects for Inflammatory and Immune Diseases
		Table of Contents
		Chapter 2: Medicinal Chemistry of Adenosine A 3 Receptors
			2.1 INTRODUCTION
			2.2 A 3 AR AGONISTS
				2.2.1 O PTIMIZATION OF N 6 -S UBSTITUTION OF A DENOSINE IN B INDING TO THE A 3 AR
				2.2.2 COMBINATION OF N6-SUBSTITUTION OF ADENOSINE WITH 
5'-URONAMIDE MODIFICATION TO ACHIEVE A3AR SELECTIVITY
				2.2.3 OHER 5'-POSITION MODIFICATIONS
				2.2.4 O PTIMIZATION OF THE 2-P OSITION OF A DENOSINE IN B INDING TO THE A 3 AR
				2.2.5 OPTIMIZATION OF THE RIBOSE MOIETY OF ADENOSINE IN BINDING TO THE A3AR
				2.2.6 AGONISTS FOR REENGINEERED A3ARS: NEOCEPTORS
			2.3 A3AR ANTAGONISTS
				2.3.1 DIHYDROPYRIDINES AND PYRIDINES
				2.3.2 FLAVONOIDS
				2.3.3 TRIAZOLOQUINAZOLINES
				2.3.4 TRIAZOLOQUINOXALINES
				2.3.5 TRIAZOLOPURINES
				2.3.6 PYRAZOLOTRIAZOLOPYRIMIDINES
				2.3.7 PYRAZOLOQUINOLINES
				2.3.8 ISOQUINOLINES AND QUINAZOLINES
				2.3.9 THIAZOLES AND THIADIAZOLES
				2.3.10 FUSED XANTHINES: PURINONES AND PURINEDIONES
				2.3.11 ADENINE AND ADENOSINE DERIVATIVES
			2.4 USE OF SELECTIVE AGONISTS AND ANTAGONISTS
			2.5 CONCLUSIONS
			ACKNOWLEDGMENTS
			REFERENCES
3999_c003.pdf
	ADENOSINE RECEPTORS: Therapeutic Aspects for Inflammatory and Immune Diseases
		Table of Contents
		Chapter 3: The Role of CD73 in the Generation of Extracellular Adenosine for Adenosine Receptor Signaling
			3.1 INTRODUCTION
			3.2 GENERATION OF CD73 GENE-TARGETED MICE
			3.3 PHENOTYPES OF CD73-DEFICIENT MICE
				3.3.1 H YPOXIA - I NDUCED V ASCULAR L EAK AND N EUTROPHIL -
				3.3.2 C ORONARY B LOOD F LOW, P LATELET A GGREGATION,
				3.3.3 TUBULOGLOMERULAR FEEDBACK
			3.4 FUTURE STUDIES
			ACKNOWLEDGMENT
			REFERENCES
3999_c004.pdf
	ADENOSINE RECEPTORS: Therapeutic Aspects for Inflammatory and Immune Diseases
		Table of Contents
		Chapter 4: Regulation of Monocyte/ Macrophage Function by Adenosine Receptors
			4.1 INTRODUCTION
			4.2 FUNCTIONAL HETEROGENEITY OF MACROPHAGES
			4.3 ADENOSINE METABOLISM INTRA-
			4.4 EFFECT OF ADENOSINE ON MONOCYTE/MACROPHAGE
			4.5 OPPOSING ROLES FOR A 1 AND A2 RECEPTORS IN MODULATING FC- RECEPTOR- MEDIATED PHAGOCYTOSIS
			4.6 ADENOSINE-INHIBITED MONOCYTE/MACROPHAGE
			4.7 ADENOSINE-MODULATED NITRIC OXIDE (NO)
			4.8 REGULATION OF PATTERN RECOGNITION RECEPTOR
				4.8.1 ADENOSINE-MODULATED TNF-
				4.8.2 ADENOSINE SUPPRESSION OF IL-12 PRODUCTION
				4.8.3 ADENOSINE-AUGMENTED IL-10 RELEASE
			4.9 ADENOSINE-INHIBITED TISSUE FACTOR EXPRESSION
			4.10 REGULATION OF VASCULAR ENDOTHELIAL
			4.11 FUTURE PERSPECTIVES AND THERAPEUTIC
			ACKNOWLEDGMENT
			REFERENCES
3999_c005.pdf
	ADENOSINE RECEPTORS: Therapeutic Aspects for Inflammatory and Immune Diseases
		Table of Contents
		Chapter 5: Impaired Lymphocyte Activation in the Presence of Adenosine: Mechanisms and Physiologic Relevance
			5.1 INTRODUCTION
			5.2 ADENOSINE RECEPTOR SUBTYPES EXPRESSED
				5.2.1 A DENOSINE R ECEPTOR S UBTYPES
				5.2.2 T L YMPHOCYTES
				5.2.3 B L YMPHOCYTES
				5.2.4 N ATURAL K ILLER C ELLS
			5.3 ADENOSINE EFFECTS ON LYMPHOCYTE
				5.3.1 T LYMPHOCYTES
				5.3.2 B LYMPHOCYTES
				5.3.3 NATURAL KILLER CELLS
			5.4 CYTOTOXIC EFFECT OF ADENOSINE
			5.5 LYMPHOCYTE-ASSOCIATED ADENOSINE DEAMINASE
			5.6 ADENOSINE SIGNALING IN DISEASE PROCESSES
			5.7 CONCLUSIONS
			REFERENCES
3999_c006.pdf
	ADENOSINE RECEPTORS: Therapeutic Aspects for Inflammatory and Immune Diseases
		Table of Contents
		Chapter 6: Adenosine and Neutrophil Functions
			6.1 INTRODUCTION
				6.1.1 T HE N EUTROPHIL: A R OLE IN O RCHESTRATING
				6.1.2 A DENOSINE R ECEPTOR E XPRESSION IN N EUTROPHILS
			6.2 IMPACT OF ADENOSINE ON NEUTROPHIL FUNCTIONS
				6.2.1 C HEMOTAXIS AND T RANSMIGRATION
				6.2.2 S UPEROXIDE G ENERATION AND D EGRANULATION
				6.2.3 G ENERATION OF L IPID M EDIATORS
				6.2.4 GENERATION OF CYTOKINES AND CHEMOKINES
			6.3 SUMMARY AND CONCLUDING REMARKS
			REFERENCES
3999_c007.pdf
	ADENOSINE RECEPTORS: Therapeutic Aspects for Inflammatory and Immune Diseases
		Table of Contents
		Chapter 7: Dendritic Cells Regulated by Nucleotides and Nucleosides
			7.1 NUCLEOTIDES AS ENDOGENOUS MODIFIER SIGNALS
			7.2 NUCLEOTIDE AND NUCLEOSIDE RECEPTORS
			7.3 ADENOSINE BREAKDOWN
			7.4 EXTRACELLULAR NUCLEOTIDEÒDC INTERACTION
			7.5 CONCLUSION
			REFERENCES
3999_c008.pdf
	ADENOSINE RECEPTORS: Therapeutic Aspects for Inflammatory and Immune Diseases
		Table of Contents
		Chapter 8: Adenosine and Endothelial Cell Function
			8.1 INTRODUCTION
			8.2 HETEROGENEITY OF ENDOTHELIAL CELLS
			8.3 REGULATION OF VASCULAR TONE
			8.4 REGULATION OF ENDOTHELIAL BARRIER FUNCTION
			8.5 RECRUITMENT OF INFLAMMATORY CELLS
			8.6 THE ROLE OF ADENOSINE IN THE ANTICOAGULANT
			8.7 ROLE OF ADENOSINE IN ANGIOGENESIS
			8.8 CONCLUDING REMARKS
			ACKNOWLEDGMENT
			REFERENCES
3999_c009.pdf
	ADENOSINE RECEPTORS: Therapeutic Aspects for Inflammatory and Immune Diseases
		Table of Contents
		Chapter 9: Adenosine A 2B Receptor in the Intestinal Epithelia
			9.1 INTRODUCTION
			9.2 ADENOSINE IN THE INTESTINE
			9.3 DISTRIBUTION OF A 2B RECEPTORS IN THE INTESTINE
			9.4 SIGNALING AND TRAFFICKING OF THE A 2B RECEPTOR IN THE INTESTINE
			9.5 DESENSITIZATION OF THE A2B RECEPTOR
			9.6 BIOLOGICAL EFFECTS MEDIATED BY THE
				9.6.1 ADENOSINE- MEDIATED VECTORIAL CHLORIDE SECRETION
				9.6.2 ADENOSINE-INDUCED POLARIZED SECRETION OF IL-6
				9.6.3 F IBRONECTIN S ECRETION
			9.7 REGULATION OF THE INTESTINAL A 2B RECEPTOR
				9.7.1 E FFECT OF IFN-
				9.7.2 EFFECT OF TNF-
			9.8 A2B RECEPTOR EXPRESSION DURING COLITIS
			9.9 SUMMARY
			REFERENCES
3999_c010.pdf
	ADENOSINE RECEPTORS: Therapeutic Aspects for Inflammatory and Immune Diseases
		Table of Contents
		Chapter 10: Adenosine, Adenosine Receptors, and the Regulation of Glial Cells in Neuronal Damage
			10.1 ADENOSINEÌS ROLE IN ISCHEMIC BRAIN DAMAGE:
			10.2 GLIAL CELLS AND MODULATION
				10.2.1 A STROCYTES
				10.2.2 O LIGODENDROCYTES
				10.2.3 M ICROGLIA
			10.3 GENERAL CONCLUSION
			ACKNOWLEDGMENTS
			REFERENCES
3999_c011.pdf
	ADENOSINE RECEPTORS: Therapeutic Aspects for Inflammatory and Immune Diseases
		Table of Contents
		Chapter 11: Adenosine Receptors, Wound Healing, and Angiogenesis
			11.1 INTRODUCTION
			11.2 ADENOSINE A 2A RECEPTOR AGONISTS AND WOUND HEALING
			11.3 ADENOSINE-MEDIATED TRANSFORMATION
			11.4 ADENOSINE RECEPTORS AND MATRIX PRODUCTION
			11.5 ADENOSINE RECEPTORS AND ANGIOGENESIS
			11.6 ADENOSINE RECEPTORS AND
			11.7 CONCLUSION
			ACKNOWLEDGMENTS
			REFERENCES
3999_c012.pdf
	ADENOSINE RECEPTORS: Therapeutic Aspects for Inflammatory and Immune Diseases
		Table of Contents
		Chapter 12: A 2A Adenosine Receptors and Ischemia Reperfusion Injury
			12.1 ISCHEMIA REPERFUSION INJURY
			12.2 MEDIATORS OF IRI
				12.2.1 R EACTIVE O XYGEN S PECIES
				12.2.2 F ORMATION OF X ANTHINE O XIDASE
				12.2.3 NADPH-D EPENDENT O XIDASE IN M ACROPHAGES
				12.2.4 NF- KB
				12.2.5 R OLE OF C YTOKINES IN IRI
				12.2.6 R OLE OF T C ELLS IN IRI
			12.3 STRATEGIES FOR LIMITING IRI
			12.4 ADENOSINE AND IRI
				12.4.1 HEPATIC IRI
				12.4.2 RENAL IRI
				12.4.3 SPINAL CORD IRI
				12.4.4 CARDIAC IRI
			12.5 CONCLUSIONS
			REFERENCES
3999_c013.pdf
	ADENOSINE RECEPTORS: Therapeutic Aspects for Inflammatory and Immune Diseases
		Table of Contents
		Chapter 13: Adenosine Signaling in Chronic Lung Disease
			13.1 INTRODUCTION
			13.2 CHRONIC LUNG DISEASE
			13.3 ADENOSINE PRODUCTION, METABOLISM,
				13.3.1 A DENOSINE P RODUCTION , M ETABOLISM , AND T RANSPORT
				13.3.2 A DENOSINE P RODUCTION AND M ETABOLISM IN C HRONIC
			13.4 ADENOSINE IN ANIMAL MODELS
				13.4.1 ADA-D EFICIENT M ICE
				13.4.2 PULMONARY FIBROSIS IN PARTIALLY ADA-DEFICIENT MICE
				13.4.3 IL-13-OVEREXPRESSING MICE
				13.4.4 ALLERGIC MODELS OF LUNG DISEASE
			13.5 ADENOSINE RECEPTOR CONTRIBUTIONS
				13.5.1 CONTRIBUTION OF THE A3AR
				13.5.2 CONTRIBUTION OF THE A1AR
				13.5.3 CONTRIBUTION OF THE A2AAR
				13.5.4 CONTRIBUTION OF THE A2BAR
			13.6 PURINERGIC REMODELING IN CHRONIC
			13.7 TH1 VS. TH2 CYTOKINES, ADENOSINE,
			13.8 CONCLUDING REMARKS
			ACKNOWLEDGMENTS
			REFERENCES
3999_c014.pdf
	ADENOSINE RECEPTORS: Therapeutic Aspects for Inflammatory and Immune Diseases
		Table of Contents
		Chapter 14: Role of Adenosine in the Control of Inflammatory Events Associated with Acute and Chronic Neurodegenerative Disorders
			14.1 NEUROINFLAMMATION IN ACUTE AND CHRONIC
			14.2 ANTI-INFLAMMATORY ACTIONS OF
			14.3 ANTI-INFLAMMATORY ACTIONS OF ADENOSINE
				14.3.1 I SCHEMIC S TROKE
				14.3.2 H EMORRHAGIC S TROKE
				14.3.3 TRAUMATIC BRAIN INJURY
			14.4 ANTI-INFLAMMATORY ACTIONS OF ADENOSINE
				14.4.1 MULTIPLE SCLEROSIS
				14.4.2 ALZHEIMERÌS DISEASE
				14.4.3 PARKINSONÌS DISEASE
				14.4.4 HIV-1 ASSOCIATED DEMENTIA
				14.4.5 HUNTINGTONÌS DISEASE
				14.4.6 SEIZURES AND EPILEPSY
			14.5 SUMMARY
			ACKNOWLEDGMENTS
			REFERENCES
3999_c015.pdf
	ADENOSINE RECEPTORS: Therapeutic Aspects for Inflammatory and Immune Diseases
		Table of Contents
		Chapter 15: Anti- Inflammatory and Cytoprotective Effects of Inosine
			15.1 THE FORMATION AND DEGRADATION OF INOSINE
			15.2 INOSINE-SENSITIVE CELL SURFACE RECEPTORS
			15.3 INOSINE AND MAST CELL DEGRANULATION
			15.4 INOSINEÌS ROLE IN SUPPRESSION OF MACROPHAGE,
			15.5 INOSINE AND PROINFLAMMATORY
			15.6 INOSINE AND CHRONIC
			15.7 INOSINE AND ISCHEMIA-REPERFUSION INJURY
			15.8 INOSINE AND HYPEROXIC CELL INJURY
			15.9 INOSINE AND GLIAL AND NEURONAL
			15.10 INOSINE AND AXONAL REGROWTH AFTER INJURY
			15.11 THE MULTIPLE MECHANISMS OF INOSINEÌS ACTION
				15.11.1 INTERACTION WITH SURFACE RECEPTORS
				15.11.2 INDIRECT ENHANCEMENT OF ADENOSINEÌS ACTIONS
				15.11.3 ENHANCEMENT OF URIC ACID PRODUCTION
				15.11.4 INHIBITION OF POLY(ADP-RIBOSE) POLYMERASE (PARP)
				15.11.5 ADDITIONAL CELLULAR MECHANISMS
			15.12 FUTURE PROSPECTS
			REFERENCES
3999_c016.pdf
	ADENOSINE RECEPTORS: Therapeutic Aspects for Inflammatory and Immune Diseases
		Table of Contents
		Chapter 16: Adenosine and Infection
			16.1 INTRODUCTION
			16.2 BACKGROUND
			16.3 CELLULAR RESPONSE
				16.3.1 E FFECTS OF A DENOSINE ON N EUTROPHIL A CTIVATION
				16.3.2 E FFECT OF A DENOSINE ON M ONOCYTE AND M ACROPHAGE A CTIVATION
				16.3.3 R EGULATION BY THE A 2A AR OF T C ELLS
			16.4 MENINGITIS
			16.5 PERITONITIS
			16.6 SEPTIC ARTHRITIS
			16.7 SEPSIS
			16.8 CONCLUSION
			REFERENCES
3999_c017.pdf
	ADENOSINE RECEPTORS: Therapeutic Aspects for Inflammatory and Immune Diseases
		Table of Contents
		Chapter 17: Regulation of Peripheral Inflammation by Spinal Adenosine
			17.1 INTRODUCTION
			17.2 THE EFFECT OF INTRATHECAL ADENOSINE
			17.3 AFFERENT INPUT: THE EFFECT ON
			17.4 PERIPHERAL ANTI-INFLAMMATORY EFFECT MEDIATED BY
			17.5 THE EFFECT OF IT ADENOSINE AGONIST
			17.6 POTENTIAL CENTRAL MECHANISMS IN THE
			17.7 POTENTIAL PERIPHERAL MECHANISMS IN THE
			17.8 CONCLUSIONS AND IMPLICATIONS
			REFERENCES
3999_c018.pdf
	ADENOSINE RECEPTORS: Therapeutic Aspects for Inflammatory and Immune Diseases
		Table of Contents
		Chapter 18: Adenosine, Tumors, and Immunity
			18.1 INTRODUCTION
			18.2 THE EFFECT OF ADENOSINE ON TUMOR CELL GROWTH
				18.2.1 T HE A NTITUMOR E FFECT OF A DENOSINE: M EDIATED
				18.2.2 D IRECT A NTITUMOR E FFECTS I NDUCED BY A 3 AR A GONISTS
				18.2.3 INDIRECT ANTITUMOR EFFECTS MEDIATED
			18.3 ENHANCEMENT OF CHEMOTHERAPEUTIC
				18.3.1 A3AR AGONISTS AND ANTAGONISTS AND CHEMOTHERAPEUTIC INDEX ENHANCEMENT
				18.3.2 THE A1 AND THE A3 ADENOSINE RECEPTORS: MEDIATING CHEMOPROTECTIVE EFFECTS
			18.4 CONCLUSIONS
			REFERENCES
3999_c019.pdf
	ADENOSINE RECEPTORS: Therapeutic Aspects for Inflammatory and Immune Diseases
		Table of Contents
		Chapter 19: Adenosine in Atherosclerosis
			19.1 INTRODUCTION
			19.2 ADENOSINE IN THE VESSEL WALL
				19.2.1 V ASCULAR S MOOTH M USCLE C ELLS
				19.2.2 E NDOTHELIAL C ELLS
				19.2.3 PLATELETS
			19.3 ADENOSINE IN CHOLESTEROL HOMEOSTASIS
			19.4 CONCLUSIONS
			ACKNOWLEDGMENTS
			REFERENCES
3999_c020.pdf
	ADENOSINE RECEPTORS: Therapeutic Aspects for Inflammatory and Immune Diseases
		Table of Contents
		Chapter 20: Regulation of Macrophage- Dependent Angiogenesis by Adenosine and Toll- Like Receptors
			20.1 INTRODUCTION
			20.2 PATHWAYS OF MACROPHAGE ACTIVATION
			20.3 TOLL-LIKE RECEPTORS (TLRs)
			20.4 ADENOSINE AND ADENOSINE RECEPTORS
			20.5 REGULATION OF MACROPHAGE ACTIVATION
			20.6 ROLE FOR THE ADENOSINE-TLR-MEDIATED
			ACKNOWLEDGMENTS
			REFERENCES
                        
Document Text Contents
Page 1

ADENOSINE
RECEPTORS
Therapeutic Aspects for
Inflammatory and
Immune Diseases

© 2007 by Taylor & Francis Group, LLC

Page 2

CRC is an imprint of the Taylor & Francis Group,
an informa business

Boca Raton London New York

ADENOSINE
RECEPTORS
Therapeutic Aspects for
Inflammatory and
Immune Diseases

Edited by
György Haskó
Bruce N. Cronstein
Csaba Szabó

© 2007 by Taylor & Francis Group, LLC

Page 175

A



2A



Adenosine Receptors and Ischemia Reperfusion Injury



169



12.2.5 R



OLE







OF



C



YTOKINES







IN



IRI



The functions of proinflammatory cytokines are both varied and complex. These
polypeptide or glycoprotein mediators influence the differentiation, proliferation,
and activation state of many cell types, and they also interact with and regulate the
activity of other cytokines.



36



Although we will not present a complete review of
proinflammatory cytokine activity, we will point out some key features as they
pertain to IRI. TNF-



α



is an early-response gene that is involved in many facets of
inflammatory responses. TNF-



α



mRNA is elevated within 15 min of ischemia, and
this macrophage- and neutrophil-derived cytokine can both directly (via the inhibi-
tion of nitric oxide production by the endothelium and the activation of the neutrophil
oxidative burst) and indirectly (via the upregulation of cytokine and adhesion mol-
ecule expression) contribute to IR-induced tissue dysfunction.



37–39



The upregulation
of IL-1 and TNF-



α



by NF-



κ



B is significant in that these cytokines are chemoattractant,
drawing neutrophils out of circulation by facilitating their rolling and firm adhesion
along the endothelium via the upregulation of E-selectin and ICAM-1.



39–41



Addi-
tionally, both TNF-



α



and IL-1 stimulate the production of IL-8, which along with
PAF also stimulates neutrophil accumulation and activation in ischemic tissue.



42



The
activity of these proinflammatory cytokines is redundant and interrelated, and they
serve to propagate the initial xanthine-oxidase-driven ROS response and an accom-
panying increase in vascular permeability and cell death.



12.2.6 R



OLE







OF



T C



ELLS







IN



IRI



In addition to the aforementioned cytokines, the expression of the T cell chemotactic
factors, RANTES, MCP-1, and IP-10, are upregulated after IRI.



43



Multiple studies
have demonstrated that in addition to neutrophils and macrophages, T lymphocytes
are also intimately involved in the pathogenesis of IRI. When mice lacking T
lymphocytes are utilized in models of renal or hepatic IRI, there is a resulting
decrease in neutrophil recruitment and inflammation after reperfusion, and reduced
injury.



44–48



Because large numbers of T lymphocytes are not detected in affected
tissue until 48 to 72 h after the initiation of reperfusion, it was initially believed that
these cells were involved only in the late stage of reperfusion injury. However,
evidence is accumulating to suggest that T lymphocytes play a role in subacute
phases of IRI.



49–51



The production of chemokines such as IP-10 and MCP-1 by
activated macrophages may serve to recruit both T lymphocytes and neutrophils to
ischemic tissue, whereupon both cell types are likely to play a role in the propagation
of injury; neutrophils via the release of MPO, the generation of superoxide anion,
and the release of proteases, and T cells via the production and release of proinflam-
matory cytokines (particularly IFN-



γ



) that may serve to further activate macrophages.



12.3 STRATEGIES FOR LIMITING IRI



Although the pathogenesis of IRI is extremely complex and many aspects are still
unclear, a preponderance of evidence indicates that ROS and leukocytes play integral
roles in the pathophysiology of this disorder. It is even possible that ROS production



3999_C012.fm Page 169 Wednesday, May 24, 2006 11:06 AM

© 2007 by Taylor & Francis Group, LLC

Page 176

170



Adenosine Receptors



by xanthine oxidase or other oxidases in response to reperfusion could initiate a
cascade of inflammatory events leading ultimately to cellular damage and death.
Although the onset of an ischemic episode cannot generally be predicted, it may be
possible to control further injury due to the subsequent reperfusion phase of the
phenomenon. Several attempts have been made to achieve this goal; treatments with
free radical scavengers, antioxidants, and neutralizing antibodies have been used in
several models of IRI with varying degrees of success. The inflammatory component
of IRI provides a clear target at which therapeutic agents may be directed. Although
the inhibition of the reperfusion-induced inflammatory cascade may not provide
complete protection from injury, data indicate that this approach shows significant
promise.



12.4 ADENOSINE AND IRI



Periods of ischemia are accompanied by a significant outpouring of adenosine from
injured tissue, and this endogenously released adenosine participates in a phenomenon
known as



ischemic preconditioning



, defined as the protection conferred during a
sustained ischemic period by a preceding brief ischemic episode.



52–54



The role of
adenosine in ischemic preconditioning was first identified in the myocardium, and
although the mechanism by which preconditioning protects the heart has not yet
been fully elucidated, evidence indicates that the activation of the A



1



AR or A



3



AR
on cardiomocytes activates a signaling cascade involving K



+



-ATP channels and
alterations in mitochondrial function.



55,56



These observations suggest that the admin-
istration of exogenous adenosine either before or during ischemia or reperfusion
may mimic (or supplement) this protection. The therapeutic relevancy of adenosine,
however, is limited by its short half-life and nonselective activation of all four AR
subtypes.



57



Thus, the administration of more stable, subtype-selective AR agonists
is an attractive alternative. Although the A



1



AR and A



3



AR are presumably involved
in preconditioning, the activation of A



1



receptors can produce heart block, and the
activation of A



3



receptors is sometimes proinflammatory. In contrast to A



1



AR and
A



3



AR agonists that appear to block ischemic injury, A



2A



agonists block inflammation
and protect against reperfusion injury. A



2AAR receptor activation inhibits inflamma-
tion by effects on virtually all cells of the immune system including, but not limited
to, T lymphocytes, macrophages, monocytes, platelets, and neutrophils.58–60 Multiple
manifestations of inflammatory cell activation, including proinflammatory cytokine
production and adhesion molecule expression, are inhibited by A2AAR activation.

61–64

One mechanism by which the anti-inflammatory effects of A2AAR agonists may be
mediated is via the inhibition of NF-κB signaling. Evidence indicates that A2AAR
activation blocks the NF-κB pathway downstream of immunoreceptors by interfering
with the activation of the IKK complex or by hindering the IKK-IκB interaction; this
activity is cAMP and PKA dependent.31 It has also been shown in murine models
that adenosine suppresses IκBα degradation induced by cardiac ischemia.65 Addi-
tionally, the ability of NF-κB to bind DNA after TNF-α-induced activation is inhib-
ited by adenosine in a variety of cell types including T lymphocytes, epithelial cells,
and myeloid cells.32 In addition to their effects as anti-inflammatory agents, A2AAR
agonists are also vasodilators. It is notable, however, that inhibition of inflammation

3999_C012.fm Page 170 Wednesday, May 24, 2006 11:06 AM

© 2007 by Taylor & Francis Group, LLC

Page 350

Regulation of Macrophage-Dependent Angiogenesis 345

160. Pugh, C.W. and Ratcliffe, P.J., Regulation of angiogenesis by hypoxia: role of the
HIF system, Nat. Med., 9, 677, 2003.

161. Salceda, S. and Caro, J., Hypoxia-inducible factor 1 alpha (HIF-1alpha) protein is
rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its
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22642, 1997.

162. Semenza, G., HIF-1 and mechanisms of hypoxia sensing, Curr. Opin. Cell Biol., 13,
167, 2001.

163. Semenza, G.L., HIF-1, O2, and the three PHDs: how animal cells signal hypoxia in
the nucleus, Cell, 107, 1, 2001.

164. Yu, F. et al., HIF-1alpha binding toVHL is regulated by stimulus-sensitive proline
hydroxylation, Proc. Natl. Acad. Sci. U.S.A., 98, 9630, 2001.

165. Hon, W.C. et al., Structural basis for the recognition of hydroxyproline in HIF-1 alpha
by pVHL, Nature, 417, 975, 2002.

166. Mole, D.R. et al., Regulation of the HIF pathway: enzymatic hydroxylation of a
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