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Exciting times for life without a nucleus: broad roles for platelets in vascular inflammation
Drug Discovery Today: Disease Mechanisms
DRUG DISCOVERY
TODAY
Vol. 8, No. 1-2 2011
Editors-in-Chief Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA Charles Lowenstein – University of Rochester Medical Center, Rochester, NY.
DISEASE Editorial MECHANISMS
Exciting times for life without a nucleus: broad roles for platelets in vascular inflammation Craig N. Morrell Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, ACVRI - 211 Bailey Road, Rochester, NY 14642, United States. Email: ([email protected])
Despite their status as the most numerous blood cell types, the roles for platelets and red blood cells (RBCs) in both initiating and driving vascular inflammatory diseases are often overlooked, in large part due to their anucleate status. Platelets are orders of magnitude more numerous than other inflammatory cell types found in the blood. But it is more than just a numbers game that accounts for the role of platelets as a major cellular mediator of vascular inflammation. Platelets contain, produce and secrete a large number of immune and thrombotic molecules that reach very high local and systemic concentrations. Platelets therefore initiate or accelerate the outcomes of numerous vascular pathologies and diseases including cancer, malaria, dengue virus infection, human immunodeficiency virus (HIV) infection and antiphosopholipid antibody (APL) syndromes. This set of reviews discusses relevant and important emerging roles for platelets in a range of diseases that they are not traditionally associated with. A common thread in platelet and RBC research is the difficulty in modeling their production using in vitro culture systems, therefore limiting our ability to easily define molecular interactions involved in platelet and RBC production and signaling. However, advances in RBC culture systems have been made and are discussed in the review by Dr. James Palis. Platelet transfusions are used to treat severely thrombocytopenic patients or those with serious ongoing bleeding. Although fairly common, platelet transfusion is not a benign procedure and platelet transfusion reactions can occur. In light of the multitude of pro-inflammatory mediators that platelets secrete or express, this is not surprising. During the collection and storage process platelets undergo changes that alter their in vivo function, and during storage platelets may produce and release pro-inflammatory mediators that have adverse effects when infused into an already sick patient. This is often termed the ‘platelet storage lesion’ (PSL). The review by Blumberg and colleagues addresses this important complication of platelet 1740-6765/$ ß 2011 Published by Elsevier Ltd.
DOI: 10.1016/j.ddmec.2011.12.001
transfusions, some of the mechanisms involved and considers means to ameliorate complications associated with platelet transfusions. Platelet microparticles (PMPs) have been recognized since the 1980s, but it has only been more recent that an appreciation of their ability to significantly contribute to inflammation and thrombosis has been popularized. Platelets represent the source of about 70% of all circulating microparticles. PMPs are increased in many vascular and inflammatory conditions including atherosclerosis, some types of cancer, arthritis and cerebral malaria. PMPs are not simply platelet membrane fragment markers of disease, but directly contribute to thrombosis and vascular inflammation. The review by Wasmer, Combs and Grau explores the current state of our knowledge of PMPs and their potentially important role in the pathogenesis of cerebral malaria. Not only do platelets have a key role in the pathogenesis of this infectious disease, but platelets may also contribute to the pathogenesis of other infectious disease processes through their immune functions. Other infectious diseases with a platelet relevance discussed in this set of reviews are HIV and dengue virus. Both HIV and dengue infection often have concurrent thrombocytopenia, and thrombocytopenia is associated with worse outcomes.
Dr. Morrell is an Associate Professor in the Aab Cardiovascular Research Institute at the University of Rochester School of Medicine. His lab is interested in the major roles platelets have in vascular biology as mediators of thrombosis and inflammation. Dr. Morrell received his Sc.B. at Brown University, D.V.M. degree at Tufts University School of Veterinary Medicine, and Ph.D. at The Johns Hopkins University School of Medicine. He began his research career at Johns Hopkins before moving to the University of Rochester in 2009.
e1
Drug Discovery Today: Disease Mechanisms | Editorial
Furthermore, low platelet counts not only represent a clinical side effect, but may also contribute to disease pathology. This is discussed in reviews by Dr. Joseph Mankowski and Drs. Fernando Bozza and Andrew Weyrich. An important cause of morbidity and mortality in cancer patients are secondary complications from thrombotic disease. This is particularly problematic in certain types of cancers, such as pancreatic cancer. Tissue factor expression by the tumor, and from other sources appears to be a main mediator of the thrombotic complications. New strategies are in development to try to lessen these often severe complications, but like all antithrombotic therapies, it demands a balance between blunting thrombotic risk without greatly increasing bleeding risk. The review by Alok Khorana addresses the need for a better understanding of the pathogenesis of cancer-associated thrombosis and better means to predict risk. Antiphospholipid antibody syndrome (APS) is an autoimmune disease that occurs in the context of systemic lupus erythematosus (SLE). APS is a major cause of multiple miscarriages and thrombosis in young women, and is typified by an increased rate of thrombocytopenia and risk of both
e2
www.drugdiscoverytoday.com
Vol. 8, No. 1-2 2011
arterial and venous thrombosis. The cause of APS is primarily secondary to antibodies to self-b2 glycoprotein or cardiolipin. The mechanisms behind this antibody-mediated disease risk are probably multifactorial and only now becoming clearer. Recent work by one of the review authors, Dr. Chieko Mineo, has implicated a blunting of endothelial nitric oxide synthase (eNOS) activity as a potential contributor to increased thrombotic risk and vascular inflammation associated with APS. This is reviewed in this edition. This collection of review articles highlights new insights into platelet-related disease complications, and through the example of strategies for RBC production in culture, provide insights on how to perhaps better culture and genetically manipulate anucleate cells in vitro. The contribution of platelets to inflammation on an individual cell-to-cell interaction level may not be as great as other more classical immune cells, but due to their high numbers and multiple cell interactions, the impact of platelets in immune responses is well worth consideration. With best wishes, Craig N. Morrell
DRUG DISCOVERY
TODAY
Vol. 8, No. 1-2 2011
Editors-in-Chief Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA Charles Lowenstein – University of Rochester Medical Center, Rochester, NY.
DISEASE Editorial MECHANISMS
Exciting times for life without a nucleus: broad roles for platelets in vascular inflammation Craig N. Morrell Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, ACVRI - 211 Bailey Road, Rochester, NY 14642, United States. Email: ([email protected])
Despite their status as the most numerous blood cell types, the roles for platelets and red blood cells (RBCs) in both initiating and driving vascular inflammatory diseases are often overlooked, in large part due to their anucleate status. Platelets are orders of magnitude more numerous than other inflammatory cell types found in the blood. But it is more than just a numbers game that accounts for the role of platelets as a major cellular mediator of vascular inflammation. Platelets contain, produce and secrete a large number of immune and thrombotic molecules that reach very high local and systemic concentrations. Platelets therefore initiate or accelerate the outcomes of numerous vascular pathologies and diseases including cancer, malaria, dengue virus infection, human immunodeficiency virus (HIV) infection and antiphosopholipid antibody (APL) syndromes. This set of reviews discusses relevant and important emerging roles for platelets in a range of diseases that they are not traditionally associated with. A common thread in platelet and RBC research is the difficulty in modeling their production using in vitro culture systems, therefore limiting our ability to easily define molecular interactions involved in platelet and RBC production and signaling. However, advances in RBC culture systems have been made and are discussed in the review by Dr. James Palis. Platelet transfusions are used to treat severely thrombocytopenic patients or those with serious ongoing bleeding. Although fairly common, platelet transfusion is not a benign procedure and platelet transfusion reactions can occur. In light of the multitude of pro-inflammatory mediators that platelets secrete or express, this is not surprising. During the collection and storage process platelets undergo changes that alter their in vivo function, and during storage platelets may produce and release pro-inflammatory mediators that have adverse effects when infused into an already sick patient. This is often termed the ‘platelet storage lesion’ (PSL). The review by Blumberg and colleagues addresses this important complication of platelet 1740-6765/$ ß 2011 Published by Elsevier Ltd.
DOI: 10.1016/j.ddmec.2011.12.001
transfusions, some of the mechanisms involved and considers means to ameliorate complications associated with platelet transfusions. Platelet microparticles (PMPs) have been recognized since the 1980s, but it has only been more recent that an appreciation of their ability to significantly contribute to inflammation and thrombosis has been popularized. Platelets represent the source of about 70% of all circulating microparticles. PMPs are increased in many vascular and inflammatory conditions including atherosclerosis, some types of cancer, arthritis and cerebral malaria. PMPs are not simply platelet membrane fragment markers of disease, but directly contribute to thrombosis and vascular inflammation. The review by Wasmer, Combs and Grau explores the current state of our knowledge of PMPs and their potentially important role in the pathogenesis of cerebral malaria. Not only do platelets have a key role in the pathogenesis of this infectious disease, but platelets may also contribute to the pathogenesis of other infectious disease processes through their immune functions. Other infectious diseases with a platelet relevance discussed in this set of reviews are HIV and dengue virus. Both HIV and dengue infection often have concurrent thrombocytopenia, and thrombocytopenia is associated with worse outcomes.
Dr. Morrell is an Associate Professor in the Aab Cardiovascular Research Institute at the University of Rochester School of Medicine. His lab is interested in the major roles platelets have in vascular biology as mediators of thrombosis and inflammation. Dr. Morrell received his Sc.B. at Brown University, D.V.M. degree at Tufts University School of Veterinary Medicine, and Ph.D. at The Johns Hopkins University School of Medicine. He began his research career at Johns Hopkins before moving to the University of Rochester in 2009.
e1
Drug Discovery Today: Disease Mechanisms | Editorial
Furthermore, low platelet counts not only represent a clinical side effect, but may also contribute to disease pathology. This is discussed in reviews by Dr. Joseph Mankowski and Drs. Fernando Bozza and Andrew Weyrich. An important cause of morbidity and mortality in cancer patients are secondary complications from thrombotic disease. This is particularly problematic in certain types of cancers, such as pancreatic cancer. Tissue factor expression by the tumor, and from other sources appears to be a main mediator of the thrombotic complications. New strategies are in development to try to lessen these often severe complications, but like all antithrombotic therapies, it demands a balance between blunting thrombotic risk without greatly increasing bleeding risk. The review by Alok Khorana addresses the need for a better understanding of the pathogenesis of cancer-associated thrombosis and better means to predict risk. Antiphospholipid antibody syndrome (APS) is an autoimmune disease that occurs in the context of systemic lupus erythematosus (SLE). APS is a major cause of multiple miscarriages and thrombosis in young women, and is typified by an increased rate of thrombocytopenia and risk of both
e2
www.drugdiscoverytoday.com
Vol. 8, No. 1-2 2011
arterial and venous thrombosis. The cause of APS is primarily secondary to antibodies to self-b2 glycoprotein or cardiolipin. The mechanisms behind this antibody-mediated disease risk are probably multifactorial and only now becoming clearer. Recent work by one of the review authors, Dr. Chieko Mineo, has implicated a blunting of endothelial nitric oxide synthase (eNOS) activity as a potential contributor to increased thrombotic risk and vascular inflammation associated with APS. This is reviewed in this edition. This collection of review articles highlights new insights into platelet-related disease complications, and through the example of strategies for RBC production in culture, provide insights on how to perhaps better culture and genetically manipulate anucleate cells in vitro. The contribution of platelets to inflammation on an individual cell-to-cell interaction level may not be as great as other more classical immune cells, but due to their high numbers and multiple cell interactions, the impact of platelets in immune responses is well worth consideration. With best wishes, Craig N. Morrell