Inflammation & Allergy-Drug Targets (v.9, #5)

Over the past few decades, our understanding of the molecular basis of the platelet production and function has substantially advanced. It has become clear that these anucleate cells are not just passively circulating fragments of megakaryocytes, but functionally active, autonomous agents, capable of producing a range of humoral mediators [1]. Though initially platelets were viewed as contributors to hemostasis and wound repair, advances in flow cytometry and proteomics research have identified numerous bioactive platelet proteins and broadened the scope of platelet-mediated physiological and pathological conditions [2]. Platelet membrane is full of functionally active proteins, facilitating platelet adhesion, aggregation and interaction with other blood and vascular cells. Examples of the critical importance of these membranous proteins are autosomal recessive hemorrhagic disorders caused by qualitative and quantitative changes of glycoprotein (GP) IIb/IIIa in Glazmann's thrombasthenia [3, 4] and by defect of GPIb/IX/V in Bernard-Soulier syndrome [5, 6]. On the other hand, genetically determined changes of these and other platelet receptors (e.g., GPIa/IIa and GPVI) predispose to unresponsiveness to antithrombotic agents, resulting in thrombotic events [7, 8]. Additionally, platelets have been found to express proteins belonging to the Toll-like receptors family, thereby facilitating the defense of the human organism against infectious agents [9, 10]. Structures inside the platelet, particularly alpha-, dense granules and lysosomes, are now well characterized. Alpha-granules are known to produce hundreds of bioactive proteins involved in the initiation and propagation of diverse thrombotic, inflammatory, immune, and metabolic disorders [11]. Some of the well-described proteins stored in and released from alphagranules are P-selectin, fibrinogen, von Willebrand factor, beta-thromboglobulin, CD40 ligand, and transforming growth factorbeta. These and many other proteins derived from alpha-granules play multiple, at times opposite roles, thus facilitating the involvement of activated platelets in a wide range of disorders. The multifaceted role of platelets and its agents has been comprehensively described within the frames of atherosclerosis, where immune, inflammatory and thrombotic pathways are intimately interrelated [12-14]. Some of the platelet agents released from alpha-granules (e.g., CD40 ligand) have been found to possess both pro-inflammatory and pro-thrombotic properties and to be independently associated with atherothrombotic events [15]. Evidence is also accumulating regarding the proinflammatory and pro-thrombotic roles of platelet-derived microparticles [16]. These microparticles are abundantly produced in conditions associated with vascular inflammation, such as acute coronary syndromes, vascular interventions, and diabetes, where the interaction of immune and inflammatory mechanisms brings about thrombosis [17]. Importantly, platelet-derived microparticles may also link inflammation with joint involvement in rheumatic diseases, particularly in rheumatoid arthritis [18]. Recently, several lines of evidence have appreciated the crucial role of activated platelets in cardiovascular involvement in rheumatoid arthritis [19] and some other autoimmune disorders [20]. A bulk of available evidence suggests that activated platelets are emerging targets of anti-inflammatory and antithrombotic therapies in rheumatic diseases [21-23]. Given the fact that functional characteristics of circulating platelets are predetermined at the stage of megakaryocytopoiesis [24], it is possible to speculate that optimal antithrombotic strategies in rheumatic and other chronic inflammatory disorders will target the megakaryocyte-platelet-microparticles axis. In this regard, the size of circulating platelets, reflecting the level of platelets production and their activity [25], may well serve as a means for monitoring antithrombotic therapies. The appreciation of platelets pro-inflammatory and pro-thrombotic roles has fueled interest toward the effects of antiplatelet agents, such as aspirin, clopidogrel, prasugrel, and abciximab, on both platelet activity and systemic inflammation [26]. Antiplatelet agents are capable of suppressing systemic and vascular inflammation by inhibiting platelet function and synthesis of platelets' inflammatory agents [27]. There is some preliminary evidence in favor of direct anti-inflammatory (pleiotropic) action of antiplatelet agents [26], which still needs confirmation in large and long-term trials [28]. It should be, however, bear in mind that anti-inflammatory potential of antiplatelet agents is limited, and in certain inflammatory conditions, such as coronary interventions, diabetes and rheumatoid arthritis, the issue of antiplatelet unresponsiveness can arise [8, 29, 30], necessitating additional monitoring of inflammatory markers and more aggressive suppression of systemic inflammation. The interrelation between platelets and inflammatory agents is also a big issue in the context of atherosclerotic disease in certain and#x201C;high-riskand#x201D; cohorts of patients. In particular, it has been shown that South Asians are genetically predisposed to accelerated atherosclerosis, type 2 diabetes and the metabolic syndrome, all of which are strongly associated with elevated markers of systemic inflammation [31, 32]. A few, relatively small studies have specifically investigated platelet-derived markers and platelet-monocyte complexes in this ethnic group compared to relevant controls [33, 34]. Though it is highly likely that activated platelets contribute to accelerated atherosclerosis in South Asians, the obtained evidence is still inconclusive on whether there are platelet-mediated pathways specific for this high-risk ethnic group. Further research is apparently needed to provide recommendations on antiplatelet therapies in South Asians [35]. Additionally, occupational and environmental exposure to diverse air pollutants, causing oxidative stress, platelet activation and inflammation [36, 37], should be taken into account when preventive strategies are planned. The latter is of particular importance in most vulnerable pediatric subjects [38] and those with underlying heightened cardiometabolic risk [39].........

Platelets are non-nucleated cellular elements that play a role in hemostasis, innate immunity, and inflammation. Platelet-linked inflammation seems essentially related to the capacity of platelets to secrete cytokines, chemokines, and related molecules upon stimulation or state change. Moreover, platelets display receptors for numerous types of cytokines/chemokines, as well as immunoglobulins (Fcand#x3B3;RI, II, III; FcRI, II; Fcand#945;RI/CD89). This secretory function confers to platelets a regulatory role in immunity. Platelets also exhibit non-self infectious danger detection molecules on their surfaces, particularly from the Toll-like receptor (TLR) family; through TLR expression, platelets can bind infectious agents and also deliver different signals for the secretion of cytokines and chemokines. Platelets may therefore be regarded as a neglected component of immune cell regulators, and they contribute to some interesting aspects in bridging innate and adaptive immunity. Recent investigations of the platelet TLR signalosome have been developed, and some studies have already confirmed the existence of a functional TLR/Myd88 pathway in platelets also (similar to as in eukaryotic nucleated cells). In eukaryotic cells, TLR adaptor and signalling proteins downstream of TLR activation typically represent a potential target on the Toll/Interleukin-1 receptor domain pathway for therapeutic drugs. Further, platelets may sense several types of infectious pathogens and limit microbial colonization by sequestering these pathogens and releasing immunomodulatory factors. This review aims to revisit some functions that platelets exert directly in antiinfection immunity; it presents experimentally-driven arguments in favor of a role for the TLR in regulating certain immune activities.

Platelet Activation in Atherogenesis Associated with Low-Grade Inflammation by Charalambos Antoniades, Constantinos Bakogiannis, Dimitris Tousoulis, Michael Demosthenous, Kyriakoula Marinou, Christodoulos Stefanadis (334-345).
Further to the established role of platelets in thrombosis and hemostasis, increasing evidence suggests that they also play a crucial role in atherogenesis. Platelets produce a number of agents contributing to the systemic low-grade inflammation implicated in atherogenesis. Platelet activation following inflammatory stimulus leads to the expression of surface receptors such as GPIb/IX/V, P-selectin, CD40, and to the release of several pro-inflammatory agents. Platelet receptors and released molecules play a critical role during the initiation and the progression of atherosclerosis by mediating leukocytes recruitment and adhesion to the vascular wall. Endothelial dysfunction, an early feature in atherosclerosis, is associated with low-grade inflammation within the vascular wall, and it leads to the reduced bioavailability of nitric oxide. Dysfunctional endothelium itself releases inflammatory molecules leading toward platelets activation and adhesion to the vascular wall. Platelets are no longer considered simply as cells participating in thrombosis. They are regulators of multiple processes in the human body, including inflammation, regulation of endothelial physiology and atherogenesis. The design of new therapeutic strategies targeting platelets and their impact in atherosclerosis-related low-grade inflammation are in the center of current cardiovascular research.

Platelets and Platelet-Derived Microparticles in Vascular Inflammatory Disease by Elena Vasina, Johan W.M. Heemskerk, Christian Weber, Rory R. Koenen (346-354).
Atherosclerosis with ensuing atherothrombosis is an inflammatory disease of the large arteries with high mortality and morbidity. Interactions between blood cells and the arterial vessel wall are considered to determine the progression of atherosclerotic plaques and the thrombotic complications. There is increasing evidence for important roles of activated platelets and platelet-derived microparticles in this disease process by contact with leukocytes, endothelial cells and smooth muscle cells. This paper gives an overview of newly described interactions of platelets and microparticles with other cells of the cardiovascular system via direct contact or via mediator release. The possible significance of these interactions is discussed within the context of vascular inflammation.

In addition to their pivotal role in hemostasis, platelets are an integral part of inflammation. Growing evidence suggests that platelets are a key component of innate and adaptive immune responses. Better understanding of the mechanisms linking platelet function to chronic inflammatory tissue damage may reveal novel targets of therapeutic intervention in immune-mediated and/or inflammatory disorders. The functional interplay between platelets and inflammation is closely implicated in the pathophysiology of a variety of human diseases. This review discusses the relationship between platelets and inflammatory and immune responses across a wide range of conditions in internal medicine.

Even though there is a strong evidence suggestive of benefits and safety of dual (aspirin plus clopidogrel) antiplatelet therapy, decreased responsiveness or and#x201C;resistanceand#x201D; to mono- and/or dual antiplatelet therapy has been described in association with an increased thrombotic risk. Various mechanisms contribute to antiplatelet resistance, with abundant production of inflammatory markers being of particular importance. The current review overviews implications of inflammation in antiplatelet resistance.

South Asian Immigrants (SAIs) have high rates of coronary artery disease (CAD) and its risk factors. This is alarming as i) SAIs are the 2nd fastest growing Asian immigrant population in the US; ii) CAD prevalence is 2 times higher than in other immigrant populations; iii) at any risk factor level, SAIs are at a greater risk of CAD; and iv) Type 2 diabetes is a major risk factor and associated co-morbidity in SAIs. Although clinical guidelines for CAD prevention recommend risk management based on Framingham Risk Scores (FRS), available data suggest that FRS underestimate CAD risk in SAIs. This review presents an overview of platelet related research in SAIs, its importance in predicting CAD risk and methods of diagnosis. Further we provide discussion on the importance of platelet function assessment for more appropriate stratification of SAIs based on cardiovascular risk.

Air Pollution, Platelet Activation and Atherosclerosis by Parinaz Poursafa, Roya Kelishadi (387-392).
Atherosclerosis begins in early life. The role of platelets is well-documented from its early stages. A wealth of evidence associates atherosclerotic cardiovascular disease with inflammatory diseases. The role of environmental factors, including air pollution, remains overlooked. Some studies have documented the effect of air pollution on inflammatory and pro-thrombotic factors implicated in the progression of cardiovascular diseases. In particular, the increase of platelet count and platelet hyper-reactivity towards agonists are emerging as markers of hematologic and hemostatic changes in response to the exposure to air pollutants. The systemic pro-inflammatory and pro-thrombotic response to the inhalation of fine and ultrafine particulate matters is seemingly associated with platelet activation. This association may have a clinical significance, particularly in the presence of cardiometabolic risk factors, and may indicate the need for antiplatelet treatment. It is of particular relevance to further study the significance of platelet activation and anti-platelet therapies in primordial/primary preventive measures in children and adolescents at risk of accelerated atherosclerosis.

The Role of Platelets in Bone Remodeling by Pooneh Salari Sharif, Mohammad Abdollahi (393-399).
Platelets play a critical role in wound healing and hemostasis, as well as in repairing bone fracture. The impact of platelets on inflammation and inflammatory diseases has been appreciated. It has been demonstrated that inflammation and oxidative stress are intimately involved in the pathogenesis of osteoporosis. Degranulation of platelets, anuclear cell fragments, leads to the release of different growth factors and chemoattractants affecting bone metabolism. The net effect is, however, not fully understood. The current review is aimed to examine available studies on the impact of platelets on bone health. We searched data from Scopus, PubMed and Web of Science using keywords such as platelets, osteoblasts, osteoclasts, bone, antiplatelet drugs, bone formation, and bone resorption. As hypothesis of the review is emerging, a small number of in vivo and in vitro studies were found. Based on the available data, platelets and platelet-derived numerous immune and inflammatory agents can be viewed as targets for therapeutic and/or preventive measures in osteoporosis.