Food is Medicine for HIV: Improved health and hospitalizations in the Changing Health through Food Support (CHEFS-HIV) pragmatic randomized trial.

BACKGROUND: Policy support for "Food is Medicine"-medically tailored meals or groceries to improve health-is rapidly growing. No randomized trials have heretofore investigated the benefits of medically tailored food programs for people living with HIV (PLHIV). METHODS: The CHEFS-HIV pragmatic randomized trial included PLHIV who were clients of Project Open Hand (POH), a San Francisco-based nonprofit food organization. The intervention arm (n = 93) received comprehensive medically tailored meals, groceries, and nutritional education. Control participants (n = 98) received less intensive (POH "standard of care") food services. Health, nutrition, and behavioral outcomes were assessed at baseline and 6 months later. Primary outcomes measured were viral non-suppression and health related quality of life. Mixed models estimated treatment effects as differences-in-differences between arms. RESULTS: The intervention arm had lower odds of hospitalization (odds ratio [OR] = 0.11), food insecurity (OR = 0.23), depressive symptoms (OR = 0.32), antiretroviral therapy adherence <90% (OR = 0.18), and unprotected sex (OR = 0.18), and less fatty food consumption (ß= -0.170 servings/day) over 6 months, compared to the control arm. There was no difference between study arms in viral non-suppression and health-related quality of life over 6 months. CONCLUSIONS: A "Food-is-Medicine" intervention reduced hospitalizations and improved mental and physical health among PLHIV, despite no impact on viral suppression. CLINICAL TRIALS REGISTRATION: NCT03191253.

Platelets Independently Recruit into Asthmatic Lungs and Models of Allergic Inflammation via CCR3.

Platelet activation and pulmonary recruitment occur in patients with asthma and in animal models of allergic asthma, in which leukocyte infiltration, airway remodeling, and hyperresponsiveness are suppressed by experimental platelet depletion. These observations suggest the importance of platelets to various characteristics of allergic disease, but the mechanisms of platelet migration and location are not understood. The aim of this study was to assess the mechanism of platelet recruitment to extravascular compartments of lungs from patients with asthma and after allergen challenge in mice sensitized to house dust mite (HDM) extract (contains the DerP1 [Dermatophagoides pteronyssinus extract peptidase 1] allergen); in addition, we assessed the role of chemokines in this process. Lung sections were immunohistochemically stained for CD42b+ platelets. Intravital microscopy in allergic mice was used to visualize platelets tagged with an anti-mouse CD49b-PE (phycoerythrin) antibody. Platelet-endothelial interactions were measured in response to HDM (DerP1) exposure in the presence of antagonists to CCR3, CCR4, and CXCR4. Extravascular CD42b+ platelets were detected in the epithelium and submucosa in bronchial biopsy specimens taken from subjects with steroid-naive mild asthma. Platelets were significantly raised in the lung parenchyma from patients with fatal asthma compared with postmortem control-lung tissue. Furthermore, in DerP1-sensitized mice, subsequent HDM exposure induced endothelial rolling, endothelial adhesion, and recruitment of platelets into airway walls, compared with sham-sensitized mice, via a CCR3-dependent mechanism in the absence of aggregation or interactions with leukocytes. Localization of singular, nonaggregated platelets occurs in lungs of patients with asthma. In allergic mice, platelet recruitment occurs via recognized vascular adhesive and migratory events, independently of leukocytes via a CCR3-dependent mechanism.

Sensory nerves mediate spontaneous behaviors in addition to inflammation in a murine model of psoriasis.

Psoriasis is characterized by keratinocyte hyperproliferation, erythema, as well as a form of pruritus, involving cutaneous discomfort. There is evidence from both clinical and murine models of psoriasis that chemical or surgical depletion of small-diameter sensory nerves/nociceptors benefits the condition, but the mechanisms are unclear. Hence, we aimed to understand the involvement of sensory nerve mediators with a murine model of psoriasis and associated spontaneous behaviors, indicative of cutaneous discomfort. We have established an Aldara model of psoriasis in mice and chemically depleted the small-diameter nociceptors in a selective manner. The spontaneous behaviors, in addition to the erythema and skin pathology, were markedly improved. Attenuated inflammation was associated with reduced dermal macrophage influx and production of reactive oxygen/nitrogen species (peroxynitrite and protein nitrosylation). Subsequently, this directly influenced observed behavioral responses. However, the blockade of common sensory neurogenic mechanisms for transient receptor potential (TRP)V1, TRPA1, and neuropeptides (substance P and calcitonin gene-related peptide) using genetic and pharmacological approaches inhibited the behaviors but not the inflammation. Thus, a critical role of the established sensory TRP-neuropeptide pathway in influencing cutaneous discomfort is revealed, indicating the therapeutic potential of agents that block that pathway. The ongoing inflammation is mediated by a distinct sensory pathway involving macrophage activation.-Kodji, X., Arkless, K. L., Kee, Z., Cleary, S. J., Aubdool, A. A., Evans, E., Caton, P., Pitchford, S. C., Brain, S. D. Sensory nerves mediate spontaneous behaviors in addition to inflammation in a murine model of psoriasis.

LPS-induced Lung Platelet Recruitment Occurs Independently from Neutrophils, PSGL-1, and P-Selectin.

Platelets are recruited to inflammatory foci and contribute to host defense and inflammatory responses. Compared with platelet recruitment in hemostasis and thrombosis, the mechanisms of platelet recruitment in inflammation and host defense are poorly understood. Neutrophil recruitment to lung airspaces after inhalation of bacterial LPS requires platelets and PSGL-1 in mice. Given this association between platelets and neutrophils, we investigated whether recruitment of platelets to lungs of mice after LPS inhalation was dependent on PSGL-1, P-selectin, or interaction with neutrophils. BALB/c mice were administered intranasal LPS (O55:B5, 5 mg/kg) and, 48 hours later, lungs were collected and platelets and neutrophils quantified in tissue sections by immunohistochemistry. The effects of functional blocking antibody treatments targeting the platelet-neutrophil adhesion molecules, P-selectin or PSGL-1, or treatment with a neutrophil-depleting antibody targeting Ly6G, were tested on the extent of LPS-induced lung platelet recruitment. Separately in Pf4-Cre × mTmG mice, two-photon intravital microscopy was used to image platelet adhesion in live lungs. Inhalation of LPS caused both platelet and neutrophil recruitment to the lung vasculature. However, decreasing lung neutrophil recruitment by blocking PSGL-1, P-selectin, or depleting blood neutrophils had no effect on lung platelet recruitment. Lung intravital imaging revealed increased adhesion of platelets in the lung microvasculature which was not associated with thrombus formation. In conclusion, platelet recruitment to lungs in response to LPS occurs through mechanisms distinct from those mediating neutrophil recruitment, or the occurrence of pulmonary emboli.

Platelets Play a Central Role in Sensitization to Allergen.

Platelet activation occurs in patients with allergic inflammation, and platelets can be activated directly by allergen via an IgE-dependent process. Platelets have been shown to activate APCs such as CD11c+ dendritic cells in vitro. Although CD11c+ dendritic cells are a requisite for allergen sensitization, the role of platelets in this process is unknown. In this study, we investigated whether platelets were necessary for allergen sensitization. Balb/c mice sensitized to ovalbumin were exposed to subsequent aerosolized allergen (ovalbumin challenge). We analyzed lung CD11c+ cell activation, colocalization with platelets, and some other indices of inflammation. The role of platelets at the time of allergen sensitization was assessed through platelet depletion experiments restricted to the period of sensitization. Platelets colocalized with airway CD11c+ cells, and this association increased after allergen sensitization as well as after subsequent allergen exposure. Temporary platelet depletion (>95%) at the time of allergen sensitization led to a suppression of IgE and IL-4 synthesis and to a decrease in the pulmonary recruitment of eosinophils, macrophages, and lymphocytes after subsequent allergen exposure. Furthermore, in mice previously depleted of platelets at the time of sensitization, the recovered platelet population was shown to have reduced expression of FcεRI. Pulmonary CD11c+ cell recruitment was suppressed in these mice after allergen challenge, suggesting that the migration of CD11c+ cells in vivo may be dependent on direct platelet recognition of allergen. We conclude that platelets are necessary for efficient host sensitization to allergen. This propagates the subsequent inflammatory response during secondary allergen exposure and increases platelet association with airway CD11c+ cells.

Platelet Depletion Impairs Host Defense to Pulmonary Infection with Pseudomonas aeruginosa in Mice.

Platelets have been implicated in pulmonary inflammatory cell recruitment after exposure to allergic and nonallergic stimuli, but little is known about the role of platelets in response to pulmonary infection with Pseudomonas aeruginosa. In this study, we have investigated the impact of the experimental depletion of circulating platelets on a range of inflammatory and bacterial parameters, and their subsequent impact on mortality in a murine model of pulmonary infection with P. aeruginosa. P. aeruginosa infection in mice induced a mild, but significant, state of peripheral thrombocytopenia in addition to pulmonary platelet accumulation. Increased platelet activation was detected in infected mice through increased levels of the platelet-derived mediators, platelet factor-4 and ß-thromboglobulin, in BAL fluid and blood plasma. In mice depleted of circulating platelets, pulmonary neutrophil recruitment was significantly reduced 24 hours after infection, whereas the incidence of systemic dissemination of bacteria was significantly increased compared with non-platelet-depleted control mice. Furthermore, mortality rates were increased in bacterial-infected mice depleted of circulating platelets. This work demonstrates a role for platelets in the host response toward a gram-negative bacterial respiratory infection.

Platelets in neutrophil recruitment to sites of inflammation.

PURPOSE OF REVIEW: This review describes the essential roles of platelets in neutrophil recruitment from the bloodstream into inflamed and infected tissues, with a focus on recent findings. RECENT FINDINGS: Platelets are required for the recruitment of neutrophils to sites of inflammation and infection. They fulfil this role largely by enabling contacts of circulating neutrophils with the inflamed blood vessel wall prior to extravasation. Platelets promote both early stages of neutrophil recruitment (tethering, rolling, arrest, firm adhesion) and - as recent work has demonstrated - later stages (intravascular crawling and diapedesis). Recent studies have also begun to identify platelet-signaling pathways that can elicit the underlying interactions between platelets, neutrophils and vascular endothelial cells without stimulating concomitant platelet aggregation and thrombus formation. These pathways include Rho-guanine-nucleotide binding proteins and Rho-guanine-nucleotide exchange factors. SUMMARY: Recent findings have contributed to our burgeoning understanding of the platelet-dependent mechanisms that control neutrophil recruitment to sites of inflammation and have opened up new avenues of research aimed at increasing our knowledge of these mechanisms further. These insights might lead to the development of novel anti-inflammatory drugs that will be useful in a wide range of inflammatory diseases without causing immunodeficiency.

P-Rex and Vav Rac-GEFs in platelets control leukocyte recruitment to sites of inflammation.

The small GTPase Rac is required for neutrophil recruitment during inflammation, but its guanine-nucleotide exchange factor (GEF) activators seem dispensable for this process, which led us to investigate the possibility of cooperation between Rac-GEF families. Thioglycollate-induced neutrophil recruitment into the peritoneum was more severely impaired in P-Rex1(-/-) Vav1(-/-) (P1V1) or P-Rex1(-/-) Vav3(-/-) (P1V3) mice than in P-Rex null or Vav null mice, suggesting cooperation between P-Rex and Vav Rac-GEFs in this process. Neutrophil transmigration and airway infiltration were all but lost in P1V1 and P1V3 mice during lipopolysaccharide (LPS)-induced pulmonary inflammation, with altered intercellular adhesion molecule 1-dependent slow neutrophil rolling and strongly reduced L- and E-selectin-dependent adhesion in airway postcapillary venules. Analysis of adhesion molecule expression, neutrophil adhesion, spreading, and migration suggested that these defects were only partially neutrophil-intrinsic and were not obviously involving vascular endothelial cells. Instead, P1V1 and P1V3 platelets recapitulated the impairment of LPS-induced intravascular neutrophil adhesion and recruitment, showing P-Rex and Vav expression in platelets to be crucial. Similarly, during ovalbumin-induced allergic inflammation, pulmonary recruitment of P1V1 and P1V3 eosinophils, monocytes, and lymphocytes was compromised in a platelet-dependent manner, and airway inflammation was essentially abolished, resulting in improved airway responsiveness. Therefore, platelet P-Rex and Vav family Rac-GEFs play important proinflammatory roles in leukocyte recruitment.

Comprehensive and Medically Appropriate Food Support Is Associated with Improved HIV and Diabetes Health.

Food insecurity is associated with negative chronic health outcomes, yet few studies have examined how providing medically appropriate food assistance to food-insecure individuals may improve health outcomes in resource-rich settings. We evaluated a community-based food support intervention in the San Francisco Bay Area for people living with HIV and/or type 2 diabetes mellitus (T2DM) to determine the feasibility, acceptability, and potential impact of the intervention on nutritional, mental health, disease management, healthcare utilization, and physical health outcomes. The 6-month intervention provided meals and snacks designed to comprise 100% of daily energy requirements and meet nutritional guidelines for a healthy diet. We assessed paired outcomes at baseline and 6 months using validated measures. Paired t tests and McNemar exact tests were used with continuous and dichotomous outcomes, respectively, to compare pre-post changes. Fifty-two participants (out of 72 initiators) had both baseline and follow-up assessments, including 23 with HIV, 24 with T2DM, and 7 with both HIV and T2DM. Median food pick-up adherence was 93%. Comparing baseline to follow-up, very low food security decreased from 59.6% to 11.5% (p < 0.0001). Frequency of consumption of fats (p = 0.003) decreased, while frequency increased for fruits and vegetables (p = 0.011). Among people with diabetes, frequency of sugar consumption decreased (p = 0.006). We also observed decreased depressive symptoms (p = 0.028) and binge drinking (p = 0.008). At follow-up, fewer participants sacrificed food for healthcare (p = 0.007) or prescriptions (p = 0.046), or sacrificed healthcare for food (p = 0.029). Among people with HIV, 95% adherence to antiretroviral therapy increased from 47 to 70% (p = 0.046). Among people with T2DM, diabetes distress (p < 0.001), and perceived diabetes self-management (p = 0.007) improved. Comprehensive, medically appropriate food support is feasible and may improve multiple health outcomes for food-insecure individuals living with chronic health conditions. Future studies should formally test the impact of medically appropriate food support interventions for food-insecure populations through rigorous, randomized controlled designs.

A Non-Anticoagulant Fraction of Heparin Inhibits Leukocyte Diapedesis into the Lung by an Effect on Platelets.

We have investigated whether the mechanism by which the non-anticoagulant N-acetyl-de-O-sulfated-heparin (NSH) inhibits leukocyte infiltration is mediated by an effect on platelet function. We show that oral treatment with two doses of NSH significantly inhibits eosinophil and neutrophil recruitment into the lungs. Intravital microscopy analysis shows that NSH inhibits leukocyte and platelet diapedesis in the microcirculation of the cremaster muscle and in the trachea. More importantly, there were significantly lower numbers of leukocytes recruited into the lung in response to LPS in thrombocytopenic mice when transfused with platelets pretreated with NSH in vitro when compared with mice transfused with untreated platelets. Using intravital analysis of the microvasculature of the cremaster muscle, we have demonstrated that the reinfusion of activated platelets significantly re-established leukocyte diapedesis in response to LPS but that this effect was not observed when platelets were pretreated in vitro with NSH. Finally, we investigated whether the effect of NSH altered the expression of adhesion molecules on the surface of platelets and leukocytes in blood samples collected from mice treated orally with NSH. Our results demonstrate that NSH significantly inhibited the detection of P-selectin as evaluated by flow cytometry, confirming that part of the antiinflammatory action of NSH is via an effect on platelet function.

Base-modified UDP-sugars reduce cell surface levels of P-selectin glycoprotein 1 (PSGL-1) on IL-1ß-stimulated human monocytes.

P-selectin glycoprotein ligand-1 (PSGL-1, CD162) is a cell-surface glycoprotein that is expressed, either constitutively or inducibly, on all myeloid and lymphoid cell lineages. PSGL-1 is implicated in cell-cell interactions between platelets, leukocytes and endothelial cells, and a key mediator of inflammatory cell recruitment and transmigration into tissues. Here, we have investigated the effects of the ß-1,4-galactosyltransferase inhibitor 5-(5-formylthien-2-yl) UDP-Gal (5-FT UDP-Gal, compound 1: ) and two close derivatives on the cell surface levels of PSGL-1 on human peripheral blood mononuclear cells (hPBMCs). PSGL-1 levels were studied both under basal conditions, and upon stimulation of hPBMCs with interleukin-1ß (IL-1ß). Between 1 and 24 hours after IL-1ß stimulation, we observed initial PSGL-1 shedding, followed by an increase in PSGL-1 levels on the cell surface, with a maximal window between IL-1ß-induced and basal levels after 72 h. All three inhibitors reduce PSGL-1 levels on IL-1ß-stimulated cells in a concentration-dependent manner, but show no such effect in resting cells. Compound 1: also affects the cell surface levels of adhesion molecule CD11b in IL-1ß-stimulated hPBMCs, but not of glycoproteins CD14 and CCR2. This activity profile may be linked to the inhibition of global Sialyl Lewis presentation on hPBMCs by compound 1: , which we have also observed. Although this mechanistic explanation remains hypothetical at present, our results show, for the first time, that small molecules can discriminate between IL-1ß-induced and basal levels of cell surface PSGL-1. These findings open new avenues for intervention with PSGL-1 presentation on the cell surface of primed hPBMCs and may have implications for anti-inflammatory drug development.

Role of platelets in allergic airway inflammation.

Increasing evidence suggests an important role for platelets and their products (e.g., platelet factor 4, ß-thromboglobulin, RANTES, thromboxane, or serotonin) in the pathogenesis of allergic diseases. A variety of changes in platelet function have been observed in patients with asthma, such as alterations in platelet secretion, expression of surface molecules, aggregation, and adhesion. Moreover, platelets have been found to actively contribute to most of the characteristic features of asthma, including bronchial hyperresponsiveness, bronchoconstriction, airway inflammation, and airway remodeling. This review brings together the current available data from both experimental and clinical studies that have investigated the role of platelets in allergic airway inflammation and asthma. It is anticipated that a better understanding of the role of platelets in the pathogenesis of asthma might lead to novel promising therapeutic approaches in the treatment of allergic airway diseases.

RhoA signaling through platelet P2Y1 receptor controls leukocyte recruitment in allergic mice.

BACKGROUND: Clinical studies reveal platelet activation in patients with asthma, allergic rhinitis, and eczema. This is distinct from platelet aggregation, which is critical for the maintenance of hemostasis and in which a role for platelet purinergic receptors is well documented. However, purines are also essential for inflammatory cell trafficking in animal models of allergic lung inflammation, which are known to be platelet dependent, yet the role of purines in the platelet activation accompanying inflammation is unknown. OBJECTIVES: We investigated whether the involvement of purine activation of platelets during allergic inflammation is distinct from purine involvement in platelet aggregation. METHODS: BALB/c mice were sensitized to ovalbumin and subsequent airway ovalbumin challenge. Bronchoalveolar lavage fluid was analyzed for inflammatory cells, and blood samples were assessed for platelet activation. The role of platelet purinergic receptors and associated signaling mechanisms (RhoA) were assessed. RESULTS: P2Y1, but not P2Y12 or P2X1, antagonism inhibited pulmonary leukocyte recruitment. The formation of platelet-leukocyte complexes in vivo and platelet/P-selectin-dependent polymorphonuclear cell migration in vitro were exclusively platelet P2Y1 receptor dependent. Furthermore, platelet P2Y1 activation resulted in RhoA activity in vivo after allergen challenge, and RhoA signaling in platelets through P2Y1 stimulation was required for platelet-dependent leukocyte chemotaxis in vitro. Leukocyte recruitment in thrombocytopenic mice remained suppressed after reinfusion of platelets pretreated with a P2Y1 antagonist or a Rho-associated kinase 1 inhibitor, confirming the crucial role of platelet P2Y1 receptor and subsequent activation of RhoA. CONCLUSION: RhoA signaling downstream of platelet P2Y1, but not P2Y12, represents a clear dichotomy in platelet activation during allergic inflammation versus hemostasis.

VEGFR1 stimulates a CXCR4-dependent translocation of megakaryocytes to the vascular niche, enhancing platelet production in mice.

It has previously been reported that VEGF-A stimulates megakaryocyte (MK) maturation in vitro. Here we show that treatment of mice with the isoform VEGF-A(165) resulted in a significant increase in circulating numbers of platelets. Using specific VEGFR1 and VEGFR2 blocking mAbs and selective VEGFR1 and 2 agonists, PlGF-2 and VEGF-E, respectively, we show directly that stimulation of VEGFR1, but not VEGFR2, increases circulating platelet numbers in vivo. Using flow cytometric analysis of harvested MKs, we show that while PlGF does not change the absolute numbers of MKs present in the bone marrow and the spleen, it increases both their maturation and cell-surface expression of CXCR4 in the bone marrow. Histology of the bone marrow revealed a redistribution of MKs from the endosteal to the vascular niche in response to both VEGF-A(165) and PlGF-2 treatment in vivo. Antagonism of CXCR4 suppressed both the VEGFR1-stimulated redistribution of megakyocytes within the bone marrow compartment and the VEGF-A(165)-induced thrombocytosis. In conclusion, we define a novel proinflammatory VEGFR1-mediated pathway that stimulates the maturation and up-regulation of CXCR4 on megakaryocytes, leading to their redistribution within the bone marrow environment, thereby enhancing platelet production in vivo.

Platelet purinergic receptors and non-thrombotic diseases.

LINKED ARTICLES: This article is part of a themed issue on Platelet purinergic receptor and non-thrombotic disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.4/issuetoc.

Exploring bias in platelet P2Y1 signalling: Host defence versus haemostasis.

Platelets are necessary for maintaining haemostasis. Separately, platelets are important for the propagation of inflammation during the host immune response against infection. The activation of platelets also causes inappropriate inflammation in various disease pathologies, often in the absence of changes to haemostasis. The separate functions of platelets during inflammation compared with haemostasis are therefore varied and this will be reflected in distinct pathways of activation. The activation of platelets by the nucleotide adenosine diphosphate (ADP) acting on P2Y1 and P2Y12 receptors is important for the development of platelet thrombi during haemostasis. However, P2Y1 stimulation of platelets is also important during the inflammatory response and paradoxically in scenarios where no changes to haemostasis and platelet aggregation occur. In these events, Rho-GTPase signalling, rather than the canonical phospholipase Cß (PLCß) signalling pathway, is necessary. We describe our current understanding of these differences, reflecting on recent advances in knowledge of P2Y1 structure, and the possibility of biased agonism occurring from activation via other endogenous nucleotides compared with ADP. Knowledge arising from these different pathways of P2Y1 stimulation of platelets during inflammation compared with haemostasis may help therapeutic control of platelet function during inflammation or infection, while preserving essential haemostasis. LINKED ARTICLES: This article is part of a themed issue on Platelet purinergic receptor and non-thrombotic disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.4/issuetoc.

Stimulation of platelet P2Y1 receptors by different endogenous nucleotides leads to functional selectivity via biased signalling.

BACKGROUND AND PURPOSE: Platelet function during inflammation is dependent on activation by endogenous nucleotides. Non-canonical signalling via the P2Y1 receptor is important for these non-thrombotic functions of platelets. However, apart from ADP, the role of other endogenous nucleotides acting as agonists at P2Y1 receptors is unknown. This study compared the effects of ADP, Ap3A, NAD+ , ADP-ribose, and Up4A on platelet functions contributing to inflammation or haemostasis. EXPERIMENTAL APPROACH: Platelets obtained from healthy human volunteers were incubated with ADP, Ap3A, NAD+ , ADP-ribose, or Up4A, with aggregation and fibrinogen binding measured (examples of function during haemostasis) or before exposure to fMLP to measure platelet chemotaxis (an inflammatory function). In silico molecular docking of these nucleotides to the binding pocket of P2Y1 receptors was then assessed. KEY RESULTS: Platelet aggregation and binding to fibrinogen induced by ADP was not mimicked by NAD+ , ADP-ribose, and Up4A. However, these endogenous nucleotides induced P2Y1 -dependent platelet chemotaxis, an effect that required RhoA and Rac-1 activity, but not canonical PLC activity. Analysis of molecular docking of the P2Y1 receptor revealed distinct differences of amino acid interactions and depth of fit within the binding pocket for Ap3A, NAD+ , ADP-ribose, or Up4A compared with ADP. CONCLUSION AND IMPLICATIONS: Platelet function (aggregation vs motility) can be differentially modulated by biased-agonist activation of P2Y1 receptors. This may be due to the character of the ligand-binding pocket interaction. This has implications for future therapeutic strategies aimed to suppress platelet activation during inflammation without affecting haemostasis as is the requirement of current ant-platelet drugs. LINKED ARTICLES: This article is part of a themed issue on Platelet purinergic receptor and non-thrombotic disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.4/issuetoc.

INVESTIGATION INTO P2Y RECEPTOR FUNCTION IN PLATELETS FROM PATIENTS WITH SEPSIS.

ABSTRACT: Key underlying pathological mechanisms contributing to sepsis are hemostatic dysfunction and overwhelming inflammation. Platelet aggregation is required for hemostasis, and platelets are also separately involved in inflammatory responses that require different functional attributes. Nevertheless, P2Y receptor activation of platelets is required for this dichotomy of function. The aim of this study was to elucidate whether P2YR-dependent hemostatic and inflammatory functions were altered in platelets isolated from sepsis patients, compared with patients with mild sterile inflammation. Platelets from patients undergoing elective cardiac surgery (20 patients, 3 female) or experiencing sepsis after community-acquired pneumonia (10 patients, 4 female) were obtained through the IMMunE dysfunction and Recovery from SEpsis-related critical illness in adults (IMMERSE) Observational Clinical Trial. In vitro aggregation and chemotaxis assays were performed with platelets after stimulation with ADP and compared with platelets isolated from healthy control subjects (7 donors, 5 female). Cardiac surgery and sepsis both induced a robust inflammatory response with increases in circulating neutrophil counts with a trend toward decreased circulating platelet counts being observed. The ability of platelets to aggregate in response to ex vivo ADP stimulation was preserved in all groups. However, platelets isolated from patients with sepsis lost the ability to undergo chemotaxis toward N -formylmethionyl-leucyl-phenylalanine, and this suppression was evident at admission through to and including discharge from hospital. Our results suggest that P2Y 1 -dependent inflammatory function in platelets is lost in patients with sepsis resulting from community-acquired pneumonia. Further studies will need to be undertaken to determine whether this is due to localized recruitment to the lungs of a platelet responsive population or loss of function as a result of dysregulation of the immune response.

Pharmacological modulation of the inflammatory actions of platelets.

Patients with inflammatory diseases often exhibit a change in platelet function, with these alterations being clearly distinct from the well-characterized role of platelets in haemostasis and thrombosis. It has recently been revealed that platelets can behave as innate inflammatory cells in immune responses with roles in leukocyte recruitment, migration into tissues, release of cytotoxic mediators, and in tissue remodelling following injury.Platelets exhibit a wide range of receptors for mediators involved in the inflammatory pathway and the immune response (Fig. 1). These include purinergic receptors, selectins, integrins, toll-like receptors, immunoglobulins, and chemokine receptors, but the precise role platelets play in the inflammatory process is still under investigation. Nevertheless, given that many of these receptors are distinct from those involved in thrombosis and haemostasis, this raises the real possibility of targeting these receptors to regulate inflammatory diseases without compromising haemostasis.