Haem oxygenase protects against thrombocytopaenia and malaria-associated lung injury.

Background: Malaria-triggered lung injury can occur in both severe and non-severe cases. Platelets may interact with parasitized erythrocytes, leukocytes and endothelium. These interactions can lead to microvessel obstructions and induce release of inflammatory mediators.

Integrin αDβ2 influences cerebral edema, leukocyte accumulation and neurologic outcomes in experimental severe malaria.

Malaria is an infectious disease of major worldwide clinical importance that causes a variety of severe, or complicated, syndromes including cerebral malaria, which is often fatal. Leukocyte integrins are essential for host defense but also mediate physiologic responses of the innate and adaptive immune systems. We previously showed that targeted deletion of the αD subunit (αD-/-) of the αDβ2 integrin, which is expressed on key leukocyte subsets in mice and humans, leads to absent expression of the integrin heterodimer on murine macrophages and reduces mortality in mice infected with Plasmodium berghei ANKA (P.

MicroRNA-7a overexpression in VMH restores the sympathoadrenal response to hypoglycemia.

It is proposed that the impaired sympathoadrenal response to hypoglycemia induced by recurrent insulin-induced hypoglycemia (RH) is an adaptive phenomenon induced by specific changes in microRNA expression in the ventromedial hypothalamus (VMH). To test this hypothesis, genome-wide microRNAomic profiling of the VMH by RNA-sequencing was performed in control rats and rats treated for RH. Differential expression analysis identified microRNA-7a-5p and microRNA-665 as potential mediators of this phenomenon.

Altered Central Nutrient Sensing in Male Mice Lacking Insulin Receptors in Glut4-Expressing Neurons.

Insulin signaling in the central nervous system influences satiety, counterregulation, and peripheral insulin sensitivity. Neurons expressing the Glut4 glucose transporter influence peripheral insulin sensitivity. Here, we analyzed the effects of insulin receptor (IR) signaling in hypothalamic Glut4 neurons on glucose sensing as well as leptin and amino acid signaling.

Insulin regulates GLUT4 in the ventromedial hypothalamus to restore the sympathoadrenal response to hypoglycemia in diabetic rats.

It is proposed that the impaired counterregulatory response (CRR) to hypoglycemia in insulin-deficient diabetes may be due to chronic brain insulin deficiency. To test this hypothesis, streptozotocin-induced diabetic Sprague-Dawley rats were infused with insulin (3 mU/day) or artificial cerebrospinal fluid (aCSF) bilaterally into the ventromedial hypothalamus (VMH) for 2 wk and compared with nondiabetic rats. Rats underwent hyperinsulinemic (50 mU·kg·min)-hypoglycemic (~45 mg/dl) clamps.

Integrin αβ (CD11d/CD18) Modulates Leukocyte Accumulation, Pathogen Clearance, and Pyroptosis in Experimental Typhimurium Infection.

β integrins are critical in host defense responses to invading pathogens and inflammation. Previously, we reported that genetic deficiency of integrin αβ in mice altered outcomes in experimental systemic infections including accelerated mortality in animals infected with serovar Typhimurium. Here, we show that deficiency of αβ results in impaired accumulation of leukocytes in response to peritoneal infection by .

Prevention of Severe Hypoglycemia-Induced Brain Damage and Cognitive Impairment With Verapamil.

People with insulin-treated diabetes are uniquely at risk for severe hypoglycemia-induced brain damage. Because calcium influx may mediate brain damage, we tested the hypothesis that the calcium-channel blocker, verapamil, would significantly reduce brain damage and cognitive impairment caused by severe hypoglycemia. Sprague-Dawley rats (10 weeks old) were randomly assigned to one of three treatments: ) control hyperinsulinemic (200 mU ⋅ kg ⋅ min)-euglycemic (80-100 mg/dL) clamps ( = 14), ) hyperinsulinemic-hypoglycemic (10-15 mg/dL) clamps ( = 16), or ) hyperinsulinemic-hypoglycemic clamps, followed by a single treatment with verapamil (20 mg/kg) ( = 11).

Clots Are Potent Triggers of Inflammatory Cell Gene Expression: Indications for Timely Fibrinolysis.

Objective: Blood vessel wall damage often results in the formation of a fibrin clot that traps inflammatory cells, including monocytes. The effect of clot formation and subsequent lysis on the expression of monocyte-derived genes involved in the development and progression of ischemic stroke and other vascular diseases, however, is unknown. Determine whether clot formation and lysis regulates the expression of human monocyte-derived genes that modulate vascular diseases.

RGDfK-functionalized gold nanorods bind only to activated platelets.

Integrin-targeting peptide RGDfK-labeled gold nanorods (GNR) seek to improve hyperthermia targeted to solid tumors by exploiting the known up-regulation of integrin αvβ3 cell membrane proteins on solid tumor vasculature surfaces. Tumor binding specificity might be expected since surrounding tissues and endothelial cells have limited numbers of these receptors. However, RGD peptide binding to many proteins is promiscuous, with known affinity to several families of cell integrin receptors, and also possible binding to platelets after intravenous infusion via a different integrin receptor, αIIbβ3, on platelets.

Neonatal NET-inhibitory factor and related peptides inhibit neutrophil extracellular trap formation.

Neutrophil granulocytes, also called polymorphonuclear leukocytes (PMNs), extrude molecular lattices of decondensed chromatin studded with histones, granule enzymes, and antimicrobial peptides that are referred to as neutrophil extracellular traps (NETs). NETs capture and contain bacteria, viruses, and other pathogens. Nevertheless, experimental evidence indicates that NETs also cause inflammatory vascular and tissue damage, suggesting that identifying pathways that inhibit NET formation may have therapeutic implications.

Integrin αDβ2 (CD11d/CD18) mediates experimental malaria-associated acute respiratory distress syndrome (MA-ARDS).

Background: Malaria-associated acute respiratory distress syndrome (MA-ARDS) is a potentially lethal complication of clinical malaria. Acute lung injury in MA-ARDS shares features with ARDS triggered by other causes, including alveolar inflammation and increased alveolar-capillary permeability, leading to leak of protein-rich pulmonary oedema fluid. Mechanisms and physiologic alterations in MA-ARDS can be examined in murine models of this syndrome.

Integrin αDβ2 (CD11d/CD18) is expressed by human circulating and tissue myeloid leukocytes and mediates inflammatory signaling.

Integrin α(D)β(2) is the most recently identified member of the leukocyte, or β(2), subfamily of integrin heterodimers. Its distribution and functions on human leukocytes have not been clearly defined and are controversial. We examined these issues and found that α(D)β(2) is prominently expressed by leukocytes in whole blood from healthy human subjects, including most polymorphonuclear leukocytes and monocytes.

Platelet activation and apoptosis modulate monocyte inflammatory responses in dengue.

Dengue is the most prevalent human arbovirus disease in the world. Dengue infection has a large spectrum of clinical manifestations, from self-limited febrile illness to severe syndromes accompanied by bleeding and shock. Thrombocytopenia and vascular leak with altered cytokine profiles in plasma are features of severe dengue.

Curine inhibits eosinophil activation and airway hyper-responsiveness in a mouse model of allergic asthma.

Allergic asthma is a chronic inflammatory airway disease with increasing prevalence around the world. Current asthma therapy includes drugs that usually cause significant side effects, justifying the search for new anti-asthmatic drugs. Curine is a bisbenzylisoquinoline alkaloid that modulates calcium influx in many cell types; however, its anti-allergic and putative toxic effects remain to be elucidated.

Methicillin-resistant Staphylococcus aureus-induced thrombo-inflammatory response is reduced with timely antibiotic administration.

Methicillin-resistant Staphylococcus aureus (MRSA) induces a pro-thrombotic and pro-inflammatory milieu. Although timely antibiotic administration in MRSAsepsis may improve outcomes by arresting bacterial growth, the effects of antibiotics on mitigating injurious thrombo-inflammatory cellular responses remains unexplored. Using a newly developed human whole blood model and an in vivo mouse model of MRSAinfection, we examined how antibiotics inhibit MRSAinduced thrombo-inflammatory pathways.

Bacteria differentially induce degradation of Bcl-xL, a survival protein, by human platelets.

Bacteria can enter the bloodstream in response to infectious insults. Bacteremia elicits several immune and clinical complications, including thrombocytopenia. A primary cause of thrombocytopenia is shortened survival of platelets.

Cationic PAMAM dendrimers disrupt key platelet functions.

Poly(amidoamine) (PAMAM) dendrimers have been proposed for a variety of biomedical applications and are increasingly studied as model nanomaterials for such use. The dendritic structure features both modular synthetic control of molecular size and shape and presentation of multiple equivalent terminal groups. These properties make PAMAM dendrimers highly functionalizable, versatile single-molecule nanoparticles with a high degree of consistency and low polydispersity.

Effectiveness of Cissampelos sympodialis and its isolated alkaloid warifteine in airway hyperreactivity and lung remodeling in a mouse model of asthma.

Background: Cissampelos sympodialis Eichl. (Menispermaceae) is a plant found in Northeastern and Southeast of Brazil and hot water infusion of C. sympodialis root bark is largely used in the indigenous and folk medicine to treat several inflammatory disorders, including asthma.

Platelets: versatile effector cells in hemostasis, inflammation, and the immune continuum.

Platelets are chief effector cells in hemostasis. In addition, however, their specializations include activities and intercellular interactions that make them key effectors in inflammation and in the continuum of innate and adaptive immunity. This review focuses on the immune features of human platelets and platelets from experimental animals and on interactions between inflammatory, immune, and hemostatic activities of these anucleate but complex and versatile cells.

NFAT1 transcription factor is central in the regulation of tissue microenvironment for tumor metastasis.

Members of the nuclear factor of activated T cell (NFAT) family of transcription factors were originally described in T lymphocytes but later shown to be expressed in several immune and non-immune cell types. NFAT proteins can modulate cellular transformation intrinsically, and NFAT-deficient (NFAT1-/-) mice are indeed more susceptible to transformation than wild-type counterparts. However, the contribution of an NFAT1-/- microenvironment to tumor progression has not been studied.

Bone marrow-derived mononuclear cell therapy in experimental pulmonary and extrapulmonary acute lung injury.

Objective: To hypothesize that bone marrow-derived mononuclear cell (BMDMC) therapy might act differently on lung and distal organs in models of pulmonary or extrapulmonary acute lung injury with similar mechanical compromises. The pathophysiology of acute lung injury differs according to the type of primary insult.

Design: Prospective, randomized, controlled, experimental study.

Cross-talk between macrophage migration inhibitory factor and eotaxin in allergic eosinophil activation forms leukotriene C₄-synthesizing lipid bodies.

Recent studies have demonstrated an essential and nonredundant role for macrophage migration inhibitory factor (MIF) in asthma pathogenesis. Here we investigate the mechanisms involved in MIF-induced eosinophil activation. By using a model of allergic pulmonary inflammation, we observed that allergen challenge-elicited eosinophil influx, lipid body (also known as lipid droplets) biogenesis, and leukotriene (LT) C₄ synthesis are markedly reduced in Mif(-/-) compared with wild-type mice.

Lipid bodies in oxidized LDL-induced foam cells are leukotriene-synthesizing organelles: a MCP-1/CCL2 regulated phenomenon.

Lipid-laden foam macrophages are emerging as key players in early atherogenesis. Even though cytoplasmic lipid bodies (lipid droplets) are now recognized as organelles with cell functions beyond lipid storage, the mechanisms controlling lipid body biogenesis within macrophages and their additional functions in atherosclerosis are not completely elucidated. Here we studied oxLDL-elicited macrophage machinery involved in lipid body biogenesis as well as lipid body roles in leukotriene (LT) synthesis.

Macrophage migration inhibitory factor is critical to interleukin-5-driven eosinophilopoiesis and tissue eosinophilia triggered by Schistosoma mansoni infection.

Macrophage migration inhibitory factor (MIF) participates in the pathogenesis of inflammatory diseases, including asthma, in which it enhances airway hypersensitivity and tissue eosinophilia. Herein, we investigated the role of MIF in eosinophilopoiesis and tissue eosinophilia using Schistosoma mansoni infection. MIF-deficient (Mif(-/-)) mice had similar numbers of adult worms, eggs, and granulomas compared to wild-type mice, but the size of granulomas was strikingly reduced due to smaller numbers of eosinophils.

Integrin alphaDbeta2 is dynamically expressed by inflamed macrophages and alters the natural history of lethal systemic infections.

The leukocyte integrins have critical roles in host defense and inflammatory tissue injury. We found that integrin alphaDbeta2, a novel but largely uncharacterized member of this family, is restricted to subsets of macrophages and a small population of circulating leukocytes in wild-type mice in the absence of inflammatory challenge and is expressed in regulated fashion during cytokine-induced macrophage differentiation in vitro. alphaDbeta2 is highly displayed on splenic red pulp macrophages and mediates their adhesion to local targets, identifying key functional activity.