Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury.

There is emerging evidence that platelets are major contributors to inflammatory processes through intimate associations with innate immune cells. Here, we report that activated platelets induce the formation of neutrophil extracellular traps (NETs) in transfusion-related acute lung injury (TRALI), which is the leading cause of death after transfusion therapy. NETs are composed of decondensed chromatin decorated with granular proteins that function to trap extracellular pathogens; their formation requires the activation of neutrophils and release of their DNA in a process that may or may not result in neutrophil death. In a mouse model of TRALI that is neutrophil and platelet dependent, NETs appeared in the lung microvasculature and NET components increased in the plasma. We detected NETs in the lungs and plasma of human TRALI and in the plasma of patients with acute lung injury. In the experimental TRALI model, targeting platelet activation with either aspirin or a glycoprotein IIb/IIIa inhibitor decreased NET formation and lung injury. We then directly targeted NET components with a histone blocking antibody and DNase1, both of which protected mice from TRALI. These data suggest that NETs contribute to lung endothelial injury and that targeting NET formation may be a promising new direction for the treatment of acute lung injury.

Reducing noninfectious risks of blood transfusion.

As screening for transfusion-associated infections has improved, noninfectious complications of transfusion now cause the majority of morbidity and mortality associated with transfusion in the United States. For example, transfusion-related acute lung injury, transfusion-associated circulatory overload, and hemolytic transfusion-reactions are the first, second, and third leading causes of death from transfusion, respectively. These complications and others are reviewed, and several controversial methods for prevention of noninfectious complications of transfusion are discussed, including universal leukoreduction of erythrocyte units, use of male-only plasma, and restriction of erythrocyte storage age.

Experimental models of transfusion-related acute lung injury.

Transfusion-related acute lung injury (TRALI) is defined clinically as acute lung injury occurring within six hours of the transfusion of any blood product. It is the leading cause of transfusion-related death in the United States, but under-recognition and diagnostic uncertainty have limited clinical research to smaller case control studies. In this review we discuss the contribution of experimental models to the understanding of TRALI pathophysiology and potential therapeutic approaches. Experimental models suggest that TRALI occurs when a host, with a primed immune system, is exposed to an activating agent such as anti-leukocyte antibody or a biologic response modifier such as lysophosphatidylcholines. Recent work has suggested a critical role for platelets in antibody-based experimental models and identified potential therapeutic strategies for TRALI.

Pathophysiology of transfusion-related acute lung injury.

PURPOSE OF REVIEW: The purpose of this review is to summarize the recent experimental and clinical literature on the pathogenesis of transfusion-related acute lung injury (TRALI). RECENT FINDINGS: In both experimental and clinical TRALI, an immune priming step is generally necessary to produce lung injury. Experimental studies have used mainly lipopolysaccharide (LPS) as the priming step, whereas in clinical TRALI the specific priming events are currently being defined and include recent surgery and active infections. Experimental studies have modeled TRALI by using anti-major histocompatibility complex antibodies, antineutrophil antibodies, and also bioactive lipids isolated from stored human blood. A common theme among the experimental TRALI models is the central importance of neutrophils in mediating the early immune response and lung vascular injury. New work has focused on the interplay between neutrophils and platelets in the lung microcirculation. Finally, plasma mitigation strategies implemented in several countries are showing early promise in decreasing the incidence of TRALI from high plasma volume blood products. SUMMARY: TRALI requires an immune priming step followed by transfusion of a blood product with either leukocyte allo-antibodies or biological response modifiers. TRALI invokes an acute immune response dominated by neutrophils interacting with platelets and the lung endothelium.

GATA4 is a direct transcriptional activator of cyclin D2 and Cdk4 and is required for cardiomyocyte proliferation in anterior heart field-derived myocardium.

The anterior heart field (AHF) comprises a population of mesodermal progenitor cells that are added to the nascent linear heart to give rise to the majority of the right ventricle, interventricular septum, and outflow tract in mammals and birds. The zinc finger transcription factor GATA4 functions as an integral member of the cardiac transcription factor network in the derivatives of the AHF. In addition to its role in cardiac differentiation, GATA4 is also required for cardiomyocyte replication, although the transcriptional targets of GATA4 required for proliferation have not been previously identified. In the present study, we disrupted Gata4 function exclusively in the AHF and its derivatives. Gata4 AHF knockout mice die by embryonic day 13.5 and exhibit hypoplasia of the right ventricular myocardium and interventricular septum and display profound ventricular septal defects. Loss of Gata4 function in the AHF results in decreased myocyte proliferation in the right ventricle, and we identified numerous cell cycle genes that are dependent on Gata4 by microarray analysis. We show that GATA4 is required for cyclin D2, cyclin A2, and Cdk4 expression in the right ventricle and that the Cyclin D2 and Cdk4 promoters are bound and activated by GATA4 via multiple consensus GATA binding sites in each gene's proximal promoter. These findings establish Cyclin D2 and Cdk4 as direct transcriptional targets of GATA4 and support a model in which GATA4 controls cardiomyocyte proliferation by coordinately regulating numerous cell cycle genes.

Cocaine and SKF-82958 potentiate brain stimulation reward in Swiss-Webster mice.

RATIONALE: The dopamine D(1)-like receptor agonist SKF-82958 reportedly blocks reinstatement of cocaine-seeking behavior in rats and non-human primates. It is not known if SKF-82958 reduces drug-seeking behaviors in animals exposed previously to cocaine by causing reward-like effects or withdrawal-like aversive effects. OBJECTIVES: Intracranial self-stimulation (ICSS) studies were conducted to determine if SKF-82958 has reward-like or withdrawal-like effects in mice exposed previously to cocaine, or under the influence of cocaine at the time of testing. METHODS: Swiss-Webster mice with lateral hypothalamic stimulating electrodes were trained to self-administer rewarding brain stimulation. The mice were tested in a "curve-shift" variant of the ICSS procedure after intraperitoneal administration of cocaine alone (2.5-20 mg/kg), SKF-82958 alone (0.03-0.3 mg/kg), or a mixture of both drugs (SKF 0.03 mg/kg + 2.5 or 5.0 mg/kg cocaine). Each treatment was given twice. RESULTS: Cocaine and SKF-82958 each caused dose-dependent decreases in brain stimulation reward thresholds that were largest immediately after administration. A dose of SKF-82958 with no reward-related effects of its own potentiated the reward-related effects of low doses of cocaine. Repeated administration did not cause progressive changes in the ability of any treatment to decrease thresholds. CONCLUSIONS: Cocaine and SKF-82958 each potentiate the rewarding effects of lateral hypothalamic brain stimulation in Swiss-Webster mice, implying that these drugs have rewarding effects of their own. The reward-facilitating effects of low doses of cocaine and SKF-82958 are additive (or synergistic). These data suggest that SKF-82958 may decrease cocaine-seeking behavior by mechanisms related to reward rather than aversion.