Platelet-neutrophil Interactions as a Target for Prevention and Treatment of Transfusion- related Acute Lung Injury
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143-0130, USA.Current pharmaceutical design (Impact Factor: 3.45). 05/2012; 18(22):3260-6. DOI: 10.2174/1381612811209023260
Transfusion-related acute lung injury (TRALI) is a major cause of morbidity and mortality in transfused hosts and like other causes of acute lung injury, there is no effective pharmacologic treatment. The pathophysiology of TRALI is still being defined, but neutrophils have a major role in the pathogenesis of both human and experimental studies. Recently, MHC antibody-based experimental TRALI models have revealed that platelets sequester in the lung microvasculature and that platelet activation contributes to lung injury. Platelets, in general, have been increasingly implicated as major contributors to acute inflammation and injury in a variety of diseases. The role of platelets in TRALI may be through critical interactions with neutrophils and therapeutically this could present a target for pharmacologic intervention. Experimentally, aspirin pre-treatment of mice before TRALI is protective from acute lung injury and mortality. Other therapeutic interventions could include agents that uncouple neutrophils and platelets or prevent aggregation and activation, however targeting platelet activation in TRALI is complicated by the presence of bleeding as the indication for many transfusions. In conclusion, experimental studies are elucidating the role of platelets in acute lung injury and with this new understanding, clinical trials of anti-platelet agents should be considered.
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- "NET release requires the NADPH oxidase, reactive oxygen species, MPO, HNE and PAD4-mediated histone citrullination [18,26,31–34]. The originally described MPO–DNA ELISA method does not detect neutrophils' apoptotic or necrotic deaths  . "
ABSTRACT: Cystic fibrosis (CF) airway disease is characterized by Pseudomonas aeruginosa infection and recruitment of neutrophil granulocytes. Neutrophil granule components (myeloperoxidase (MPO), human neutrophil elastase (HNE)), extracellular DNA and Pseudomonas aeruginosa can all be found in the CF respiratory tract and have all been associated with worsening CF lung function. Pseudomonas-induced formation of neutrophil extracellular traps (NETs) offers a likely mechanism for release of MPO, HNE and DNA from neutrophils. NETs are composed of a DNA backbone decorated with granule proteins like MPO and HNE. Here we sought to examine whether CF clinical isolates of Pseudomonas are capable of inducing NET release from human neutrophil granulocytes. We used two methods to quantify NETs. We modified a previously employed ELISA that detects MPO-DNA complexes and established a new HNE-DNA ELISA. We show that these methods reliably quantify MPO-DNA and HNE-DNA complexes, measures of NET formation. We have found that CF isolates of Pseudomonas aeruginosa stimulate robust respiratory burst and NET release in human neutrophils. By comparing paired “early” and “late” bacterial isolates obtained from the same CF patient we have found that early isolates induced significantly more NET release than late isolates. Our data support that Pseudomonas-induced NET release represents an important mechanism for release of neutrophil-derived CF inflammatory mediators, and confirm that decreased induction of NET formation is required for long-term adaptation of Pseudomonas aeruginosa to CF airways.Immunology letters 08/2014; 160(2). DOI:10.1016/j.imlet.2014.03.003 · 2.51 Impact Factor
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ABSTRACT: Extracorporeal membrane oxygenation (ECMO) facilitates organ support in patients with refractory cardiorespiratory failure whilst disease-modifying treatments can be administered. Improvements to the ECMO process have resulted in its increased utilisation. However, iatrogenic injuries remain, with bleeding and thrombosis the most significant concerns. Many factors contribute to the formation of thrombi, with the hyperoxaemia experienced during ECMO a potential contributor. Outside of ECMO, emerging evidence associates hyperoxaemia with increased mortality. Currently, no universal definition of hyperoxaemia exists, a gap in clinical standards that may impact patient outcomes. Hyperoxaemia has the potential to induce platelet activation, aggregation and, subsequently, thrombosis through markedly increasing the production of reactive oxygen species. There are minimal data in the current literature that explore the relationship between ECMO-induced hyperoxaemia and the production of reactive oxygen species - a putative link towards pathology. Furthermore, there is limited research directly linking hyperoxaemia and platelet activation. These are areas that warrant investigation as definitive data regarding the nascence of these pathological processes may delineate and define the relative risk of supranormal oxygen tension. These data could then assist in defining optimal oxygenation practice, reducing the risks associated with extracorporeal support.Perfusion 01/2013; 28(3). DOI:10.1177/0267659112473172 · 0.94 Impact Factor
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ABSTRACT: Neutrophils have long been viewed as short-lived cells crucial for the elimination of extracellular pathogens, possessing a limited role in the orchestration of the immune response. This dogma has been challenged by recent lines of evidence demonstrating the expression of an increasing number of cytokines and effector molecules by neutrophils. Moreover, in analogy with their "big brother" macrophages, neutrophils integrate the environmental signals and can be polarized towards an antitumoural or protumoural phenotype. Neutrophils are a major source of humoral fluid phase pattern recognition molecules and thus contribute to the humoral arm of innate immunity. Neutrophils cross talk and shape the maturation and effector functions of other leukocytes in a direct or indirect manner, through cell-cell contact or cytokine production, respectively. Therefore, neutrophils are integrated in the activation and regulation of the innate and adaptive immune system and play an important role in the resolution or exacerbation of diverse pathologies, including infections, chronic inflammation, autoimmunity and cancer.Seminars in Immunopathology 04/2013; 35(4). DOI:10.1007/s00281-013-0374-8 · 7.75 Impact Factor
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