13 research outputs found
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Sepsis promotes splenic production of a protective platelet pool with high CD40 ligand expression.
Platelets have a wide range of functions including critical roles in hemostasis, thrombosis, and immunity. We hypothesized that during acute inflammation, such as in life-threatening sepsis, there are fundamental changes in the sites of platelet production and phenotypes of resultant platelets. Here, we showed during sepsis that the spleen was a major site of megakaryopoiesis and platelet production. Sepsis provoked an adrenergic-dependent mobilization of megakaryocyte-erythrocyte progenitors (MEPs) from the bone marrow to the spleen, where IL-3 induced their differentiation into megakaryocytes (MKs). In the spleen, immune-skewed MKs produced a CD40 ligandhi platelet population with potent immunomodulatory functions. Transfusions of post-sepsis platelets enriched from splenic production enhanced immune responses and reduced overall mortality in sepsis-challenged animals. These findings identify a spleen-derived protective platelet population that may be broadly immunomodulatory in acute inflammatory states such as sepsis.NHS Blood and Transplant
European Union's Horizon 2020 (ERC-2014-CoG-648765)
MRC-AMED (MR/V005421/1
ADAM8 signaling drives neutrophil migration and ARDS severity
Acute respiratory distress syndrome (ARDS) results in catastrophic lung failure and has an urgent,
unmet need for improved early recognition and therapeutic development. Neutrophil influx is a
hallmark of ARDS and is associated with the release of tissue-destructive immune effectors, such
as matrix metalloproteinases (MMPs) and membrane-anchored metalloproteinase disintegrins
(ADAMs). Here, we observed using intravital microscopy that Adam8–/– mice had impaired
neutrophil transmigration. In mouse pneumonia models, both genetic deletion and pharmacologic
inhibition of ADAM8 attenuated neutrophil infiltration and lung injury while improving bacterial
containment. Unexpectedly, the alterations of neutrophil function were not attributable to impaired
proteolysis but resulted from reduced intracellular interactions of ADAM8 with the actin-based
motor molecule Myosin1f that suppressed neutrophil motility. In 2 ARDS cohorts, we analyzed
lung fluid proteolytic signatures and identified that ADAM8 activity was positively correlated with
disease severity. We propose that in acute inflammatory lung diseases such as pneumonia and
ARDS, ADAM8 inhibition might allow fine-tuning of neutrophil responses for therapeutic gain
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NEXT GENERATION FUNCTIONAL COMPONENTS FOR SPACE TELEMETRY DATA PROCESSING
International Telemetering Conference Proceedings / November 04-07, 1991 / Riviera Hotel and Convention Center, Las Vegas, NevadaSpace telemetry data processing elements for flight and ground systems are currently developed using discrete components on a project-by-project basis. The adoption of various standards, such as those recommended by the Consultative Committee for Space Data Systems (CCSDS), brings commonality of requirements across future NASA communications elements and affords the opportunity to create standard components to meet these requirements. Over the past five years, NASA’s Goddard Space Flight Center (GSFC) has developed a series of high performance Very Large Scale Integration (VLSI) components for space data systems. These standard components have enabled the development of high performance data systems that are an order of magnitude more compact and cost effective than systems of the previous generation. Recent advances in design automation tools and integrated circuit densities have yielded the means to achieve yet another leap in the integration levels, performance and cost reduction of space data systems. Design automation tools can generate complex integrated circuit designs from high level technology independent functional descriptions. A single reusable functional description can be targeted to a variety of circuit technologies including CMOS, ECL and GaAs. With available densities of over 1 million integrated transistors in both CMOS and GaAs technologies, standard components integrating multiple processing elements are realizable for both flight and ground projects. This paper describes the ongoing efforts of the Microelectronics Systems Branch at GSFC to create highly integrated components to meet functions outlined by the CCSDS using design automation techniques.International Foundation for TelemeteringProceedings from the International Telemetering Conference are made available by the International Foundation for Telemetering and the University of Arizona Libraries. Visit http://www.telemetry.org/index.php/contact-us if you have questions about items in this collection
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Cystic fibrosis transmembrane conductance regulator dysfunction in platelets drives lung hyperinflammation.
Cystic fibrosis (CF) lung disease is characterized by an inflammatory response that can lead to terminal respiratory failure. The cystic fibrosis transmembrane conductance regulator (CFTR) is mutated in CF, and we hypothesized that dysfunctional CFTR in platelets, which are key participants in immune responses, is a central determinant of CF inflammation. We found that deletion of CFTR in platelets produced exaggerated acute lung inflammation and platelet activation after intratracheal LPS or Pseudomonas aeruginosa challenge. CFTR loss of function in mouse or human platelets resulted in agonist-induced hyperactivation and increased calcium entry into platelets. Inhibition of the transient receptor potential cation channel 6 (TRPC6) reduced platelet activation and calcium flux, and reduced lung injury in CF mice after intratracheal LPS or Pseudomonas aeruginosa challenge. CF subjects receiving CFTR modulator therapy showed partial restoration of CFTR function in platelets, which may be a convenient approach to monitoring biological responses to CFTR modulators. We conclude that CFTR dysfunction in platelets produces aberrant TRPC6-dependent platelet activation, which is a major driver of CF lung inflammation and impaired bacterial clearance. Platelets and TRPC6 are what we believe to be novel therapeutic targets in the treatment of CF lung disease
Sepsis promotes splenic production of a protective platelet pool with high CD40 ligand expression
Platelets have a wide range of functions including critical roles in hemostasis, thrombosis, and immunity. We hypothesized that during acute inflammation, such as in life-threatening sepsis, there are fundamental changes in the sites of platelet production and phenotypes of resultant platelets. Here, we showed during sepsis that the spleen was a major site of megakaryopoiesis and platelet production. Sepsis provoked an adrenergic-dependent mobilization of megakaryocyte-erythrocyte progenitors (MEPs) from the bone marrow to the spleen, where IL-3 induced their differentiation into megakaryocytes (MKs). In the spleen, immune-skewed MKs produced a CD40 ligandhi platelet population with potent immunomodulatory functions. Transfusions of post-sepsis platelets enriched from splenic production enhanced immune responses and reduced overall mortality in sepsis-challenged animals. These findings identify a spleen-derived protective platelet population that may be broadly immunomodulatory in acute inflammatory states such as sepsis.</p
ADAM8 signaling drives neutrophil migration and ARDS severity
Acute respiratory distress syndrome (ARDS) results in catastrophic lung failure and has an urgent, unmet need for improved early recognition and therapeutic development. Neutrophil influx is a hallmark of ARDS and is associated with the release of tissue-destructive immune effectors, such as matrix metalloproteinases (MMPs) and membrane-anchored metalloproteinase disintegrins (ADAMs). Here, we observed using intravital microscopy that Adam8-/- mice had impaired neutrophil transmigration. In mouse pneumonia models, both genetic deletion and pharmacologic inhibition of ADAM8 attenuated neutrophil infiltration and lung injury while improving bacterial containment. Unexpectedly, the alterations of neutrophil function were not attributable to impaired proteolysis but resulted from reduced intracellular interactions of ADAM8 with the actin-based motor molecule Myosin1f that suppressed neutrophil motility. In 2 ARDS cohorts, we analyzed lung fluid proteolytic signatures and identified that ADAM8 activity was positively correlated with disease severity. We propose that in acute inflammatory lung diseases such as pneumonia and ARDS, ADAM8 inhibition might allow fine-tuning of neutrophil responses for therapeutic gain.</p
NKG2D receptor activation drives primary graft dysfunction severity and poor lung transplantation outcomes
Clinical outcomes after lung transplantation, a life-saving therapy for patients with end-stage lung diseases, are limited by primary graft dysfunction (PGD). PGD is an early form of acute lung injury with no specific pharmacologic therapies. Here, we present a large multicenter study of plasma and bronchoalveolar lavage (BAL) samples collected on the first posttransplant day, a critical time for investigations of immune pathways related to PGD. We demonstrated that ligands for NKG2D receptors were increased in the BAL from participants who developed severe PGD and were associated with increased time to extubation, prolonged intensive care unit length of stay, and poor peak lung function. Neutrophil extracellular traps (NETs) were increased in PGD and correlated with BAL TNF-α and IFN-γ cytokines. Mechanistically, we found that airway epithelial cell NKG2D ligands were increased following hypoxic challenge. NK cell killing of hypoxic airway epithelial cells was abrogated with NKG2D receptor blockade, and TNF-α and IFN-γ provoked neutrophils to release NETs in culture. These data support an aberrant NK cell/neutrophil axis in human PGD pathogenesis. Early measurement of stress ligands and blockade of the NKG2D receptor hold promise for risk stratification and management of PGD