Platelets in Lung Biology

Weyrich, Andrew S.; Zimmerman, Guy A.

doi:10.1146/annurev-physiol-030212-183752

Cited by 162 publications

(201 citation statements)

References 130 publications

(294 reference statements)

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“…Indeed, using lung intravital imaging, we now show that the lung is a site of de novo NPA formation under basal conditions. The unique structural features of the lung microcirculation that influence neutrophil trafficking 30 and the proposed role of the lung in thrombopoiesis 31 may enhance these interactions. With inflammation, we found an early and rapid increase in dynamic NPA formation in the lung microcirculation, and many of these aggregates were ultimately detected in the alveolar spaces.…”

Section: Discussionmentioning

confidence: 99%

Aspirin-triggered 15-epi-lipoxin A4 regulates neutrophil-platelet aggregation and attenuates acute lung injury in mice

Ortiz-Muñoz

Mallavia

Bins

et al. 2014

Blood

170

176

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• Neutrophil-platelet aggregates are dynamically formed in the lung in response to injury and are regulated by aspirin-triggered lipoxin.• The therapeutic effect of aspirin in acute lung injury is in large part mediated by the production of pro-resolving lipid mediators.Evidence is emerging that platelets are major contributors to innate immune responses in conditions such as acute lung injury (ALI). Platelets form heterotypic aggregates with neutrophils, and we hypothesized that lipoxin mediators regulate formation of neutrophilplatelet aggregates (NPA) and that NPA significantly contribute to ALI. Lipopolysaccharide (LPS)-induced lung injury was accompanied by platelet sequestration, activation, intra-alveolar accumulation, and NPA formation within both blood and alveolar compartments. Using lung intravital microscopy, we observed the dynamic formation of NPA during physiologic conditions, which sharply increased with ALI. Aspirin (ASA) treatment significantly reduced lung platelet sequestration and activation, NPA formation, and lung injury. ASA treatment increased levels of ASA-triggered lipoxin (ATL; 15-epi-lipoxin A 4 ), and blocking the lipoxin A 4 receptor (ALX) with a peptide antagonist (Boc2) or using ALX knockouts (Fpr2/3 2/2 ) reversed this protection. LPS increased NPA formation in vitro, which was reduced by ATL, and engagement of ALX by ATL on both neutrophils and platelets was necessary to prevent aggregation. In a model of transfusion-related acute lung injury (TRALI), Boc2 also reversed ASA protection, and treatment with ATL in both LPS and TRALI models protected from ALI. We conclude that ATL regulates neutrophil-platelet aggregation and that platelet-neutrophil interactions are a therapeutic target in lung injury. (Blood. 2014;124(17):2625-2634

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Section: Discussionmentioning

confidence: 99%

Aspirin-triggered 15-epi-lipoxin A4 regulates neutrophil-platelet aggregation and attenuates acute lung injury in mice

Ortiz-Muñoz

Mallavia

Bins

et al. 2014

Blood

170

176

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“…[1][2][3] Platelets are circulating anucleate cytoplasmic discs derived from differentiated megakaryocytes. 4,5 The details by which a megakaryocyte releases 10 3-4 platelets 6 are beginning to be understood, but this knowledge has been hampered by limitations of ex vivo culture systems. 4,5 In situ examination of this process has provided key insights [7][8][9] : intramedullar, mature megakaryocytes migrate to a perivascular site and extend a single process through the endothelium, releasing variable size cytoplasmic fragments that may or may not remain continuous.…”

Section: Introductionmentioning

confidence: 99%

Comparative analysis of human ex vivo–generated platelets vs megakaryocyte-generated platelets in mice: a cautionary tale

Wang

Hayes

Jarocha

et al. 2015

Blood

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• Infused human megakaryocytes release young platelets in the lungs with characteristics similar to donor platelets.• Platelets released from ex vivo-derived megakaryocytes are preactivated and compare poorly to donor platelets.Thrombopoiesis is the process by which megakaryocytes release platelets that circulate as uniform small, disc-shaped anucleate cytoplasmic fragments with critical roles in hemostasis and related biology. The exact mechanism of thrombopoiesis and the maturation pathways of platelets released into the circulation remain incompletely understood. We showed that ex vivo-generated murine megakaryocytes infused into mice release platelets within the pulmonary vasculature. Here we now show that infused human megakaryocytes also release platelets within the lungs of recipient mice. In addition, we observed a population of platelet-like particles (PLPs) in the infusate, which include platelets released during ex vivo growth conditions. By comparing these 2 platelet populations to human donor platelets, we found marked differences: platelets derived from infused megakaryocytes closely resembled infused donor platelets in morphology, size, and function. On the other hand, the PLP was a mixture of nonplatelet cellular fragments and nonuniform-sized, preactivated platelets mostly lacking surface CD42b that were rapidly cleared by macrophages. These data raise a cautionary note for the clinical use of human platelets released under standard ex vivo conditions. In contrast, human platelets released by intrapulmonary-entrapped megakaryocytes appear more physiologic in nature and nearly comparable to donor platelets for clinical application. (Blood. 2015;125(23):3627-3636)

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“…A growing body of evidence suggests that platelets also play a crucial role in the inflammatory response, in part by promoting leukocyte recruitment to sites of vascular injury (4). Recent studies also highlight the unique functions of platelets in the lungs (5) and show that platelets contribute to acute lung injury (ALI) (6).…”

mentioning

confidence: 99%

Platelet-Specific Chemokines Contribute to the Pathogenesis of Acute Lung Injury

Bdeir¹,

Gollomp²,

Stasiak

et al. 2017

Am J Respir Cell Mol Biol

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Platelets and neutrophils contribute to the development of acute lung injury (ALI). However, the mechanism by which platelets make this contribution is incompletely understood. We investigated whether the two most abundant platelet chemokines, CXCL7, which induces neutrophil chemotaxis and activation, and CXCL4, which does neither, mediate ALI through complementary pathogenic pathways. To examine the role of platelet-derived chemokines in the pathogenesis of ALI using Cxcl7 2/2 and Cxcl4 2/2 knockout mice and mice that express human CXCL7 or CXCL4, we measured levels of chemokines in these mice. ALI was then induced by acid aspiration, and the severity of injury was evaluated by histology and by the presence of neutrophils and protein in the bronchoalveolar lavage fluid. Pulmonary vascular permeability was studied in vivo by measuring extravasation of fluorescently labeled dextran. Murine CXCL7, both recombinant and native protein released from platelets, can be N-terminally processed by cathepsin G to yield a biologically active CXCL7 fragment. Although Cxcl7 2/2 mice are protected from lung injury through the preservation of endothelial/epithelial barrier function combined with impaired neutrophils transmigration, Cxcl4 2/2 mice are protected through improved barrier function without affecting neutrophils transmigration to the airways. Sensitivity to ALI is restored by transgenic expression of CXCL7 or CXCL4. Platelet-derived CXCL7 and CXCL4 contribute to the pathogenesis of ALI through complementary effects on neutrophil chemotaxis and through activation and vascular permeability.

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Platelets in Lung Biology

Cited by 162 publications

References 130 publications

Aspirin-triggered 15-epi-lipoxin A4 regulates neutrophil-platelet aggregation and attenuates acute lung injury in mice

Aspirin-triggered 15-epi-lipoxin A4 regulates neutrophil-platelet aggregation and attenuates acute lung injury in mice

Comparative analysis of human ex vivo–generated platelets vs megakaryocyte-generated platelets in mice: a cautionary tale

Platelet-Specific Chemokines Contribute to the Pathogenesis of Acute Lung Injury

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