Platelet Activation and Aggregation Promote Lung Inflammation and Influenza Virus Pathogenesis

Lê, Vuong Ba; Schneider, Jochen G.; Boergeling, Yvonne; Berri, Fatma; Ducatez, Mariette; Guérin, Jean-Luc; Adrian, Iris; Errazuriz-Cerda, Elisabeth; Frasquilho, Sónia; Antunes, Laurent; Lina, Bruno; Bordet, Jean‐Claude; Jandrot‐Perrus, Martine; Ludwig, Stephan; Riteau, Béatrice

doi:10.1164/rccm.201406-1031oc

Cited by 149 publications

(142 citation statements)

References 48 publications

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“…While the manuscript was in preparation, a report was published describing the activation of platelets during influenza virus infection of mice and demonstrating that platelet inhibition improved the outcome (52); the role of the endothelium was not explored. Our findings, which focus on the endothelial sequelae of influenza infection, thereby are complementary and extend the notion that platelets contribute pathologically to influenza-induced acute lung injury.…”

Section: Discussionmentioning

confidence: 99%

Influenza Virus Infection Induces Platelet-Endothelial Adhesion Which Contributes to Lung Injury

Sugiyama

Gamage

Zyla

et al. 2016

J Virol

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Lung injury after influenza infection is characterized by increased permeability of the lung microvasculature, culminating in acute respiratory failure. Platelets interact with activated endothelial cells and have been implicated in the pathogenesis of some forms of acute lung injury. Autopsy studies have revealed pulmonary microthrombi after influenza infection, and epidemiological studies suggest that influenza vaccination is protective against pulmonary thromboembolism; however, the effect of influenza infection on platelet-endothelial interactions is unclear. We demonstrate that endothelial infection with both laboratory and clinical strains of influenza virus increased the adhesion of human platelets to primary human lung microvascular endothelial cells. Platelets adhered to infected cells as well as to neighboring cells, suggesting a paracrine effect. Influenza infection caused the upregulation of von Willebrand factor and ICAM-1, but blocking these receptors did not prevent platelet-endothelial adhesion. Instead, platelet adhesion was inhibited by both RGDS peptide and a blocking antibody to platelet integrin ␣ 5 ␤ 1 , implicating endothelial fibronectin. Concordantly, lung histology from infected mice revealed viral dose-dependent colocalization of viral nucleoprotein and the endothelial marker PECAM-1, while platelet adhesion and fibronectin deposition also were observed in the lungs of influenza-infected mice. Inhibition of platelets using acetylsalicylic acid significantly improved survival, a finding confirmed using a second antiplatelet agent. Thus, influenza infection induces platelet-lung endothelial adhesion via fibronectin, contributing to mortality from acute lung injury. The inhibition of platelets may constitute a practical adjunctive strategy to the treatment of severe infections with influenza. Here, we show that this infection causes platelets to adhere to the lung endothelium. Importantly, blocking platelets using two distinct antiplatelet drugs improved survival in a mouse model of severe influenza infection. Thus, platelet inhibition may constitute a novel therapeutic strategy to improve the host response to severe infections with influenza.

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Section: Discussionmentioning

confidence: 99%

Influenza Virus Infection Induces Platelet-Endothelial Adhesion Which Contributes to Lung Injury

Sugiyama

Gamage

Zyla

et al. 2016

J Virol

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“…Genetic deficiency of integrin a IIb b 3 , an a IIb b 3 antagonist, and pharmacologic inhibitors of platelet activation each reduced histologic markers of ALI and mortality in infected animals. In contrast, activation of protease-activated receptor 4, a key platelet receptor for thrombin in mice, worsened ALI and increased mortality, indicating that platelets contributed to lung damage in this model and suggesting that antiplatelet drugs may interrupt inflammatory injury in influenza pneumonia (104). Observations in a second study indicated that H1N1 influenza activates platelets via a complex mechanism that includes the FcgRIIA immunoreceptor and thrombin generation, thus involving both innate and adaptive immune pathways (106).…”

Section: Platelets In Specific Conditions That Trigger Ards and Expermentioning

confidence: 94%

“…Experimental observations indicate that platelets have complex activities in influenza infection and influenza-induced ALI. Histopathologic studies demonstrated "massive" accumulation of activated platelets and platelet-leukocyte aggregates in vascular and extravascular compartments of the lungs of influenza A-infected mice (104). Viral proteins were detected in platelets in BAL fluid.…”

Section: Platelets In Specific Conditions That Trigger Ards and Expermentioning

confidence: 99%

Amicus or Adversary Revisited: Platelets in Acute Lung Injury and Acute Respiratory Distress Syndrome

Middleton

Rondina

Schwertz

et al. 2018

Am J Respir Cell Mol Biol

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Platelets are essential cellular effectors of hemostasis and contribute to disease as circulating effectors of pathologic thrombosis. These are their most widely known biologic activities. Nevertheless, recent observations demonstrate that platelets have a much more intricate repertoire beyond these traditional functions and that they are specialized for contributions to vascular barrier integrity, organ repair, antimicrobial host defense, inflammation, and activities across the immune continuum. Paradoxically, on the basis of clinical investigations and animal models of disease, some of these newly discovered activities of platelets appear to contribute to tissue injury. Studies in the last decade indicate unique interactions of platelets and their precursor, the megakaryocyte, in the lung and implicate platelets as essential effectors in experimental acute lung injury and clinical acute respiratory distress syndrome. Additional discoveries derived from evolving work will be required to precisely define the contributions of platelets to complex subphenotypes of acute lung injury and to determine if these remarkable and versatile blood cells are therapeutic targets in acute respiratory distress syndrome.

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“…Their myr-iad effects on coagulation, inflammation, and other aspects of physiology (46, 550) likely shape immune resistance, but also platelets may contribute in some cases through direct antimicrobial activities (269). During severe influenza infections, excess platelet activation amplifies inflammation, lung injury, and mortality (278), consistent with the notion that the challenge to tissue resilience from exuberant inflammation can at times be downstream of platelet activities. The lung is the site for much platelet production by megakaryocytes during homeostasis (282), and platelet production during acute inflammation is increased by maturation of committed progenitors into new megakaryocytes (178).…”

Section: Plateletsmentioning

confidence: 80%

Integrative Physiology of Pneumonia

Quinton

Walkey

Mizgerd

2018

Physiological Reviews

169

196

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Pneumonia is a type of acute lower respiratory infection that is common and severe. The outcome of lower respiratory infection is determined by the degrees to which immunity is protective and inflammation is damaging. Intercellular and interorgan signaling networks coordinate these actions to fight infection and protect the tissue. Cells residing in the lung initiate and steer these responses, with additional immunity effectors recruited from the bloodstream. Responses of extrapulmonary tissues, including the liver, bone marrow, and others, are essential to resistance and resilience. Responses in the lung and extrapulmonary organs can also be counterproductive and drive acute and chronic comorbidities after respiratory infection. This review discusses cell-specific and organ-specific roles in the integrated physiological response to acute lung infection, and the mechanisms by which intercellular and interorgan signaling contribute to host defense and healthy respiratory physiology or to acute lung injury, chronic pulmonary disease, and adverse extrapulmonary sequelae. Pneumonia should no longer be perceived as simply an acute infection of the lung. Pneumonia susceptibility reflects ongoing and poorly understood chronic conditions, and pneumonia results in diverse and often persistent deleterious consequences for multiple physiological systems.

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Platelet Activation and Aggregation Promote Lung Inflammation and Influenza Virus Pathogenesis

Cited by 149 publications

References 48 publications

Influenza Virus Infection Induces Platelet-Endothelial Adhesion Which Contributes to Lung Injury

Influenza Virus Infection Induces Platelet-Endothelial Adhesion Which Contributes to Lung Injury

Amicus or Adversary Revisited: Platelets in Acute Lung Injury and Acute Respiratory Distress Syndrome

Integrative Physiology of Pneumonia

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