Megakaryocytes and platelet homeostasis in diffuse alveolar damage

Mandal, Rajni; Mark, Eugene J.; Kradin, Richard L.

doi:10.1016/j.yexmp.2007.08.005

Cited by 50 publications

(56 citation statements)

References 18 publications

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“…They produce cytokines that induce fibrosis in the bone marrow and other organs (Reilly, 2006; Kuter et al , 2007; Thachil, 2009b) and they are involved in the maintenance of bone homeostasis (Kacena et al , 2006a,b). Under certain circumstances, they appear in blood, spleen, liver and lung, where they migrate to sites of active inflammation (Mandal et al , 2007; Thachil, 2009a,b). Hence, megakaryocytes interact with their microenvironment, but their cellular counterparts and the mechanisms of cellular interaction are incompletely understood.…”

Section: Discussionmentioning

confidence: 99%

“…Increasing evidence suggests that megakaryocytes may serve an additional, cell‐intrinsic function that extends beyond their role as platelet producers. They can be found outside the bone marrow in lung, spleen and liver and, under certain conditions of stress and inflammation, contribute to organ damage (Wells et al , 1984; Mandal et al , 2007; Thachil, 2009a,b). They are also known to express a number of genes with established immunomodulatory properties (e.g.…”

mentioning

confidence: 99%

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Regulation of fas/fas ligand‐mediated apoptosis by nuclear factor of activated T cells in megakaryocytes

Arabanian¹,

Kujawski²,

Habermann³

et al. 2011

Br J Haematol

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Summary Signal transduction pathways in megakaryocytes, a rare population of bone marrow cells, are poorly understood. We have previously shown that the calcineurin‐dependent transcription factor Nuclear Factor of Activated T cells (NFAT) is expressed in megakaryocytes and is required for the transcription of specific megakaryocytic genes. The biological role of NFAT in megakaryocytes, however, is unknown. Here we show that activation of the calcineurin/NFAT pathway in megakaryocytes forces the cells to go into apoptosis. Calcineurin/NFAT activation in megakaryocytes leads to membrane expression of Fas ligand (FASLG), a pro‐apoptotic member of the tumour necrosis factor superfamily. Expression of FASLG was augmented in cells stably overexpressing NFATC2 and suppressed in cells either pretreated with the calcineurin inhibitor ciclosporin A (CsA) or expressing the specific peptide inhibitor of NFAT, VIVIT. In cocultures with Fas‐expressing Jurkat T cells, the presence of activated megakaryocytic cells, but not of unstimulated cells or cells stimulated in the presence of CsA, significantly induced apoptosis in Jurkat cells in a Fas/FASLG‐ and NFAT‐dependent manner. These results represent the first evidence for a biological function of the calcineurin/NFAT pathway in megakaryocytes, and suggest that the biological role of megakaryocytes may include the induction of apoptosis in bystander cells.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Regulation of fas/fas ligand‐mediated apoptosis by nuclear factor of activated T cells in megakaryocytes

Arabanian¹,

Kujawski²,

Habermann³

et al. 2011

Br J Haematol

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“…Megakaryocytes have also been routinely identified in examinations of human lungs in diagnostic or forensic necropsies, and their numbers are increased in ALI/ARDS, burns, disseminated intravascular coagulation, and thrombosis (reviewed in References 7, 24, 30, and 33). Furthermore, megakaryocytes are routinely detected in diagnostic lung biopsies (7, 33).…”

Section: Pulmonary Megakaryocytes and The Lung As An Organ Of Thrombomentioning

confidence: 99%

“…Furthermore, megakaryocytes are routinely detected in diagnostic lung biopsies (7, 33). In addition, examination of selectively sampled vascular compartments consistently demonstrates circulating megakaryocytes in peripheral and central venous blood of humans and indicates that these cells are ~10-fold more abundant in pulmonary artery blood compared with aortic blood (34–39).…”

Section: Pulmonary Megakaryocytes and The Lung As An Organ Of Thrombomentioning

confidence: 99%

Platelets in Lung Biology

Weyrich

Zimmerman²

2013

Annu. Rev. Physiol.

155

187

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Platelets and the lungs have an intimate relationship. Platelets are anucleate mammalian blood cells that continuously circulate through pulmonary vessels and that have major effector activities in hemostasis and inflammation. The lungs are reservoirs for megakaryocytes, the requisite precursor cell in thrombopoiesis, which is the intricate process by which platelets are generated. Platelets contribute to basal barrier integrity of the alveolar capillaries, which selectively restricts the transfer of water, proteins, and red blood cells out of the vessels. Platelets also contribute to pulmonary vascular repair. Although platelets bolster hemostatic and inflammatory defense of the healthy lung, experimental evidence and clinical evidence indicate that these blood cells are effectors of injury in a variety of pulmonary disorders and syndromes. Newly discovered biological capacities of platelets are being explored in the context of lung defense, disease, and remodeling.

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“…Based on the abundance and intense immunoreactivity of thrombospondin-1 protein in platelets and intravascular fibrin aggregates, it is plausible that both increased numbers of pulmonary platelets and increased platelet activation may have contributed to the increased thrombospondin-1 mRNA levels in lung homogenates of ventilated preterm infants. By analogy, megakaryocyte and platelet homeostasis were reportedly altered in diffuse alveolar damage [57]. It remains to be determined whether platelet expression of thrombospondin-1 in preterm lungs is regulated by any of the candidate factors implicated in the pathogenesis of BPD, such as infection/inflammation, oxygen toxicity, hyperoxia/hypoxia, and mechanical stretch/strain [1].…”

Section: Mcp-2 and Mcp-3 Have Been Shown To Be Increased In Infants Wmentioning

confidence: 99%

Angiogenesis-related gene expression profiling in ventilated preterm human lungs

Paepe

Greco

Mao

2010

Experimental Lung Research

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Preterm infants exposed to oxygen and mechanical ventilation are at risk for bronchopulmonary dysplasia (BPD), a multifactorial chronic lung disorder characterized by arrested alveolar development and nonsprouting, dysmorphic microvascular angiogenesis. The molecular regulation of this BPD-associated pathological angiogenesis remains incompletely understood. In this study, the authors used focused microarray technology to characterize the angiogenic gene expression profile in postmortem lung samples from short-term ventilated preterm infants (born at 24 to 27 weeks' gestation) and age-matched control infants. Microarray analysis identified differential expression of 13 of 112 angiogenesis-related genes. Genes significantly up-regulated in ventilated lungs included the antiangiogenic genes thrombospondin-1, collagen XVIII alpha-1, and tissue inhibitor of metalloproteinase-1 (TIMP1), as well as endoglin, transforming growth factor-alpha, and monocyte chemoattractant protein-1 (CCL2). Increased expression of thrombospondin-1 in ventilated lungs was verified by real-time polymerase chain reaction (PCR) and immunolocalized primarily to intravascular platelets and fibrin aggregates. Down-regulated genes included proangiogenic angiogenin and midkine, as well as vascular endothelial growth factor (VEGF)-B, VEGF receptor-2, and the angiopoietin receptor TEK/Tie-2. In conclusion, short-term ventilated lungs show a shift from traditional angiogenic growth factors to alternative, often antisprouting regulators. This angiogenic shift may be implicated in the regulation of dysmorphic angiogenesis and, consequently, deficient alveolarization characteristic of infants with BPD.

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Megakaryocytes and platelet homeostasis in diffuse alveolar damage

Cited by 50 publications

References 18 publications

Regulation of fas/fas ligand‐mediated apoptosis by nuclear factor of activated T cells in megakaryocytes

Regulation of fas/fas ligand‐mediated apoptosis by nuclear factor of activated T cells in megakaryocytes

Platelets in Lung Biology

Angiogenesis-related gene expression profiling in ventilated preterm human lungs

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