Hematopoietic and nonhematopoietic cell tissue factor activates the coagulation cascade in endotoxemic mice

Pawliński, Rafał; Wang, Jingguo; Owens, A. Phillip; Williams, Julie C.; Antoniak, Silvio; Tencati, Michael; Luther, Thomas; Rowley, Jesse W.; Low, Elizabeth N.; Weyrich, Andrew S.; Mackman, Nigel

doi:10.1182/blood-2009-12-259267

Cited by 164 publications

(166 citation statements)

References 46 publications

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“…The lack of effect of deletion of myeloid TF in ALI is an unexpected finding, and provides new insight into the regulation of local coagulation in the airspace. It is well established that alveolar macrophages express TF (8)(9)(10)18). Two studies of bleomycin-induced lung injury demonstrated strong up-regulation of TF mRNA (8) and protein expression (18) on macrophages during ALI.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of Alveolar Procoagulant Activity and Permeability in Direct Acute Lung Injury by Lung Epithelial Tissue Factor

Shaver

Grove

Putz

et al. 2015

Am J Respir Cell Mol Biol

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Tissue factor (TF) initiates the extrinsic coagulation cascade in response to tissue injury, leading to local fibrin deposition. Low levels of TF in mice are associated with increased severity of acute lung injury (ALI) after intratracheal LPS administration. However, the cellular sources of the TF required for protection from LPS-induced ALI remain unknown. In the current study, transgenic mice with cell-specific deletions of TF in the lung epithelium or myeloid cells were treated with intratracheal LPS to determine the cellular sources of TF important in direct ALI. Cell-specific deletion of TF in the lung epithelium reduced total lung TF expression to 39% of wild-type (WT) levels at baseline and to 29% of WT levels after intratracheal LPS. In contrast, there was no reduction of TF with myeloid cell TF deletion. Mice lacking myeloid cell TF did not differ from WT mice in coagulation, inflammation, permeability, or hemorrhage. However, mice lacking lung epithelial TF had increased tissue injury, impaired activation of coagulation in the airspace, disrupted alveolar permeability, and increased alveolar hemorrhage after intratracheal LPS. Deletion of epithelial TF did not affect alveolar permeability in an indirect model of ALI caused by systemic LPS infusion. These studies demonstrate that the lung epithelium is the primary source of TF in the lung, contributing 60-70% of total lung TF, and that lung epithelial, but not myeloid, TF may be protective in direct ALI.Keywords: coagulation; fibrin; pulmonary; acute respiratory distress syndrome; alveolar capillary barrier permeability Clinical RelevanceThis study evaluates the role of tissue factor (TF) in direct acute lung injury using cell-specific genetic approaches. We identify the lung epithelium as the major source of TF in the airspace. Loss of epithelial TF increases lung injury, impairs coagulation, results in lung hemorrhage, and disrupts alveolar-capillary barrier permeability. These findings identify a potential new target for treatment of severe lung injury in humans.A pathologic hallmark of severe acute lung injury (ALI) in humans is intra-alveolar fibrin deposition, forming hyaline membranes lining the airspace (1). Activation of the tissue factor (TF) pathway is a major driver of coagulation in the airspace (2-5). We previously demonstrated a critical role for TF in protection from ALI caused by intratracheal LPS administration (2). LTF mice, which lack murine TF and express 1% of endogenous levels of human TF to overcome embryonic lethality, developed more severe ALI in response to intratracheal LPS than littermate controls. LTF mice had a local coagulation defect in the airspace, increased histologic lung injury, increased alveolar-capillary

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Section: Discussionmentioning

confidence: 99%

“…In addition, TF can be strongly induced on epithelial cells, macrophages, and other cell types in vitro (10)(11)(12)(13)(14)(15)(16). The cellular sources of TF that drive the protective effects of TF during direct ALI, and the mechanisms of the protective effects of TF in the airspace, are currently unknown.…”

mentioning

confidence: 99%

Regulation of Alveolar Procoagulant Activity and Permeability in Direct Acute Lung Injury by Lung Epithelial Tissue Factor

Shaver

Grove

Putz

et al. 2015

Am J Respir Cell Mol Biol

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“…negatively charged phospholipids and of tissue factor (TF), they create a procoagulant surface on which coagulation factors can bind and be activated (Morel et al 2006). Indeed, the initial concept that TF presence is limited to a hemostatic envelope surrounding blood vessels has been challenged by the identification of 'blood borne' TF, either on circulating white blood cells or microvesicles, as a soluble protein, or possibly on stimulated endothelial cells (Pawlinski et al 2010).…”

Section: Pathophysiologymentioning

confidence: 99%

Air Pollution and Cardiovascular Disease

Emmerechts¹,

Jacobs²,

Hoylaerts³

2011

The Impact of Air Pollution on Health, Economy, Environment and Agricultural Sources

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“…Importantly, the data presented here differ from observations in a mouse model of endotoxemia, where LPSinduced coagulation activation was partially attenuated by inhibition of either hematopoietic or non-hematopoietic sources of TF. 16 This difference is most likely explained by the fact that the level of coagulation activation in endotoxemic mice was much greater than in heme-treated mice, which allowed us to reveal the partial contribution of TF expressed by both cell types. 29 It has recently been proposed that in addition to cellular TF, procoagulant microparticles (MPs) may contribute to the propagation of coagulation in various pathological conditions.…”

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confidence: 99%

“…16 1H1 is a monoclonal rat anti-mouse TF antibody that competes for binding of factor VII. 21 Chimeric HTF BM /WT mice were administered anti-human TF (HTF1, 10 mg/kg), anti-mouse TF (1H1, 20 mg/kg) or control IgG (10 mg/kg) 30 min before heme.…”

Section: Administration Of Antibodiesmentioning

confidence: 99%

Excess of heme induces tissue factor-dependent activation of coagulation in mice

et al. 2015

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Hematopoietic and nonhematopoietic cell tissue factor activates the coagulation cascade in endotoxemic mice

Cited by 164 publications

References 46 publications

Regulation of Alveolar Procoagulant Activity and Permeability in Direct Acute Lung Injury by Lung Epithelial Tissue Factor

Regulation of Alveolar Procoagulant Activity and Permeability in Direct Acute Lung Injury by Lung Epithelial Tissue Factor

Air Pollution and Cardiovascular Disease

Excess of heme induces tissue factor-dependent activation of coagulation in mice

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