Blockade of tissue factor-factor X binding attenuates sepsis-induced respiratory and renal failure

Welty-Wolf, Karen E.; Carraway, Martha Sue; Ortel, Thomas L.; Ghio, Andrew J.; Idell, Steven; Egan, Jack O.; Zhu, Xiaoyun; Jiao, Jin; Wong, Hing C.; Piantadosi, Claude A.

doi:10.1152/ajplung.00155.2005

Cited by 73 publications

(72 citation statements)

References 37 publications

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“…Thrombin and fibrin can each stimulate cytokine production in monocytes and endothelial cells in vitro (33)(34)(35). In addition, TF modulates inflammation in models of systemic sepsis, and inhibition of coagulation has been shown to reduce lung inflammation in these models (36)(37)(38)(39). Our data support the concept that the role of TF in inflammation in the airspace is distinct from its effects in the circulation.…”

Section: Discussionsupporting

confidence: 74%

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: Discussionsupporting

confidence: 74%

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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“…Renal dysfunction evaluated by serum creatinine and BUN was found in acute non-survivors (<24 hours) and decreased urine output in subacute non-survivors (24-96 hours). In a baboon model, a hyperdynamic state is preactivated by injection of killed bacteria followed by injection with live E. coli; renal dysfunction was also demonstrated (91)(92)(93). It is of note that renal histological changes, including tubular epithelial cell injury, fibrin deposits, and inflammatory cell infiltration, were found in this model.…”

Section: Large Animal Models and Bacterial Infusion/inoculationmentioning

confidence: 72%

Animal models of sepsis and sepsis-induced kidney injury

Doi

Leelahavanichkul²,

Yuen³

et al. 2009

J. Clin. Invest.

491

424

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Sepsis and sepsis-induced acute kidney injury: a life-threatening conditionSepsis is a characteristic set of systemic reactions to overwhelming infection. Sepsis, severe sepsis, and septic shock are defined according to established criteria (Table 1) (1). Discovery of antibiotics has dramatically improved the morbidity and mortality of the infectious diseases for the last decades; indeed, antibiotics and volume resuscitation are the first line of sepsis treatment strategy (2). However, overwhelming inflammatory response accompanied by depression in immunological function causes multiple organ injury and determines clinical outcomes. In addition to inflammation and immunological dysregulation, a number of different mechanisms contribute to sepsis at different phases (Figure 1). For instance, systemic hemodynamics evolves from an early hyperdynamic ("warm shock") state to a late hypodynamic ("cold shock") state.Sepsis is the leading cause of death in critically ill patients, and the incidence of sepsis is increasing (3, 4). The mortality rate of severe sepsis is very high (up to 70%), and the calculated costs exceed $15 billion per year in the United States (3). The rate of severe sepsis during hospitalization almost doubled during the last decade and is considerably greater than previously predicted (5). Sepsis causes multiorgan failure, including acute kidney injury (AKI) (6), and patients with both sepsis and AKI have an especially high mortality rate (7). AKI is diagnosed by a sudden decrease in glomerular filtration rate (GFR), the primary measure of kidney function, which is currently detected clinically as a rise in serum creatinine. A multinational prospective observational study including 29,269 critically ill patients revealed that the occurrence of AKI in the intensive care unit (ICU) was approximately 6%, the most frequent contributing factor to AKI being sepsis (50%) (8). Other reports showed that between 45% and 70% of all AKI is associated with sepsis (9-11). Several different pathophysiological mechanisms have been proposed for sepsis-induced AKI: vasodilation-induced glomerular hypoperfusion, dysregulated circulation within the peritubular capillary network, inflammatory reactions by systemic cytokine storm or local cytokine production (12), and tubular dysfunction induced by oxidative stress (13).Continuing concern over the efficacy and safety of the only FDAapproved therapy for severe sepsis (activated protein C) highlights the critical need to improve our understanding of the pathophysiology of sepsis and sepsis-induced AKI and to develop novel treatment strategies for critically ill patients (14). A multitude of potential drug targets have been identified in animal models of sepsis; however, translation from animals to humans has been exceedingly difficult. Several reviews have pointed out that the failure to translate results from animals to humans has been attributed to disease characteristics of sepsis (complexity and heterogeneity), inappropriate clinical trials (study of ineffective drugs...

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“…TF represents a potential therapeutic target for multiple disease conditions. Several TF antagonists have been tested in humans for coronary artery disease [36] and in animal models of sepsis [37] and tumor growth [38]. Given the low sequence homology between human TF and that of animal model species, TF antagonists are often species-specific.…”

Section: Discussionmentioning

confidence: 99%

Expression of human tissue factor under the control of the mouse tissue factor promoter mediates normal hemostasis in knock-in mice

Snyder¹,

Rudnick²,

Tawadros³

et al. 2008

J Thromb Haemost

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Blockade of tissue factor-factor X binding attenuates sepsis-induced respiratory and renal failure

Cited by 73 publications

References 37 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

Animal models of sepsis and sepsis-induced kidney injury

Expression of human tissue factor under the control of the mouse tissue factor promoter mediates normal hemostasis in knock-in mice

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