Low levels of tissue factor lead to alveolar haemorrhage, potentiating murine acute lung injury and oxidative stress

Bastarache, Julie A.; Sebag, Sara C.; Clune, Jennifer K.; Grove, Brandon S.; Lawson, William; Janz, David R.; Roberts, L. Jackson; Dworski, Ryszard; Mackman, Nigel; Ware, Lorraine B.

doi:10.1136/thoraxjnl-2012-201781

Cited by 56 publications

(71 citation statements)

References 29 publications

(31 reference statements)

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“…All samples were stored at 280 8 C until further study. For histologic analysis, lungs were perfused with saline and inflated with formalin, as previously reported (2).…”

Section: Sample Collectionmentioning

confidence: 99%

“…For direct LPS-induced lung injury, mice were anesthetized with isoflurane and treated with 10 mg LPS in 100 ml (Escherichia coli, LPS; Sigma, St. Louis, MO) or 100 ml PBS (control; Mediatech, Manassas, VA) by intratracheal injection (2,25). Indirect lung injury was induced by continuous infusion of LPS (8 mg/h for 24 h) or equal volume PBS delivered by osmotic pump (Durect, Cupertino, CA) with a single intraperitoneal dose of LPS (3 mg/mouse) or PBS at the time of pump implantation (26).…”

Section: Models Of Alimentioning

confidence: 99%

“…Activation of the tissue factor (TF) pathway is a major driver of coagulation in the airspace (2)(3)(4)(5). We previously demonstrated a critical role for TF in protection from ALI caused by intratracheal LPS administration (2).…”

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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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“…All samples were stored at 280 8 C until further study. For histologic analysis, lungs were perfused with saline and inflated with formalin, as previously reported (2).…”

Section: Sample Collectionmentioning

confidence: 99%

Section: Models Of Alimentioning

confidence: 99%

See 1 more Smart Citation

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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“…Patients with ARDS have evidence of increased RBCs and hemoglobin in tissues on histological sections (35). Studies in mice also indicate that there is hemorrhage and free hemoglobin in the intraalveolar space following intratracheal injection of LPS (36). In studies of patients with sepsis, elevated free plasma studies, hHx-B did not inhibit neutrophil migration to the peritoneal cavity induced by thioglycolate ( Figure 6).…”

Section: Discussionmentioning

confidence: 92%

Purified and Recombinant Hemopexin: Protease Activity and Effect on Neutrophil Chemotaxis

Tian

Liu

Feng

et al. 2016

Mol Med

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Infusion of the heme-binding protein hemopexin has been proposed as a novel approach to decrease heme-induced inflammation in settings of red blood cell breakdown, but questions have been raised as to possible side effects related to protease activity and inhibition of chemotaxis. We evaluated protease activity and effects on chemotaxis of purified plasma hemopexin obtained from multiple sources as well as a novel recombinant fusion protein Fc-hemopexin. Amidolytic assay was performed to measure the protease activity of several plasma-derived hemopexin and recombinant Fc-hemopexin. Hemopexin was added to the human monocyte culture in the presence of lipopolysaccharides (LPS), and also injected into mice intravenously (i.v.) 30 min before inducing neutrophil migration via intraperitoneal (i.p.) injection of thioglycolate. Control groups received the same amount of albumin. Protease activity varied widely between hemopexins. Recombinant Fc-hemopexin bound heme, inhibited the synergy of heme with LPS on tumor necrosis factor (TNF) production from monocytes, and had minor but detectable protease activity. There was no effect of any hemopexin preparation on chemotaxis, and purified hemopexin did not alter the migration of neutrophils into the peritoneal cavity of mice. Heme and LPS synergistically induced the release of LTB4 from human monocytes, and hemopexin blocked this release, as well as chemotaxis of neutrophils in response to activated monocyte supernatants. These results suggest that hemopexin does not directly affect chemotaxis through protease activity, but may decrease heme-driven chemotaxis and secondary inflammation by attenuating the induction of chemoattractants from monocytes. This property could be beneficial in some settings to control potentially damaging inflammation induced by heme.

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“…Decreased TF activity in tissue samples contributes to high thromboplastin levels and cellular damage. Low levels of TF lead to alveolar hemorrhage, potentiating murine acute lung injury and oxidative stress (Bastarache et al, 2012). Emekli-Alturfan et al (2007) indicated a decrease in lung TF activity in STZ-treated rat.…”

Section: Discussionmentioning

confidence: 99%

Chard (Beta vulgarisvar.cicla) extract improved hyperglycemia-induced oxidative stress and surfactant-associated protein alterations in rat lungs

Öztay¹,

Saçan

Kayalar³

et al. 2015

Pharmaceutical Biology

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Context: Chard is used as an antidiabetic agent by the diabetic patients in Turkey. Objective: The effect of chard extract [Beta vulgaris L. var. cicla (Chenopodiaceae)] on the antioxidant system and the expression of surfactant-associated proteins (SP) in the lungs of hyperglycemic rats were examined. Materials and methods: Hyperglycemia was induced by a single dose of streptozotocin (60 mg/kg) provided intraperitoneally. Fourteen days after the rats were rendered hyperglycemic, the chard (2 g/kg/d), insulin (6 U/kg/d), and chard plus insulin (as mentioned above) were administered to rats for 45 d. On day 60, rats' lungs were removed. Oxidative stress parameters and SP expression were assayed. Results: The lungs of hyperglycemic rats were characterized by the induced lipid and protein oxidation, elevated myeloperoxidase and xanthine oxidase activities, decreased glutathione levels, and reduced tissue factor and antioxidant enzymes activities (catalase, superoxide dismutase, glutathione peroxidase, and glutathione-S-transferase). Chard treatment alone and chard treatment combined with insulin were capable of achieving a regression of pulmonary oxidative stress, by inhibiting lipid and protein oxidation, and restoring the antioxidant system of hyperglycemic rats. SP-A expressions were significantly unchanged in all groups, whereas pro-SP-C and SP-D expressions were reduced in hyperglycemic rats. Pro-SP-C and SP-D levels were increased by chard and insulin administrations alone and combined in hyperglycemic rats. Discussion and conclusion: All treatments have a positive effect on the surfactant and antioxidant systems of the lungs of hyperglycemic rats. The best therapeutic effect was provided by treatment with chard extract alone in the compensation of hyperglycemic symptoms.

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Low levels of tissue factor lead to alveolar haemorrhage, potentiating murine acute lung injury and oxidative stress

Cited by 56 publications

References 29 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

Purified and Recombinant Hemopexin: Protease Activity and Effect on Neutrophil Chemotaxis

Chard (Beta vulgarisvar.cicla) extract improved hyperglycemia-induced oxidative stress and surfactant-associated protein alterations in rat lungs

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