Early elevation of plasma von Willebrand factor antigen in pediatric acute lung injury is associated with an increased risk of death and prolonged mechanical ventilation*

Flori, Heidi R.; Ware, Lorraine B.; Milet, Meredith; Matthay, Michael A.

doi:10.1097/01.pcc.0000257097.42640.6f

Cited by 53 publications

(33 citation statements)

References 39 publications

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“…A major discrepancy, however, exists between the presence of hypoxia-induced injury in the pulmonary vascular endothelium, as shown by the elec- tron microscopic analysis, and the absence of hypoxia-induced vWF:Ag release into the pulmonary circulation in the current study. vWF:Ag has been shown to be a sensitive marker for endothelial damage, and has been used for the diagnosis and prognosis of several types of acute lung injury in humans (27,44,45) and in rats (46). The failure of this marker in reflecting hypoxia-induced injury in pulmonary endothelial cells in the current study was therefore unexpected.…”

Section: Discussionmentioning

confidence: 38%

Type I Epithelial Cells Are the Main Target of Whole-Body Hypoxic Preconditioning in the Lung

Zhang¹,

Miller²,

Stolz³

et al. 2009

Am J Respir Cell Mol Biol

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Whole-body hypoxic preconditioning (WHPC) prolongs survival of mice exposed to severe hypoxia by attenuating pulmonary edema and preserving gas exchange. However, the cellular and molecular mechanism(s) of this protection remains unclear. The objective of this study was to identify the cellular target(s) of WHPC in the lung. Conscious mice were exposed to hypoxia (7% O 2 ) for 6 hours with or without pretreatment of WHPC ([8% O 2 ] 3 10 min/[21% O 2 ] 3 10 min; 6 cycles). Hypoxia caused severe lung injury, as shown by the development of high-permeability-type pulmonary edema and the release of lactate dehydrogenase and creatine kinase into the airspace and the circulation. All these signs of hypoxic lung injury were significantly attenuated by WHPC. Hypoxia also caused a remarkable release of type I cell markers (caveolin-2 and receptor for advanced glycation end products) in lung lavage that was almost completely abolished by WHPC. Conversely, hypoxia-induced release of type II cell markers (surfactant-associated proteins A and D) was only marginal, and was unaffected by WHPC. Electron microscopic analysis demonstrated considerable hypoxic damage in alveolar type I cells and vascular endothelial cells. Notably, WHPC completely eliminated hypoxic damage in the former and alleviated it in the latter. Type II cells appeared normal. Furthermore, WHPC upregulated protein expression of cytoprotective genes in the lung, such as heat shock proteins and manganese superoxide dismutase. Thus, WHPC attenuates hypoxic lung injury through protection of cells constituting the respiratory membrane, especially hypoxiavulnerable type I epithelial cells. This beneficial effect may involve up-regulation of cytoprotective genes.

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Section: Discussionmentioning

confidence: 38%

Type I Epithelial Cells Are the Main Target of Whole-Body Hypoxic Preconditioning in the Lung

Zhang¹,

Miller²,

Stolz³

et al. 2009

Am J Respir Cell Mol Biol

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“…Elevated VWF levels [23][24][25] and reduced ADAMTS13 activity in plasma have been described in many conditions associated with systemic inflammation, such as acute respiratory distress, acute pancreatitis, sepsis and septic shock, sepsis-induced organ failure, and sepsis-induced disseminated intravascular coagulation. 10,11,13,26,27 Elevated VWF levels in plasma in these syndromes may be the result of enhanced release of ULVWF and reduced processing of ULVWF and/or VWF by ADAMTS13.…”

Section: Discussionmentioning

confidence: 99%

ADAMTS13 reduces vascular inflammation and the development of early atherosclerosis in mice

Gandhi

Khan

Lentz

et al. 2012

Blood

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ADAMTS13, a metalloprotease, plays a pivotal role in preventing spontaneous microvascular thrombosis by cleaving hyperactive ultra large von Willebrand factor multimers into smaller, less active multimers. Reduced ADAMTS13 activity in plasma has been described in many diseases associated with systemic inflammation. It remains uncertain, however, whether ADAMTS13 contributes to disease pathogenesis or rather simply serves as an inflammation-associated marker. We hypothesized that, by decreasing vascular inflammation, ADAMTS13 reduces the development of early atherosclerotic plaques. Using intravital fluorescence microscopy, we observed excessive leukocyte adhesion and accelerated atherosclerotic plaque formation at the carotid sinus of Adamts13 ؊/؊ /ApoE ؊/؊ mice compared with ApoE ؊/؊ mice fed a high-fat Western diet. At 4 months of age, there was a significant increase in atherosclerosis in the aorta and aortic sinus of Adamts13 ؊/؊ / ApoE ؊/؊ mice compared with ApoE ؊/؊ mice. Interestingly, we detected a 2-fold increase in macrophage recruitment to the atherosclerotic plaque of the Adamts13 ؊/؊ /ApoE ؊/؊ mice compared with ApoE ؊/؊ mice, suggesting that the atherosclerotic lesions in these mice were not only larger but also more inflammatory. These findings reveal a new functional role for the antithrombotic enzyme ADAMTS13 in reducing excessive vascular inflammation and plaque formation during early atherosclerosis. (Blood. 2012; 119(10):2385-2391) Introduction ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I repeats-13) is a zinc-containing protease that is synthesized primarily by hepatic stellate cells 1,2 and, to a lesser extent, by endothelial cells, 3 both of which secrete ADAMTS13 into the bloodstream. The only known substrate for ADAMTS13 is von Willebrand factor (VWF), a hemostatic glycoprotein that is stored as ultra large VWF (ULVWF) multimers in platelet ␣-granules and endothelial storage granules called Weibel-Palade bodies. 4 ULVWF multimers, which can be as large as 20 000 kDa and are considered to be the most hyperactive and thrombogenic form of VWF, 4,5 are not present in blood plasma under normal conditions. However, on endothelial cell activation or injury, ULVWF multimers are released into the circulation from WeibelPalade bodies. During the process of secretion, ULVWF remains transiently bound to the endothelial surface where they are cleaved by ADAMTS13 into smaller, less active VWF multimers, thereby reducing its thrombotic potential. 6 The essential role of VWF in hemostasis is evidenced clinically in patients with von Willebrand disease, a bleeding disorder caused by a lack of functional VWF. 7 In distinction, deficiency of ADAMTS13 increases plasma levels of ULVWF and causes thrombotic thrombocytopenic purpura, a disorder of thrombotic microangiopathy. 8 Several epidemiologic studies have demonstrated reduced plasma ADAMTS13 activity in inflammatory conditions, including aging, 9 systemic inflammation, 10 pancreatitis, 11 and sepsis. 12,13 It remains uncertain, ...

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“…4,5 Elevated VWF levels in plasma have been described in diseases associated with systemic inflammation, such as acute lung injury/acute respiratory distress syndrome 6,7 and sepsis. 8 In each of these disorders, increased plasma VWF levels correlated independently with increased risk of death.…”

Section: Introductionmentioning

confidence: 99%

Oxidative modification of von Willebrand factor by neutrophil oxidants inhibits its cleavage by ADAMTS13

Chen

Wang

et al. 2010

Blood

133

124

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Elevated plasma von Willebrand factor (VWF) and low ADAMTS13 activity have been reported in several inflammatory states, including sepsis and acute respiratory distress syndrome. One hallmark of inflammation is neutrophil activation and production of reactive oxygen species, including superoxide radical, hydrogen peroxide, and hypochlorous acid (HOCl). HOCl is produced from hydrogen peroxide and chloride ions through the action of myeloperoxidase. HOCl can oxidize methionine to methionine sulfoxide and tyrosine to chlorotyrosine. This is of interest because the ADAMTS13 cleavage site in VWF, the Tyr 1605 -Met 1606 peptide bond, contains both oxidation-prone residues. We hypothesized that HOCl would oxidize either or both of these residues and possibly inhibit ADAMTS13-mediated cleavage. We therefore treated ADAMTS13 substrates with HOCl and examined their oxidative modification by mass spectrometry. Met 1606 was oxidized to the sulfoxide in a concentration-dependent manner, with complete oxidation at 75M HOCl, whereas only a miniscule percentage of Tyr 1605 was converted to chlorotyrosine. The oxidized substrates were cleaved much more slowly by ADAMTS13 than the nonoxidized substrates. A similar result was obtained with multimeric VWF. Taken IntroductionDuring acute inflammation, endothelial cells are activated by inflammatory cytokines such as interleukin-1 and tumor necrosis factor-␣. Activated endothelial cells release von Willebrand factor (VWF) and expose P-selectin on the cell surface, a result of exocytosis of Weibel-Palade bodies, the major endothelial storage granules. 1,2 On a longer time scale, other adhesion molecules, such as E-selectin and intracellular adhesion molecule-1, are synthesized and exposed on the cell surface. 3 These molecules provide an adhesive surface for neutrophils, which attach to and roll on the endothelium, then become activated and migrate through the vessel wall into the surrounding tissues.Although a fraction of the VWF remains transiently attached to the activated endothelium, most is secreted into the plasma. 4,5 Elevated VWF levels in plasma have been described in diseases associated with systemic inflammation, such as acute lung injury/acute respiratory distress syndrome 6,7 and sepsis. 8 In each of these disorders, increased plasma VWF levels correlated independently with increased risk of death. The elevated plasma VWF level is primarily a consequence of endothelial cell activation, but other mechanisms may be involved. Several recent studies have shown that systemic inflammation is also associated with reduced activity of the VWF-processing enzyme ADAMTS13 activity in syndromes such as acute systemic inflammation caused by endotoxin, 9 acute pancreatitis, 10 severe sepsis and septic shock, 11 sepsis-induced disseminate intravascular coagulation, 12 and sepsis-induced organ dysfunction. [13][14][15] It is therefore likely that in addition to enhanced release of VWF, delayed or reduced VWF processing by ADAMTS13 contributes to the elevated level and adhesiveness of VW...

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Early elevation of plasma von Willebrand factor antigen in pediatric acute lung injury is associated with an increased risk of death and prolonged mechanical ventilation*

Abstract: Early injury to the systemic and pulmonary endothelium, as measured by plasma vWF-Ag levels, is associated with an increased risk of death and prolonged mechanical ventilation in pediatric patients with ALI.

Cited by 53 publications

References 39 publications

Type I Epithelial Cells Are the Main Target of Whole-Body Hypoxic Preconditioning in the Lung

Type I Epithelial Cells Are the Main Target of Whole-Body Hypoxic Preconditioning in the Lung

ADAMTS13 reduces vascular inflammation and the development of early atherosclerosis in mice

Oxidative modification of von Willebrand factor by neutrophil oxidants inhibits its cleavage by ADAMTS13

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