Antithrombin attenuates vascular leakage via inhibiting neutrophil activation in acute lung injury

Sebastian Rehberg, Yusuke Yamamoto, Linda Sousse, Collette Jonkam, Yong Zhu, Lillian D. Traber, Robert A. Cox, Donald Prough, Daniel L. Traber, Perenlei Enkhbaatar

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

OBJECTIVE:: To test the hypothesis that restoration of antithrombin plasma concentrations attenuates vascular leakage by inhibiting neutrophil activation through syndecan-4 receptor inhibition in an established ovine model of acute lung injury. DESIGN:: Randomized controlled laboratory experiment. SETTING:: University animal research facility. SUBJECTS:: Eighteen chronically instrumented sheep. INTERVENTIONS:: Following combined burn and smoke inhalation injury (40% of total body surface area, third-degree flame burn; 4 × 12 breaths of cold cotton smoke), chronically instrumented sheep were randomly assigned to receive an IV infusion of 6 IU/kg/hr recombinant human antithrombin III or normal saline (n = 6 each) during the 48-hour study period. In addition, six sham animals (not injured, continuous infusion of vehicle) were used to obtain reference values for histological and immunohistochemical analyses. MEASUREMENTS AND MAIN RESULTS:: Compared to control animals, recombinant human antithrombin III reduced the number of neutrophils per hour in the pulmonary lymph (p < 0.01 at 24 and 48 hr), alveolar neutrophil infiltration (p = 0.04), and pulmonary myeloperoxidase activity (p = 0.026). Flow cytometric analysis revealed a significant reduction of syndecan-4-positive neutrophils (p = 0.002 vs control at 24 hr). Treatment with recombinant human antithrombin III resulted in a reduction of pulmonary nitrosative stress (p = 0.002), airway obstruction (bronchi: p = 0.001, bronchioli: p = 0.013), parenchymal edema (p = 0.044), and lung bloodless wet-to-dry-weight ratio (p = 0.015). Clinically, recombinant human antithrombin III attenuated the increased pulmonary transvascular fluid flux (12-48 hr: p ≤ 0.001 vs control each) and the deteriorated pulmonary gas exchange (12-48 hr: p < 0.05 vs control each) without increasing the risk of bleeding. CONCLUSIONS:: The present study provides evidence for the interaction between antithrombin and neutrophils in vivo, its pathophysiological role in vascular leakage, and the therapeutic potential of recombinant human antithrombin III in a large animal model of acute lung injury.

Original languageEnglish (US)
JournalCritical Care Medicine
Volume41
Issue number12
DOIs
StatePublished - Dec 2013

Fingerprint

Neutrophil Activation
Antithrombins
Antithrombin III
Acute Lung Injury
Blood Vessels
Syndecan-4
Sheep
Lung
Neutrophils
Smoke Inhalation Injury
Pulmonary Gas Exchange
Neutrophil Infiltration
Body Surface Area
Lymph
Pulmonary Edema
Airway Obstruction
Bronchi
Smoke
Peroxidase
Edema

Keywords

  • Acute respiratory distress syndrome
  • Burn and smoke inhalation injury
  • Neutrophil migration
  • Syndecan-4 receptor

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Antithrombin attenuates vascular leakage via inhibiting neutrophil activation in acute lung injury. / Rehberg, Sebastian; Yamamoto, Yusuke; Sousse, Linda; Jonkam, Collette; Zhu, Yong; Traber, Lillian D.; Cox, Robert A.; Prough, Donald; Traber, Daniel L.; Enkhbaatar, Perenlei.

In: Critical Care Medicine, Vol. 41, No. 12, 12.2013.

Research output: Contribution to journalArticle

Rehberg, Sebastian ; Yamamoto, Yusuke ; Sousse, Linda ; Jonkam, Collette ; Zhu, Yong ; Traber, Lillian D. ; Cox, Robert A. ; Prough, Donald ; Traber, Daniel L. ; Enkhbaatar, Perenlei. / Antithrombin attenuates vascular leakage via inhibiting neutrophil activation in acute lung injury. In: Critical Care Medicine. 2013 ; Vol. 41, No. 12.
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abstract = "OBJECTIVE:: To test the hypothesis that restoration of antithrombin plasma concentrations attenuates vascular leakage by inhibiting neutrophil activation through syndecan-4 receptor inhibition in an established ovine model of acute lung injury. DESIGN:: Randomized controlled laboratory experiment. SETTING:: University animal research facility. SUBJECTS:: Eighteen chronically instrumented sheep. INTERVENTIONS:: Following combined burn and smoke inhalation injury (40{\%} of total body surface area, third-degree flame burn; 4 × 12 breaths of cold cotton smoke), chronically instrumented sheep were randomly assigned to receive an IV infusion of 6 IU/kg/hr recombinant human antithrombin III or normal saline (n = 6 each) during the 48-hour study period. In addition, six sham animals (not injured, continuous infusion of vehicle) were used to obtain reference values for histological and immunohistochemical analyses. MEASUREMENTS AND MAIN RESULTS:: Compared to control animals, recombinant human antithrombin III reduced the number of neutrophils per hour in the pulmonary lymph (p < 0.01 at 24 and 48 hr), alveolar neutrophil infiltration (p = 0.04), and pulmonary myeloperoxidase activity (p = 0.026). Flow cytometric analysis revealed a significant reduction of syndecan-4-positive neutrophils (p = 0.002 vs control at 24 hr). Treatment with recombinant human antithrombin III resulted in a reduction of pulmonary nitrosative stress (p = 0.002), airway obstruction (bronchi: p = 0.001, bronchioli: p = 0.013), parenchymal edema (p = 0.044), and lung bloodless wet-to-dry-weight ratio (p = 0.015). Clinically, recombinant human antithrombin III attenuated the increased pulmonary transvascular fluid flux (12-48 hr: p ≤ 0.001 vs control each) and the deteriorated pulmonary gas exchange (12-48 hr: p < 0.05 vs control each) without increasing the risk of bleeding. CONCLUSIONS:: The present study provides evidence for the interaction between antithrombin and neutrophils in vivo, its pathophysiological role in vascular leakage, and the therapeutic potential of recombinant human antithrombin III in a large animal model of acute lung injury.",
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AU - Zhu, Yong

AU - Traber, Lillian D.

AU - Cox, Robert A.

AU - Prough, Donald

AU - Traber, Daniel L.

AU - Enkhbaatar, Perenlei

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N2 - OBJECTIVE:: To test the hypothesis that restoration of antithrombin plasma concentrations attenuates vascular leakage by inhibiting neutrophil activation through syndecan-4 receptor inhibition in an established ovine model of acute lung injury. DESIGN:: Randomized controlled laboratory experiment. SETTING:: University animal research facility. SUBJECTS:: Eighteen chronically instrumented sheep. INTERVENTIONS:: Following combined burn and smoke inhalation injury (40% of total body surface area, third-degree flame burn; 4 × 12 breaths of cold cotton smoke), chronically instrumented sheep were randomly assigned to receive an IV infusion of 6 IU/kg/hr recombinant human antithrombin III or normal saline (n = 6 each) during the 48-hour study period. In addition, six sham animals (not injured, continuous infusion of vehicle) were used to obtain reference values for histological and immunohistochemical analyses. MEASUREMENTS AND MAIN RESULTS:: Compared to control animals, recombinant human antithrombin III reduced the number of neutrophils per hour in the pulmonary lymph (p < 0.01 at 24 and 48 hr), alveolar neutrophil infiltration (p = 0.04), and pulmonary myeloperoxidase activity (p = 0.026). Flow cytometric analysis revealed a significant reduction of syndecan-4-positive neutrophils (p = 0.002 vs control at 24 hr). Treatment with recombinant human antithrombin III resulted in a reduction of pulmonary nitrosative stress (p = 0.002), airway obstruction (bronchi: p = 0.001, bronchioli: p = 0.013), parenchymal edema (p = 0.044), and lung bloodless wet-to-dry-weight ratio (p = 0.015). Clinically, recombinant human antithrombin III attenuated the increased pulmonary transvascular fluid flux (12-48 hr: p ≤ 0.001 vs control each) and the deteriorated pulmonary gas exchange (12-48 hr: p < 0.05 vs control each) without increasing the risk of bleeding. CONCLUSIONS:: The present study provides evidence for the interaction between antithrombin and neutrophils in vivo, its pathophysiological role in vascular leakage, and the therapeutic potential of recombinant human antithrombin III in a large animal model of acute lung injury.

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