Recombinant human activated protein C attenuates endotoxin-induced lung injury in awake sheep
Introduction: Acute lung injury often complicates severe sepsis. In Gram-negative sepsis, bacterial endotoxin activates both coagulation and inflammation. Enhanced lung vascular pressures and permeability, increased extravascular lung water content and deteriorated gas exchange characterize ovine en...
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creator | Wærhaug, Kristine Langbakk, Bodil Kuklin, Vladimir N Kirov, Mikhail Y Sovershaev, Mikhail Ingebretsen, Ole C Ytrehus, Kirsti Bjertnæs, Lars J |
description | Introduction: Acute lung injury often complicates severe sepsis.
In Gram-negative sepsis, bacterial endotoxin activates both
coagulation and inflammation. Enhanced lung vascular
pressures and permeability, increased extravascular lung water
content and deteriorated gas exchange characterize ovine
endotoxin-induced lung injury, a frequently used model of acute
lung injury. Recombinant human activated protein C (rhAPC),
with its anticoagulant, anti-inflammatory, fibrinolytic and
antiapoptotic effects, reportedly reduces the respiratordependent
days and the mortality of patients with severe sepsis.
We speculate whether rhAPC antagonizes endotoxin-induced
lung injury in sheep.
Methods: Two groups of sheep were exposed to Escherichia
coli endotoxin (lipopolysaccharide) 15 ng/kg/minute
intravenously from 0 to 24 hours; one group received only
lipopolysaccharide throughout (n = 8), and the other group
received lipopolysaccharide in combination with rhAPC 24 μg/
kg/hour from 4 to 24 hours (n = 9). In addition, one group
received rhAPC as above as the only intervention (n = 4), and
four sham-operated sheep were used for determination of the α
and ε isoforms of protein kinase C in pulmonary tissue. Data
were assessed by one-way analysis of variance for repeated
measurements. Biochemical data were analyzed using
Student's t test, or using the Mann–Whitney U test when
appropriate.
Results: Infusion of endotoxin caused lung injury, manifested by
increments in pulmonary artery pressure, in pulmonary microocclusion
pressure, in pulmonary vascular downstream
resistance, in pulmonary vascular permeability index, in
extravascular lung water index and in deterioration of
oxygenation that were all attenuated by infusion of rhAPC.
Endotoxemia led to changes in inflammation and coagulation,
including pulmonary neutrophil accumulation paralleled by
increased TNFα and decreased protein C and fibrinogen in
animal plasma, which all improved following infusion of rhAPC.
Moreover, rhAPC prevented the translocation of protein kinase
C α and ε isoforms from the cytosolic fraction of lung tissue
extracts.
Conclusion: In awake sheep, rhAPC alleviates endotoxininduced
lung injury – as characterized by improvements of
oxygenation, coagulation and inflammation, as well as by
reversal of pulmonary hemodynamic and volumetric changes. |
format | Article |
fullrecord | <record><control><sourceid>cristin_3HK</sourceid><recordid>TN_cdi_cristin_nora_10037_2172</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>10037_2172</sourcerecordid><originalsourceid>FETCH-cristin_nora_10037_21723</originalsourceid><addsrcrecordid>eNqFyjsOwjAMgOEuDAi4AvIFKvUx9AAViBmxosgkhhpap0ocHrcnAzvTJ_36l8X5SNZPFxYUhSFNKIBW-YlKDubglVigB1QlSTlGIHFe_ZulZHHJ5m1McgOWewqfDOALHwRxIJrXxeKKY6TNz1Wx3e9O_aG0gaOyGPEBTV1VbWeaumvav8MXy2469Q</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Recombinant human activated protein C attenuates endotoxin-induced lung injury in awake sheep</title><source>NORA - Norwegian Open Research Archives</source><creator>Wærhaug, Kristine ; Langbakk, Bodil ; Kuklin, Vladimir N ; Kirov, Mikhail Y ; Sovershaev, Mikhail ; Ingebretsen, Ole C ; Ytrehus, Kirsti ; Bjertnæs, Lars J</creator><creatorcontrib>Wærhaug, Kristine ; Langbakk, Bodil ; Kuklin, Vladimir N ; Kirov, Mikhail Y ; Sovershaev, Mikhail ; Ingebretsen, Ole C ; Ytrehus, Kirsti ; Bjertnæs, Lars J</creatorcontrib><description>Introduction: Acute lung injury often complicates severe sepsis.
In Gram-negative sepsis, bacterial endotoxin activates both
coagulation and inflammation. Enhanced lung vascular
pressures and permeability, increased extravascular lung water
content and deteriorated gas exchange characterize ovine
endotoxin-induced lung injury, a frequently used model of acute
lung injury. Recombinant human activated protein C (rhAPC),
with its anticoagulant, anti-inflammatory, fibrinolytic and
antiapoptotic effects, reportedly reduces the respiratordependent
days and the mortality of patients with severe sepsis.
We speculate whether rhAPC antagonizes endotoxin-induced
lung injury in sheep.
Methods: Two groups of sheep were exposed to Escherichia
coli endotoxin (lipopolysaccharide) 15 ng/kg/minute
intravenously from 0 to 24 hours; one group received only
lipopolysaccharide throughout (n = 8), and the other group
received lipopolysaccharide in combination with rhAPC 24 μg/
kg/hour from 4 to 24 hours (n = 9). In addition, one group
received rhAPC as above as the only intervention (n = 4), and
four sham-operated sheep were used for determination of the α
and ε isoforms of protein kinase C in pulmonary tissue. Data
were assessed by one-way analysis of variance for repeated
measurements. Biochemical data were analyzed using
Student's t test, or using the Mann–Whitney U test when
appropriate.
Results: Infusion of endotoxin caused lung injury, manifested by
increments in pulmonary artery pressure, in pulmonary microocclusion
pressure, in pulmonary vascular downstream
resistance, in pulmonary vascular permeability index, in
extravascular lung water index and in deterioration of
oxygenation that were all attenuated by infusion of rhAPC.
Endotoxemia led to changes in inflammation and coagulation,
including pulmonary neutrophil accumulation paralleled by
increased TNFα and decreased protein C and fibrinogen in
animal plasma, which all improved following infusion of rhAPC.
Moreover, rhAPC prevented the translocation of protein kinase
C α and ε isoforms from the cytosolic fraction of lung tissue
extracts.
Conclusion: In awake sheep, rhAPC alleviates endotoxininduced
lung injury – as characterized by improvements of
oxygenation, coagulation and inflammation, as well as by
reversal of pulmonary hemodynamic and volumetric changes.</description><language>eng</language><publisher>BioMed Central</publisher><subject>Clinical medical disciplines: 750 ; Lung diseases: 777 ; Medical disciplines: 700 ; VDP</subject><creationdate>2008</creationdate><rights>info:eu-repo/semantics/openAccess</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,780,885,26567</link.rule.ids><linktorsrc>$$Uhttp://hdl.handle.net/10037/2172$$EView_record_in_NORA$$FView_record_in_$$GNORA$$Hfree_for_read</linktorsrc></links><search><creatorcontrib>Wærhaug, Kristine</creatorcontrib><creatorcontrib>Langbakk, Bodil</creatorcontrib><creatorcontrib>Kuklin, Vladimir N</creatorcontrib><creatorcontrib>Kirov, Mikhail Y</creatorcontrib><creatorcontrib>Sovershaev, Mikhail</creatorcontrib><creatorcontrib>Ingebretsen, Ole C</creatorcontrib><creatorcontrib>Ytrehus, Kirsti</creatorcontrib><creatorcontrib>Bjertnæs, Lars J</creatorcontrib><title>Recombinant human activated protein C attenuates endotoxin-induced lung injury in awake sheep</title><description>Introduction: Acute lung injury often complicates severe sepsis.
In Gram-negative sepsis, bacterial endotoxin activates both
coagulation and inflammation. Enhanced lung vascular
pressures and permeability, increased extravascular lung water
content and deteriorated gas exchange characterize ovine
endotoxin-induced lung injury, a frequently used model of acute
lung injury. Recombinant human activated protein C (rhAPC),
with its anticoagulant, anti-inflammatory, fibrinolytic and
antiapoptotic effects, reportedly reduces the respiratordependent
days and the mortality of patients with severe sepsis.
We speculate whether rhAPC antagonizes endotoxin-induced
lung injury in sheep.
Methods: Two groups of sheep were exposed to Escherichia
coli endotoxin (lipopolysaccharide) 15 ng/kg/minute
intravenously from 0 to 24 hours; one group received only
lipopolysaccharide throughout (n = 8), and the other group
received lipopolysaccharide in combination with rhAPC 24 μg/
kg/hour from 4 to 24 hours (n = 9). In addition, one group
received rhAPC as above as the only intervention (n = 4), and
four sham-operated sheep were used for determination of the α
and ε isoforms of protein kinase C in pulmonary tissue. Data
were assessed by one-way analysis of variance for repeated
measurements. Biochemical data were analyzed using
Student's t test, or using the Mann–Whitney U test when
appropriate.
Results: Infusion of endotoxin caused lung injury, manifested by
increments in pulmonary artery pressure, in pulmonary microocclusion
pressure, in pulmonary vascular downstream
resistance, in pulmonary vascular permeability index, in
extravascular lung water index and in deterioration of
oxygenation that were all attenuated by infusion of rhAPC.
Endotoxemia led to changes in inflammation and coagulation,
including pulmonary neutrophil accumulation paralleled by
increased TNFα and decreased protein C and fibrinogen in
animal plasma, which all improved following infusion of rhAPC.
Moreover, rhAPC prevented the translocation of protein kinase
C α and ε isoforms from the cytosolic fraction of lung tissue
extracts.
Conclusion: In awake sheep, rhAPC alleviates endotoxininduced
lung injury – as characterized by improvements of
oxygenation, coagulation and inflammation, as well as by
reversal of pulmonary hemodynamic and volumetric changes.</description><subject>Clinical medical disciplines: 750</subject><subject>Lung diseases: 777</subject><subject>Medical disciplines: 700</subject><subject>VDP</subject><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>3HK</sourceid><recordid>eNqFyjsOwjAMgOEuDAi4AvIFKvUx9AAViBmxosgkhhpap0ocHrcnAzvTJ_36l8X5SNZPFxYUhSFNKIBW-YlKDubglVigB1QlSTlGIHFe_ZulZHHJ5m1McgOWewqfDOALHwRxIJrXxeKKY6TNz1Wx3e9O_aG0gaOyGPEBTV1VbWeaumvav8MXy2469Q</recordid><startdate>2008</startdate><enddate>2008</enddate><creator>Wærhaug, Kristine</creator><creator>Langbakk, Bodil</creator><creator>Kuklin, Vladimir N</creator><creator>Kirov, Mikhail Y</creator><creator>Sovershaev, Mikhail</creator><creator>Ingebretsen, Ole C</creator><creator>Ytrehus, Kirsti</creator><creator>Bjertnæs, Lars J</creator><general>BioMed Central</general><scope>3HK</scope></search><sort><creationdate>2008</creationdate><title>Recombinant human activated protein C attenuates endotoxin-induced lung injury in awake sheep</title><author>Wærhaug, Kristine ; Langbakk, Bodil ; Kuklin, Vladimir N ; Kirov, Mikhail Y ; Sovershaev, Mikhail ; Ingebretsen, Ole C ; Ytrehus, Kirsti ; Bjertnæs, Lars J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-cristin_nora_10037_21723</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Clinical medical disciplines: 750</topic><topic>Lung diseases: 777</topic><topic>Medical disciplines: 700</topic><topic>VDP</topic><toplevel>online_resources</toplevel><creatorcontrib>Wærhaug, Kristine</creatorcontrib><creatorcontrib>Langbakk, Bodil</creatorcontrib><creatorcontrib>Kuklin, Vladimir N</creatorcontrib><creatorcontrib>Kirov, Mikhail Y</creatorcontrib><creatorcontrib>Sovershaev, Mikhail</creatorcontrib><creatorcontrib>Ingebretsen, Ole C</creatorcontrib><creatorcontrib>Ytrehus, Kirsti</creatorcontrib><creatorcontrib>Bjertnæs, Lars J</creatorcontrib><collection>NORA - Norwegian Open Research Archives</collection></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Wærhaug, Kristine</au><au>Langbakk, Bodil</au><au>Kuklin, Vladimir N</au><au>Kirov, Mikhail Y</au><au>Sovershaev, Mikhail</au><au>Ingebretsen, Ole C</au><au>Ytrehus, Kirsti</au><au>Bjertnæs, Lars J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Recombinant human activated protein C attenuates endotoxin-induced lung injury in awake sheep</atitle><date>2008</date><risdate>2008</risdate><abstract>Introduction: Acute lung injury often complicates severe sepsis.
In Gram-negative sepsis, bacterial endotoxin activates both
coagulation and inflammation. Enhanced lung vascular
pressures and permeability, increased extravascular lung water
content and deteriorated gas exchange characterize ovine
endotoxin-induced lung injury, a frequently used model of acute
lung injury. Recombinant human activated protein C (rhAPC),
with its anticoagulant, anti-inflammatory, fibrinolytic and
antiapoptotic effects, reportedly reduces the respiratordependent
days and the mortality of patients with severe sepsis.
We speculate whether rhAPC antagonizes endotoxin-induced
lung injury in sheep.
Methods: Two groups of sheep were exposed to Escherichia
coli endotoxin (lipopolysaccharide) 15 ng/kg/minute
intravenously from 0 to 24 hours; one group received only
lipopolysaccharide throughout (n = 8), and the other group
received lipopolysaccharide in combination with rhAPC 24 μg/
kg/hour from 4 to 24 hours (n = 9). In addition, one group
received rhAPC as above as the only intervention (n = 4), and
four sham-operated sheep were used for determination of the α
and ε isoforms of protein kinase C in pulmonary tissue. Data
were assessed by one-way analysis of variance for repeated
measurements. Biochemical data were analyzed using
Student's t test, or using the Mann–Whitney U test when
appropriate.
Results: Infusion of endotoxin caused lung injury, manifested by
increments in pulmonary artery pressure, in pulmonary microocclusion
pressure, in pulmonary vascular downstream
resistance, in pulmonary vascular permeability index, in
extravascular lung water index and in deterioration of
oxygenation that were all attenuated by infusion of rhAPC.
Endotoxemia led to changes in inflammation and coagulation,
including pulmonary neutrophil accumulation paralleled by
increased TNFα and decreased protein C and fibrinogen in
animal plasma, which all improved following infusion of rhAPC.
Moreover, rhAPC prevented the translocation of protein kinase
C α and ε isoforms from the cytosolic fraction of lung tissue
extracts.
Conclusion: In awake sheep, rhAPC alleviates endotoxininduced
lung injury – as characterized by improvements of
oxygenation, coagulation and inflammation, as well as by
reversal of pulmonary hemodynamic and volumetric changes.</abstract><pub>BioMed Central</pub><oa>free_for_read</oa></addata></record> |
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subjects | Clinical medical disciplines: 750 Lung diseases: 777 Medical disciplines: 700 VDP |
title | Recombinant human activated protein C attenuates endotoxin-induced lung injury in awake sheep |
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