PMID- 31346884
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200930
IS  - 2197-425X (Print)
IS  - 2197-425X (Electronic)
IS  - 2197-425X (Linking)
VI  - 7
IP  - Suppl 1
DP  - 2019 Jul 25
TI  - Antithrombin plus alpha-1 protease inhibitor does not affect coagulation and 
      inflammation in two murine models of acute lung injury.
PG  - 36
LID - 10.1186/s40635-019-0240-7 [doi]
LID - 36
AB  - BACKGROUND: In acute respiratory distress syndrome (ARDS), uncontrolled 
      production of activators of coagulation and proinflammatory mediators results in 
      a shift from an adequate local innate immune response to hypercoagulability and 
      inflammation. This study aimed to investigate whether the protease inhibitors 
      antithrombin (AT) and alpha-1 protease inhibitor (A1PI) may attenuate an 
      exaggerated pulmonary immune response. METHODS: Lung injury was induced either by 
      single intranasal administration of lipopolysaccharide (LPS) (5 mg/kg) in BALB/c 
      mice or by combination of an intravenous injection of LPS (10 mg/kg) with 
      subsequent injurious ventilation using high tidal volumes (12-15 ml/kg) for 4 h 
      in RccHan Wistar rats. Animals received either a single bolus of AT (250 IU/kg) 
      or A1PI (60 mg/kg) alone or in combination, with or without intravenous low-dose 
      heparin (100 U/kg). Control animals received saline. Additional controls received 
      neither LPS, nor ventilation, nor treatment. Endpoints were local and systemic 
      markers of coagulation, e.g., thrombin-antithrombin complexes (TATc), and 
      inflammation, e.g., interleukin-6. RESULTS: Both lung injury models resulted in a 
      pronounced immune response within the pulmonary compartment shown by elevated 
      levels of markers of coagulation and inflammation. The two-hit lung injury model 
      also induced profound systemic coagulopathy and inflammation. Monotherapy with AT 
      or A1PI did not reduce pulmonary coagulopathy or inflammation in any lung injury 
      model. Nor did combination therapy with AT and A1PI result in a decrease of 
      coagulation or inflammatory parameters. AT markedly reduced systemic levels of 
      TATc in the two-hit lung injury model. Systemic inflammation was not affected by 
      the different interventions. Additional administration of heparin did not lead to 
      macroscopic bleeding incidences. CONCLUSIONS: In two different murine models of 
      acute lung injury, neither single therapy with AT or A1PI nor combination of both 
      agents attenuates the pronounced pulmonary coagulation or inflammatory response.
FAU - Juschten, Jenny
AU  - Juschten J
AUID- ORCID: 0000-0003-2176-5072
AD  - Department of Intensive Care, Amsterdam UMC, VU Medical Center, Amsterdam, 
      Netherlands. j.juschten@vumc.nl.
AD  - Research VUmc Intensive Care (REVIVE), Amsterdam UMC, VU Medical Center, 
      Amsterdam, Netherlands. j.juschten@vumc.nl.
AD  - Department of Intensive Care, Amsterdam UMC, Academic Medical Center, Amsterdam, 
      Netherlands. j.juschten@vumc.nl.
AD  - Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A), 
      Amsterdam UMC, Academic Medical Center, Amsterdam, Netherlands. 
      j.juschten@vumc.nl.
FAU - Ingelse, Sarah Anne
AU  - Ingelse SA
AD  - Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A), 
      Amsterdam UMC, Academic Medical Center, Amsterdam, Netherlands.
AD  - Emma Children's Hospital-Pediatric Intensive Care Unit, Amsterdam UMC, Academic 
      Medical Center, Amsterdam, Netherlands.
FAU - Maas, Martinus Adrianus Wilhelmus
AU  - Maas MAW
AD  - Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A), 
      Amsterdam UMC, Academic Medical Center, Amsterdam, Netherlands.
FAU - Girbes, Armand Roelof Johan
AU  - Girbes ARJ
AD  - Department of Intensive Care, Amsterdam UMC, VU Medical Center, Amsterdam, 
      Netherlands.
AD  - Research VUmc Intensive Care (REVIVE), Amsterdam UMC, VU Medical Center, 
      Amsterdam, Netherlands.
FAU - Juffermans, Nicole Petra
AU  - Juffermans NP
AD  - Department of Intensive Care, Amsterdam UMC, Academic Medical Center, Amsterdam, 
      Netherlands.
AD  - Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A), 
      Amsterdam UMC, Academic Medical Center, Amsterdam, Netherlands.
FAU - Schultz, Marcus Josephus
AU  - Schultz MJ
AD  - Department of Intensive Care, Amsterdam UMC, Academic Medical Center, Amsterdam, 
      Netherlands.
AD  - Mahidol Oxford Tropical Medicine Research Unit (MORU), Mahidol University, 
      Bangkok, Thailand.
FAU - Tuinman, Pieter Roel
AU  - Tuinman PR
AD  - Department of Intensive Care, Amsterdam UMC, VU Medical Center, Amsterdam, 
      Netherlands.
AD  - Research VUmc Intensive Care (REVIVE), Amsterdam UMC, VU Medical Center, 
      Amsterdam, Netherlands.
LA  - eng
GR  - -/Grifols/
PT  - Journal Article
DEP - 20190725
PL  - Germany
TA  - Intensive Care Med Exp
JT  - Intensive care medicine experimental
JID - 101645149
PMC - PMC6658634
OTO - NOTNLM
OT  - ARDS
OT  - Acute lung injury
OT  - Alpha-1 protease inhibitor
OT  - Antithrombin
OT  - Coagulation
OT  - Inflammation
OT  - Lung injury model
COIS- This study has been supported by an investigator-led research grant from Grifols. 
      This funding facilitated conductance of this study, but did not influence the 
      study design, collection of the data, analysis, nor interpretation or writing of 
      the article. We declare that the tested treatment agents AT and A1PI were a kind 
      gift from Grifols.
EDAT- 2019/07/28 06:00
MHDA- 2019/07/28 06:01
PMCR- 2019/07/25
CRDT- 2019/07/27 06:00
PHST- 2019/02/22 00:00 [received]
PHST- 2019/03/07 00:00 [accepted]
PHST- 2019/07/27 06:00 [entrez]
PHST- 2019/07/28 06:00 [pubmed]
PHST- 2019/07/28 06:01 [medline]
PHST- 2019/07/25 00:00 [pmc-release]
AID - 10.1186/s40635-019-0240-7 [pii]
AID - 240 [pii]
AID - 10.1186/s40635-019-0240-7 [doi]
PST - epublish
SO  - Intensive Care Med Exp. 2019 Jul 25;7(Suppl 1):36. doi: 
      10.1186/s40635-019-0240-7.