Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Critical Care
Published in: Critical Care 5/2009

Open Access 01-10-2009 | Research

Nebulized antithrombin limits bacterial outgrowth and lung injury in Streptococcus pneumoniae pneumonia in rats

Authors: Jorrit J Hofstra, Alexander D Cornet, Bart F de Rooy, Alexander P Vlaar, Tom van der Poll, Marcel Levi, Sebastian AJ Zaat, Marcus J Schultz

Published in: Critical Care | Issue 5/2009

Login to get access

Abstract

Introduction

Disturbed alveolar fibrin turnover is a cardinal feature of severe pneumonia. Clinical studies suggest that natural inhibitors of coagulation exert lung-protective effects via anticoagulant and possibly also anti-inflammatory pathways. Intravenous infusion of the natural anticoagulants increases the risk of bleeding. Local administration may allow for higher treatment dosages and increased local efficacy while at the same time reducing the risk of bleeding. We evaluated the effect of nebulized anticoagulants on pulmonary coagulopathy and inflammation in a rat model of Streptococcus pneumoniae pneumonia.

Methods

In this randomized controlled in vivo laboratory study rats were challenged intratracheally with S. pneumoniae, inducing pneumonia, and randomized to treatment with normal saline (placebo), recombinant human activated protein C (rh-APC), plasma-derived antithrombin (AT), heparin or danaparoid, by means of nebulization.

Results

S. pneumoniae infection increased pulmonary levels of thrombin-antithrombin complexes and fibrin degradation products. All nebulized anticoagulants significantly limited pulmonary coagulopathy. None of the agents except danaparoid resulted in changes in systemic coagulopathy. Treatment with plasma-derived AT reduced outgrowth of S. pneumoniae and histopathologic damage in lungs. In vitro experiments confirmed outgrowth was reduced in bronchoalveolar lavage fluid (BALF) from rats treated with plasma-derived AT compared with placebo. Neutralizing of cationic components in BALF diminished the inhibitory effects on bacterial outgrowth of BALF, suggesting a role for cationic antimicrobial proteins.

Conclusions

Nebulization of anticoagulants attenuates pulmonary coagulopathy during S. pneumoniae pneumonia in rats while only danaparoid affects systemic coagulation. Nebulized plasma-derived AT reduces bacterial outgrowth and exerts significant lung-protective effects.
Appendix
Available only for authorised users
Literature
1.
Choi G, Hofstra JJ, Roelofs JJ, Rijneveld AW, Bresser P, Zee JS, Florquin S, Poll T, Levi M, Schultz MJ: Antithrombin inhibits bronchoalveolar activation of coagulation and limits lung injury during Streptococcus pneumoniae pneumonia in rats. Crit Care Med 2008, 36: 204-210. 10.1097/01.CCM.0000292012.87482.F4CrossRefPubMed
2.
Gunther A, Mosavi P, Heinemann S, Ruppert C, Muth H, Markart P, Grimminger F, Walmrath D, Temmesfeld-Wollbrück B, Seeger W: Alveolar fibrin formation caused by enhanced procoagulant and depressed fibrinolytic capacities in severe pneumonia. Comparison with the acute respiratory distress syndrome. Am J Respir Crit Care Med 2000, 161: 454-462.CrossRefPubMed
3.
Rijneveld AW, Weijer S, Bresser P, Florquin S, Vlasuk GP, Rote WE, Spek CA, Reitsma PH, Zee JS, Levi M, Poll T: Local activation of the tissue factor-factor VIIa pathway in patients with pneumonia and the effect of inhibition of this pathway in murine pneumococcal pneumonia. Crit Care Med 2006, 34: 1725-1730. 10.1097/01.CCM.0000218807.20570.C2CrossRefPubMed
4.
Schultz MJ, Millo J, Levi M, Hack CE, Weverling GJ, Garrard CS, Poll T: Local activation of coagulation and inhibition of fibrinolysis in the lung during ventilator associated pneumonia. Thorax 2004, 59: 130-135. 10.1136/thorax.2003.013888PubMedCentralCrossRefPubMed
5.
Idell S, James KK, Levin EG, Schwartz BS, Manchanda N, Maunder RJ, Martin TR, McLarty J, Fair DS: Local abnormalities in coagulation and fibrinolytic pathways predispose to alveolar fibrin deposition in the adult respiratory distress syndrome. J Clin Invest 1989, 84: 695-705. 10.1172/JCI114217PubMedCentralCrossRefPubMed
6.
Ware LB, Matthay MA: The acute respiratory distress syndrome. N Engl J Med 2000, 342: 1334-1349. 10.1056/NEJM200005043421806CrossRefPubMed
7.
Abraham E: Coagulation abnormalities in acute lung injury and sepsis. Am J Respir Cell Mol Biol 2000, 22: 401-404.CrossRefPubMed
8.
Schultz MJ, Haitsma JJ, Zhang H, Slutsky AS: Pulmonary coagulopathy as a new target in therapeutic studies of acute lung injury or pneumonia--a review. Crit Care Med 2006, 34: 871-877.PubMed
9.
Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ, Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001, 344: 699-709. 10.1056/NEJM200103083441001CrossRefPubMed
10.
Laterre PF, Garber G, Levy H, Wunderink R, Kinasewitz GT, Sollet JP, Maki DG, Bates B, Yan SCB, Dhainaut JF, PROWESS Clinical Evaluation Committee: Severe community-acquired pneumonia as a cause of severe sepsis: data from the PROWESS study. Crit Care Med 2005, 33: 952-961. 10.1097/01.CCM.0000162381.24074.D7CrossRefPubMed
11.
Poll T, Levi M, Nick JA, Abraham E: Activated protein C inhibits local coagulation after intrapulmonary delivery of endotoxin in humans. Am J Respir Crit Care Med 2005, 171: 1125-1128. 10.1164/rccm.200411-1483OCPubMedCentralCrossRefPubMed
12.
Nick JA, Coldren CD, Geraci MW, Poch KR, Fouty BW, O'Brien J, Gruber M, Zarini S, Murphy RC, Kuhn K, Richter D, Kast KR, Abraham E: Recombinant human activated protein C reduces human endotoxin-induced pulmonary inflammation via inhibition of neutrophil chemotaxis. Blood 2004, 104: 3878-3885. 10.1182/blood-2004-06-2140CrossRefPubMed
13.
Liu KD, Levitt J, Zhuo H, Kallet RH, Brady S, Steingrub J, Tidswell M, Siegel MD, Soto G, Peterson MW, Chesnutt MS, Phillips C, Weinacker A, Thompson BT, Eisner MD, Matthay MA: Randomized clinical trial of activated protein C for the treatment of acute lung injury. Am J Respir Crit Care Med 2008, 178: 618-623. 10.1164/rccm.200803-419OCPubMedCentralCrossRefPubMed
14.
Eisele B, Lamy M, Thijs LG, Keinecke HO, Schuster HP, Matthias FR, Fourrier F, Heinrichs H, Delvos U: Antithrombin III in patients with severe sepsis. A randomized, placebo-controlled, double-blind multicenter trial plus a meta-analysis on all randomized, placebo-controlled, double-blind trials with antithrombin III in severe sepsis. Intensive Care Med 1998, 24: 663-672. 10.1007/s001340050642CrossRefPubMed
15.
Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, Chalupa P, Atherstone A, Pénzes I, Kübler A, Knaub S, Keinecke HO, Heinrichs H, Schindel F, Juers M, Bone RC, Opal SM, KyberSept Trial Study Group: Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001, 286: 1869-1878. 10.1001/jama.286.15.1869CrossRefPubMed
16.
Jaimes F, De La Rosa G, Morales C, Fortich F, Arango C, Aguirre D, Muñoz A: Unfractioned heparin for treatment of sepsis: A randomized clinical trial (The HETRASE Study). Crit Care Med 2009, 37: 1185-1196. 10.1097/CCM.0b013e31819c06bcCrossRefPubMed
17.
Schoots IG, Levi M, van Vliet AK, Maas AM, Roossink EHP, van Gulik TM: Inhibition of coagulation and inflammation by activated protein C or antithrombin reduces intestinal ischemia/reperfusion injury in rats. Crit Care Med 2004, 32: 1375-1383. 10.1097/01.CCM.0000128567.57761.E9CrossRefPubMed
18.
Harada N, Okajima K, Kohmura H, Uchiba M, Tomita T: Danaparoid sodium reduces ischemia/reperfusion-induced liver injury in rats by attenuating inflammatory responses. Thromb Haemost 2007, 97: 81-87.PubMed
19.
Choi G, Vlaar APJ, Schouten M, Van't Veer C, Poll T, Levi M, Schultz MJ: Natural anticoagulants limit lipopolysaccharide-induced pulmonary coagulation but not inflammation. Eur Respir J 2007, 30: 423-428. 10.1183/09031936.00165606CrossRefPubMed
20.
Ilias W, List W, Decruyenaere J, Lignian H, Knaub S, Schindel F, Keinecke HO, Heinrichs H, Thijs LG: Antithrombin III in patients with severe sepsis: a pharmacokinetic study. Intensive Care Med 2000, 26: 704-715. 10.1007/s001340051236CrossRefPubMed
21.
Levi M, de Boer JP, Roem D, ten Cate JW, Hack CE: Plasminogen activation in vivo upon intravenous infusion of DDAVP. Quantitative assessment of plasmin-alpha 2-antiplasmin complex with a novel monoclonal antibody based radioimmunoassay. Thromb Haemost 1992, 67: 111-116.PubMed
22.
Knapp S, Wieland CW, van't Veer C, Takeuchi O, Akira S, Florquin S, Poll T: Toll-like receptor 2 plays a role in the early inflammatory response to murine pneumococcal pneumonia but does not contribute to antibacterial defense. J Immunol 2004, 172: 3132-3138.CrossRefPubMed
23.
Lee HY, Andalibi A, Webster P, Moon SK, Teufert K, Kang SH, Li JD, Nagura M, Ganz T, Lim DJ: Antimicrobial activity of innate immune molecules against Streptococcus pneumoniae , Moraxella catarrhalis and nontypeable Haemophilus influenzae . BMC Infect Dis 2004, 4: 12. 10.1186/1471-2334-4-12PubMedCentralCrossRefPubMed
24.
Esmon CT: Role of coagulation inhibitors in inflammation. Thromb Haemost 2001, 86: 51-56.PubMed
25.
Mesters RM, Mannucci PM, Coppola R, Keller T, Ostermann H, Kienast J: Factor VIIa and antithrombin III activity during severe sepsis and septic shock in neutropenic patients. Blood 1996, 88: 881-886.PubMed
26.
Oelschlager C, Romisch J, Stauss H, Leithäuser B, Tillmanns H, Hölschermann H: Antithrombin III inhibits nuclear factor kappaB activation in human monocytes and vascular endothelial cells. Blood 2002, 99: 4015-4020. 10.1182/blood.V99.11.4015CrossRefPubMed
27.
Harada N, Okajima K, Kushimoto S, Isobe H, Tanaka K: Antithrombin reduces ischemia/reperfusion injury of rat liver by increasing the hepatic level of prostacyclin. Blood 1999, 93: 157-164.PubMed
28.
Kainoh M, Imai R, Umetsu T, Hattori M, Nishio S: Prostacyclin and beraprost sodium as suppressors of activated rat polymorphonuclear leukocytes. Biochem Pharmacol 1990, 39: 477-484. 10.1016/0006-2952(90)90053-NCrossRefPubMed
29.
Kaneider NC, Egger P, Dunzendorfer S, Wiedermann CJ: Syndecan-4 as antithrombin receptor of human neutrophils. Biochem Biophys Res Commun 2001, 287: 42-46. 10.1006/bbrc.2001.5534CrossRefPubMed
30.
Ostrovsky L, Woodman RC, Payne D, Teoh D, Kubes P: Antithrombin III prevents and rapidly reverses leukocyte recruitment in ischemia/reperfusion. Circulation 1997, 96: 2302-2310.CrossRefPubMed
31.
Duensing TD, Wing JS, van Putten JP: Sulfated polysaccharide-directed recruitment of mammalian host proteins: a novel strategy in microbial pathogenesis. Infect Immun 1999, 67: 4463-4468.PubMedCentralPubMed
32.
Minnema MC, Chang AC, Jansen PM, Lubbers YT, Pratt BM, Whittaker BG, Taylor FB, Hack CE, Friedman B: Recombinant human antithrombin III improves survival and attenuates inflammatory responses in baboons lethally challenged with Escherichia coli. Blood 2000, 95: 1117-1123.PubMed
33.
Lahteenmaki K, Kuusela P, Korhonen TK: Bacterial plasminogen activators and receptors. FEMS Microbiol Rev 2001, 25: 531-552. 10.1016/S0168-6445(01)00067-5CrossRefPubMed
34.
Robriquet L, Collet F, Tournoys A, Prangère T, Nevière R, Fourrier F, Guery BP: Intravenous administration of activated protein C in Pseudomonas-induced lung injury: impact on lung fluid balance and the inflammatory response. Respir Res 2006, 7: 41. 10.1186/1465-9921-7-41PubMedCentralCrossRefPubMed
35.
Kipnis E, Guery BP, Tournoys A, Leroy X, Robriquet L, Fialdes P, Neviere R, Fourrier F: Massive alveolar thrombin activation in Pseudomonas aeruginosa-induced acute lung injury. Shock 2004, 21: 444-451. 10.1097/00024382-200405000-00008CrossRefPubMed
36.
Mahadoo J, Hiebert LM, Jaques LB, Wright CJ: Endothelial sequestration of heparin administered by the intrapulmonary route. Artery 1980, 7: 438-447.PubMed
37.
38.
39.
Engelberg H: Orally ingested heparin is absorbed in humans. Clinical and Applied Thrombosis/Hemostasis 1995, 1: 283-285. 10.1177/107602969500100407CrossRef
40.
Baleeiro CEO, Christensen PJ, Morris SB, Mendez MP, Wilcoxen SE, Paine R: GM-CSF and the impaired pulmonary innate immune response following hyperoxic stress. Am J Physiol Lung Cell Mol Physiol 2006, 291: L1246-L1255. 10.1152/ajplung.00016.2006CrossRefPubMed
41.
Claverys JP, Håvarstein LS: Cannibalism and fratricide: mechanisms and raisons d'être. Nat Rev Microbiol 2007, 5: 219-229. 10.1038/nrmicro1613CrossRefPubMed
42.
Prudhomme M, Attaiech L, Sanchez G, Martin B, Claverys JP: Antibiotic stress induces genetic transformability in the human pathogen Streptococcus pneumoniae . Science 2006, 313: 89-92. 10.1126/science.1127912CrossRefPubMed
Metadata
Title
Nebulized antithrombin limits bacterial outgrowth and lung injury in Streptococcus pneumoniae pneumonia in rats
Authors
Jorrit J Hofstra
Alexander D Cornet
Bart F de Rooy
Alexander P Vlaar
Tom van der Poll
Marcel Levi
Sebastian AJ Zaat
Marcus J Schultz
Publication date
01-10-2009
Publisher
BioMed Central
Published in
Critical Care / Issue 5/2009
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/cc8040

Other articles of this Issue 5/2009

Critical Care 5/2009 Go to the issue

Commentary

The evolving story of medical emergency teams in quality improvement

Research

Statin prophylaxis and inflammatory mediators following cardiopulmonary bypass: a systematic review

Research

Cardiac effects of induction agents in the septic rat heart

Commentary

Thoracic epidural anesthesia in sepsis – is it harmful or protective?

Research

Sepsis-associated microvascular dysfunction measured by peripheral arterial tonometry: an observational study

Letter

Reflections on off hour admissions to ICU