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CC BY-NC-ND 4.0 · Thromb Haemost 2017; 117(11): 2125-2134
DOI: 10.1160/TH17-05-0347
Blood Cells, Inflammation and Infection
Schattauer GmbH Stuttgart

Nebulized Heparin Attenuates Pulmonary Coagulopathy and Inflammation through Alveolar Macrophages in a Rat Model of Acute Lung Injury

Laura Chimenti   #
1   Institut d'Investigació i Innovació Parc Taulí (I3PT), Sabadell, Catalonia, Spain
,
Marta Camprubí-Rimblas   #
1   Institut d'Investigació i Innovació Parc Taulí (I3PT), Sabadell, Catalonia, Spain
2   Universitat Autònoma de Barcelona, Bellaterra, Catalonia, Spain
,
Raquel Guillamat-Prats
1   Institut d'Investigació i Innovació Parc Taulí (I3PT), Sabadell, Catalonia, Spain
3   Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
,
Maria Nieves Gomez
1   Institut d'Investigació i Innovació Parc Taulí (I3PT), Sabadell, Catalonia, Spain
,
Jessica Tijero
1   Institut d'Investigació i Innovació Parc Taulí (I3PT), Sabadell, Catalonia, Spain
,
Lluis Blanch
1   Institut d'Investigació i Innovació Parc Taulí (I3PT), Sabadell, Catalonia, Spain
2   Universitat Autònoma de Barcelona, Bellaterra, Catalonia, Spain
3   Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
4   Critical Care Center, Corporació Sanitària i Universitària Parc Taulí-UAB, Sabadell, Catalonia, Spain
,
Antonio Artigas
1   Institut d'Investigació i Innovació Parc Taulí (I3PT), Sabadell, Catalonia, Spain
2   Universitat Autònoma de Barcelona, Bellaterra, Catalonia, Spain
3   Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
4   Critical Care Center, Corporació Sanitària i Universitària Parc Taulí-UAB, Sabadell, Catalonia, Spain
› Author Affiliations
Further Information

Publication History

20 May 2017

20 July 2017

Publication Date:
30 November 2017 (online)

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Abstract

Objective Alveolar macrophages play a key role in the development and resolution of acute respiratory distress syndrome (ARDS), modulating the inflammatory response and the coagulation cascade in lungs. Anti-coagulants may be helpful in the treatment of ARDS. This study investigated the effects of nebulized heparin on the role of alveolar macrophages in limiting lung coagulation and inflammatory response in an animal model of acute lung injury (ALI).

Methods Rats were randomized to four experimental groups. In three groups, ALI was induced by intratracheal instillation of lipopolysaccharide (LPS) and heparin was nebulized at constant oxygen flow: the LPS/Hep group received nebulized heparin 4 and 8 hours after injury; the Hep/LPS/Hep group received nebulized heparin 30 minutes before and 4 and 8 hours after LPS-induced injury; the LPS/Sal group received nebulized saline 4 and 8 hours after injury. The control group received only saline. Animals were exsanguinated 24 hours after LPS instillation. Lung tissue, bronchoalveolar lavage fluid (BALF) and alveolar macrophages isolated from BALF were analysed.

Results LPS increased protein concentration, oedema and neutrophils in BALF as well as procoagulant and proinflammatory mediators in lung tissue and alveolar macrophages. In lung tissue, nebulized heparin attenuated ALI through decreasing procoagulant (tissue factor, thrombin–anti-thrombin complexes, fibrin degradation products) and proinflammatory (interleukin 6, tumour necrosis factor alpha) pathways. In alveolar macrophages, nebulized heparin reduced expression of procoagulant genes and the effectors of transforming growth factor beta (Smad 2, Smad 3) and nuclear factor kappa B (p-selectin, CCL-2). Pre-treatment resulted in more pronounced attenuation.

Conclusion Nebulized heparin reduced pulmonary coagulopathy and inflammation without producing systemic bleeding, partly by modulating alveolar macrophages.

Keywords

acute respiratory distress syndrome - acute lung injury - anti-coagulants - heparin - alveolar macrophages

Author Contribution

L. C., M. C.-R., R. G.-P. and A. A. designed the experiments; L. C., M. C.-R., R. G.-P., M. N. G. and J. T. performed the experiments; L. C., M. C.-R. and R. G.-P. analysed the data and, together with A. A., interpreted the data; M. C.-R., L. C., R. G.-P. and A. A. wrote the manuscript and L. B. and A. A. helped to revise the manuscript. All the authors approved the last version of the manuscript.


# These authors contributed equally


Supplementary Material

 

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