Nebulized antithrombin limits bacterial outgrowth and lung injury in Streptococcus pneumoniae pneumonia in rats.
BACKGROUND
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.
Hofstra
Jorrit J
JJ
Laboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands. j.j.hofstra@amc.uva.nl
Cornet
Alexander D
AD
de Rooy
Bart F
BF
Vlaar
Alexander P
AP
van der Poll
Tom
T
Levi
Marcel
M
Zaat
Sebastian Aj
SA
Schultz
Marcus J
MJ
D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000991:Antithrombins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005342:Fibrinolysis / Q000187:drug effects; D055370:Lung Injury / Q000517:prevention & control*; D008297:Male; D010919:Placebos; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000254:growth & development*; D016896:Treatment Outcome
D000925:Anticoagulants; D000991:Antithrombins; D010919:Placebos