(a) After five hours outgrowth of S. pneumoniae in bronchoalveolar lavage fluid from …Bacterial numbers in BALF-AT in TSB medium were strongly reduced after six hours compared with the start of the experiment, which confirmed that BALF-AT had an antimicrobial effect on S. pneumoniae. Adding SPS to the BALF-AT samples rescued the bacteria, further information because no decrease in CFU relative to the start of the experiment was seen after six hours.DiscussionIn this series of experiments we show local anticoagulant treatment through nebulization of rh-aPC, plasma-derived AT, heparin or danaparoid to attenuate pulmonary coagulopathy in S. pneumoniae pneumonia in rats. Reduction of pulmonary coagulopathy with nebulized rh-aPC, heparin or danaparoid did not affect the course of pneumonia and ALI.

However, reduction of pulmonary coagulopathy with treatment plasma-derived AT was associated with reduced bacterial outgrowth and pulmonary inflammation in this model. Although local administration of rh-aPC, plasma-derived AT or heparin did not affect systemic thrombin generation, nebulized danaparoid reduced systemic thrombin generation.Lung-protective effects of plasma-derived ATOf the investigated nebulized anticoagulant agents only plasma-derived AT treatment resulted in significant lung-protective effects, with less bacterial outgrowth and less histopathological changes. This finding confirms earlier results with systemically administered plasma-derived AT in the same model [1]. AT is one of the major physiologic inhibitors of coagulation, capable of inactivating thrombin and factors Xa, IXa, and VIIa bound to tissue factor [24].

Severe inflammatory processes result in increased consumption of AT [25]. In a small group of sepsis patients, AT treatment improved lung function [14]. In a larger phase III trial with sepsis patients, AT treatment reduced the prevalence of new pulmonary dysfunction, but patient outcome was unchanged [14]. Unfortunately, outcome of preexistent respiratory failure was neither assessed nor reported.AT may exert its protective effects through increased prostacyclin-mediated inhibition of cytokines, decreased nuclear factor-kB activation [26], and consequent inhibition of leukocyte activation and migration [27-30]. AT may compete with bacterial toxins for binding on endothelial cell proteoglycans [31], limiting the inflammatory response after bacterial challenge and thereby limiting cell and neutrophil influx into the pulmonary department [32].

Here we show that plasma-derived AT treatment strongly inhibited bacterial outgrowth consequently limiting inflammatory response, neutrophil influx and histopathological changes. It remains unclear whether these effects are associated with Dacomitinib prostacyclin formation, interference with bacterial toxins (e.g.