Intrabronchial activated protein C enhances lipopolysaccharide-induced pulmonary responses.
Intravenous administration of activated protein C (APC) inhibits coagulation and inflammation in the lungs of humans and animals. Investigations in rodents demonstrated that direct intrapulmonary delivery of APC also exerts anticoagulant and anti-inflammatory effects. The effect of intrabronchial administration of recombinant human (rh)APC on lipopolysaccharide (LPS)-induced haemostatic and inflammatory alterations in the bronchoalveolar space of humans was studied. Eight subjects received rhAPC via intrabronchial instillation by bronchoscope, while in a contralateral subsegment subjects received saline; all subjects were challenged bilaterally with LPS in the same lung subsegments. Four additional subjects received rhAPC (75 μg), with saline as a control in the contralateral subsegment, while they were bilaterally "challenged" with saline. After 6 h a bronchoalveolar lavage was performed and coagulation and inflammatory parameters were measured. rhAPC enhanced LPS-induced coagulation activation in the bronchoalveolar space, when compared with the control side. In addition, rhAPC amplified LPS-induced pro-inflammatory responses, as indicated by higher concentrations of cytokines and chemokines. rhAPC alone did not have procoagulant or pro-inflammatory effects. Locally administered rhAPC has unexpected procoagulant and pro-inflammatory effects in LPS-challenged lung subsegments. These data argue against a role for intrapulmonary delivery of rhAPC as a treatment strategy for lung inflammatory disorders in humans.
Center of Experimental and Molecular Medicine, Academic Medical Center/University ofAmsterdam, Amsterdam, The Netherlands. l.m.kager@amc.uva.nl
Liesbeth M
LM
Kager
J Daan
JD
de Boer
Paul
P
Bresser
Jaring S
JS
van der Zee
Sacha
S
Zeerleder
Joost C M
JC
Meijers
Cornelis
C
van 't Veer
Tom
T
van der Poll
D000328:Adult; D018893:Bronchoalveolar Lavage; D001999:Bronchoscopy; D006487:Hemostasis; D006801:Humans; D007249:Inflammation; D008070:Lipopolysaccharides / Q000737:chemistry*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011486:Protein C / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology*; D016037:Single-Blind Method; D013997:Time Factors; D055815:Young Adult
D008070:Lipopolysaccharides; D011486:Protein C; D011994:Recombinant Proteins