Nebulized C1-Esterase Inhibitor does not Reduce Pulmonary Complement Activation in Rats with Severe Streptococcus Pneumoniae Pneumonia.
Complement activation plays an important role in the pathogenesis of pneumonia. We hypothesized that inhibition of the complement system in the lungs by repeated treatment with nebulized plasma-derived human C1-esterase inhibitor reduces pulmonary complement activation and subsequently attenuates lung injury and lung inflammation. This was investigated in a rat model of severe Streptococcus pneumoniae pneumonia. Rats were intra-tracheally challenged with S. pneumoniae to induce pneumonia. Nebulized C1-esterase inhibitor or saline (control animals) was repeatedly administered to rats, 30 min before induction of pneumonia and every 6 h thereafter. Rats were sacrificed 20 or 40 h after inoculation with bacteria. Brochoalveolar lavage fluid and lung tissue were obtained for measuring levels of complement activation (C4b/c), lung injury and inflammation. Induction of pneumonia was associated with pulmonary complement activation (C4b/c at 20 h 1.24 % [0.56-2.59] and at 40 h 2.08 % [0.98-5.12], compared to 0.50 % [0.07-0.59] and 0.03 % [0.03-0.03] in the healthy control animals). The functional fraction of C1-INH was detectable in BALF, but no effect was found on pulmonary complement activation (C4b/c at 20 h 0.73 % [0.16-1.93] and at 40 h 2.38 % [0.54-4.19]). Twenty hours after inoculation, nebulized C1-esterase inhibitor treatment reduced total histology score, but this effect was no longer seen at 40 h. Nebulized C1-esterase inhibitor did not affect other markers of lung injury or lung inflammation. In this negative experimental animal study, severe S. pneumoniae pneumonia in rats is associated with pulmonary complement activation. Repeated treatment with nebulized C1-esterase inhibitor, although successfully delivered to the lungs, does not affect pulmonary complement activation, lung inflammation or lung injury.
Laboratory of Experimental Intensive Care and Anesthesiology (L·E·I·C·A), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. f.m.debeer@amc.uva.nl.|Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. f.m.debeer@amc.uva.nl.
Friso
F
de Beer
Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Wim
W
Lagrand
Laboratory of Experimental Intensive Care and Anesthesiology (L·E·I·C·A), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Gerie J
GJ
Glas
Laboratory of Experimental Intensive Care and Anesthesiology (L·E·I·C·A), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Charlotte J P
CJ
Beurskens
Department of Immunopathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Gerard
G
van Mierlo
Department of Immunopathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Diana
D
Wouters
Department of Immunopathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Hematology, Sanquin Research and Landsteiner laboratory, Academic Medical Center, Amsterdam, The Netherlands.
Sacha
S
Zeerleder
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Joris J T H
JJ
Roelofs
Laboratory of Experimental Intensive Care and Anesthesiology (L·E·I·C·A), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Nicole P
NP
Juffermans
Laboratory of Experimental Intensive Care and Anesthesiology (L·E·I·C·A), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Janneke
J
Horn
Laboratory of Experimental Intensive Care and Anesthesiology (L·E·I·C·A), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Marcus J
MJ
Schultz
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016022:Case-Control Studies; D003167:Complement Activation / Q000187:drug effects*; D050718:Complement C1 Inhibitor Protein / Q000494:pharmacology*; D003181:Complement C4 / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D015850:Interleukin-6 / Q000032:analysis; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D011014:Pneumonia / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D013296:Streptococcus pneumoniae / Q000472:pathogenicity*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D050718:Complement C1 Inhibitor Protein; D003181:Complement C4; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha
C1-esterase inhibitor; Complement; Complement activation; Complement inhibition; Lung inflammation; Lung injury; Pneumonia; Pulmonary complement activation; Pulmonary inflammation
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