Intravenous administration of activated protein C in Pseudomonas-induced lung injury: impact on lung fluid balance and the inflammatory response.
BACKGROUND
Acute lung injury (ALI) induces a coagulation/fibrinolysis imbalance and leads to fibrin deposition. The protein C pathway is an important regulator of the coagulation system and reduces the inflammatory response. The aim of the study was to examine the effects of recombinant human activated protein C (rhAPC) in the early phase of Pseudomonas aeruginosa (Pa)-induced lung injury.


METHODS
The study was conducted in vivo on a rat model of Pa-induced ALI. Continuous intravenous (IV) rhAPC was administrated simultaneously with intratracheal (IT) Pa. We instilled into the airspaces a 5% bovine albumin solution with 1 mu(Ci of (125)I-albumin and injected IV 1 mu(Ci of (111)In-albumin to measure lung liquid clearance (LLC) and endothelial injury. Cytokines levels (TNFalpha and IL-6) and thrombin-antithrombin (TAT) complexes were measured in blood and bronchoalveolar lavage fluid (BALF) at 4 hours. Four groups were compared: control (CTR), pneumonia (PNP) receiving IT Pa (0.5 ml/kg of 1 x 10(9) cfu), APC: IV rhAPC (300 microg/kg/h), A-PNP: IT Pa /IV rhAPC.


RESULTS
Alveolar-capillary permeability was increased in the PNP versus the CTR group (0.28 +/- 0.08 vs. 0.03 +/- 0.01, p < 0.05). IV rhAPC in Pa-induced ALI led to further injury (0.47 +/- 0.17 vs. 0.28 +/- 0.08, p = 0.2). The LLC was significantly decreased in the A-PNP group compared to PNP group (9.1 +/- (4.3% vs. 33.4 +/- 2.6%, p < 0.05). The lung wet to dry weight ratio was significantly increased in the PNP group (4.62 +/- 0.31) compared to the CTR group (3.87 +/- 0.22, p < 0.05). IV rhAPC administration tends to increase this parameter in Pa-induced ALI (5.80 +/- 0.66, p = 0.07). These findings were associated with a loss of inflammatory response compartmentalization measured by TNFalpha and IL-6 systemic levels. TAT complexes in BALF were increased in the A-PNP group (23.17 +/- 2.89 ng/ml) compared to the CTR group (0.92 +/- 0.17 ng/ml, p < 0.05) and the PNP group (11.06 +/- 2.76 ng/ml, p < 0.05).


CONCLUSIONS
rhAPC reduces LLC following Pa-induced ALI and may influence pulmonary edema formation. The early massive fibrin formation is probably beneficial in ALI limiting both the extent of injury and permeability disorders.
Robriquet
Laurent
L
EA 2689, Faculté de Médecine, Université de Lille 2, 1 place de Verdun, 59045 Lille Cedex, France. l-robriquet@chru-lille.fr
Collet
François
F
Tournoys
Antoine
A
Prangère
Thierry
T
Nevière
Rémi
R
Fourrier
François
F
Guery
Benoît P
BP
D000818:Animals; D000990:Antithrombin III / Q000378:metabolism; D001777:Blood Coagulation / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology / Q000382:microbiology; D004195:Disease Models, Animal; D015633:Extravascular Lung Water / Q000187:drug effects* / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007249:Inflammation / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D007262:Infusions, Intravenous; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D010100:Oxygen / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D018410:Pneumonia, Bacterial / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D011486:Protein C / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D012128:Respiratory Distress Syndrome / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D005343:Fibrinolytic Agents; D015850:Interleukin-6; D011486:Protein C; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C046193:antithrombin III-protease complex; D000990:Antithrombin III; D010447:Peptide Hydrolases; D010100:Oxygen