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.
EA 2689, Faculté de Médecine, Université de Lille 2, 1 place de Verdun, 59045 Lille Cedex, France. l-robriquet@chru-lille.fr
Laurent
L
Robriquet
François
F
Collet
Antoine
A
Tournoys
Thierry
T
Prangère
Rémi
R
Nevière
François
F
Fourrier
Benoît P
BP
Guery
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