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Decreased Protein C Activation is Associated with Increased Lung Injury in Response to Prolonged Oxygen Exposure in Mice
Author(s) -
Perkowski Sandra Z,
Kowalska M Anna
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a211-c
Subject(s) - thrombomodulin , protein c , thrombin , chemokine , chemistry , bronchoalveolar lavage , platelet , platelet activation , genetically modified mouse , endocrinology , medicine , platelet factor 4 , lung , microbiology and biotechnology , andrology , immunology , transgene , inflammation , biology , biochemistry , gene
We have shown significant decreases in the pulmonary protein expression and functional activity of the endothelial surface protein thrombomodulin (TM) by 24h of exposure to >95% oxygen (O2) in 8–10 wk C57/B6 mice. Given the key role of TM in binding thrombin and activating protein C (PC), abnormalities in the PC cascade could contribute to O2‐induced lung injury. To investigate this hypothesis, we studied two transgenic mouse models with an impaired ability to activate PC. First, we found plasma APC levels generated after murine thrombin (80U/kg IV) in heterozygous PC deficient (PC +/− ) mice (n=5) were 65±21% those in wildtype (WT) mice (n=7; p=0.05). Second, we studied mice deficient in platelet factor 4 (PF4 −/− ), a platelet α‐granule‐specific chemokine shown to accelerate thrombin·TM complex APC generation. Plasma APC generation by thrombin was 74 ± 6% in PF4 −/− mice (n=7) vs. WT (n=15, p<0.1). Next, mice were exposed to >95% O2 for 72h. Lung injury, as assessed by bronchoalveolar lavage fluid (BAL) protein was significantly increased about 2 ‐fold in both the PC +/− mice vs. WT (2.46 + 0.55, n = 4 vs. 1.37 + 0.11mg/ml, n=6; mean + SEM; p<0.05) and in the PF4 −/− mice vs. WT (11.11 + 2.48, n = 7 vs. 6.68 + 1.03 mg/ml, n = 9; mean+SEM; p<0.05). Survival rates were also lower in the PC +/− and PF4 −/− mice. Total WBC counts in BAL were similar between groups, suggesting changes in pulmonary inflammation did not account for the increased lung injury. Given the added role of protein C in the coagulation and fibrinolytic cascades, increased intra‐alveolar fibrin deposition could contribute to the increased lung injury in these mice. Supported by NIH K08HL67913‐01