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Blood, 1 March 2007, Vol. 109, No. 5, pp. 1992-1997.
Prepublished online as a Blood First Edition Paper on November 14, 2006; DOI 10.1182/blood-2006-03-012567.
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Submitted March 24, 2006
Accepted August 22, 2006
Thrombin-activatable procarboxypeptidase B regulates activated complement C5a in vivo
Toshihiko Nishimura, Timothy Myles, Adrian Piloponsky, Peter N Kao, Gerald J Berry, and Lawrence LK Leung*
Department of Pulmonary & Critical Care Medicine, Stanford University School of Medicine, Stanford, CA, United States
Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
Department of Pathology, Stanford University School of Medicine, Stanford, CA, United States
VA Palo Alto Health Care System, Palo Alto, CA, United States
* Corresponding author; email: lawrence.leung{at}stanford.edu.
Plasma procarboxypeptidase B (proCPB) is activated by the endothelial thrombin-thrombomodulin complex. Activated CPB functions as a fibrinolysis inhibitor, but may play a broader role by inactivating inflammatory mediators. To test this hypothesis, C5a-induced alveolitis was studied in wild type (WT) and proCPB-deficient mice (proCPB-/-). C5a-induced alveolitis, as measured by cell counts and total protein contents in bronchoalveolar lavage fluids, was markedly enhanced in the proCPB-/- mice. E229K thrombin, a thrombin mutant with minimal clotting activity but retaining its ability to activate protein C and proCPB, attenuated C5a-induced alveolitis in WT but not in proCPB-/- mice, indicating that its beneficial effect is mediated primarily by its activation of proCPB. Lung tissue histology confirmed these cellular inflammatory responses. Delayed administration of E229K thrombin after the C5a instillation was ineffective in reducing alveolitis in WT mice, suggesting that the beneficial effect of E229K thrombin is due to the direct inhibition of C5a by activated proCPB (CPB). Our studies show that thrombin-activatable proCPB, in addition to its role in fibrinolysis, has intrinsic anti-inflammatory functions. Its activation, along with protein C, by the endothelial thrombin-TM complex represents a homeostatic response to counteract the inflammatory mediators generated at the site of vascular injury.
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