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Thrombin-activatable procarboxypeptidase B regulates activated complement C5a in vivo.
Toshihiko Nishimura1, Timothy Myles, Adrian M Piliponsky
1Department of Medicine, Stanford University School of Medicine and Veterans Administration Palo Alto Health Care System, Palo Alto, CA 94304, USA.
Blood
|November 16, 2006
Summary
Plasma procarboxypeptidase B (proCPB) has anti-inflammatory functions beyond inhibiting fibrinolysis. Studies in mice show proCPB activation by thrombin-thrombomodulin reduces lung inflammation, highlighting its broader homeostatic role.
Area of Science:
- Biochemistry
- Immunology
- Vascular Biology
Background:
- Plasma procarboxypeptidase B (proCPB) is activated by the thrombin-thrombomodulin complex.
- Activated proCPB (CPB) is known to inhibit fibrinolysis.
- A potential broader role in inactivating inflammatory mediators is hypothesized.
Purpose of the Study:
- To investigate the anti-inflammatory functions of thrombin-activatable proCPB.
- To determine if proCPB plays a role in regulating C5a-induced alveolitis.
Main Methods:
- C5a-induced alveolitis model in wild-type and proCPB-deficient mice.
- Administration of a modified thrombin (E229K) to assess proCPB activation.
- Analysis of bronchoalveolar lavage fluid for cell counts and protein content.
- Lung tissue histology to evaluate inflammatory responses.
Main Results:
- C5a-induced alveolitis was significantly enhanced in proCPB-deficient mice.
- E229K thrombin attenuated alveolitis in wild-type mice but not in proCPB-deficient mice.
- Delayed administration of E229K thrombin was ineffective, suggesting direct inhibition of C5a by CPB.
Conclusions:
- Thrombin-activatable proCPB possesses intrinsic anti-inflammatory functions.
- The thrombin-thrombomodulin complex activates proCPB, contributing to homeostasis by counteracting inflammatory mediators.
- CPB's role extends beyond fibrinolysis to include the regulation of inflammatory responses at sites of vascular injury.
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