brosis through inhibition of plasminogen activation via a PDE4/cAMP/PKA pathway

Tissue scarring, characterized by cell activation, excessive deposition of ECM, and extravascular fi brin deposition, is considered a limiting factor for tissue repair. Fibrin, the major substrate of the serine protease plasmin, is a provisional matrix deposited after vascular injury (Bugge et al., 1996). The two plasminogen activators (PAs), namely tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) and their inhibitors, such as plasminogen activator inhibitor-1 (PAI-1), are key modulators of scar resolution by spatially and temporally regulating the conversion of plasminogen to plasmin resulting in fi brin degradation and ECM remodeling (Lijnen, 2001). In the peripheral nervous system, previous work by us and others showed that inhibition of fi brinolysis in mice defi cient in plasminogen or tPA exacerbated axonal damage (Akassoglou et al., 2000) and impaired functional recovery after nerve injury (Siconolfi and Seeds, 2001). In accordance, mice defi cient for fi brinogen showed increased regenerative capacity (Akassoglou et al., 2002). Studies of fi brin deposition in human diseases, in combination with experiments from mice defi cient in plasminogen and PAs, have provided information about a wide range of physiological and pathological conditions that are exacerbated by defective fi brin degradation, such as wound healing, metastasis, atherosclerosis, lung ischemia, rheumatoid arthritis, muscle regeneration, and multiple sclerosis (MS) (Degen et al., 2001; Adams et al., 2004). p75 neurotrophin receptor regulates tissue fi brosis through inhibition of plasminogen activation via a PDE4/cAMP/PKA pathway