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EDITORIAL FOCUS

A complex, tissue-specific role for plasmin and its regulators in modulating fibrogenic activity

Department of Genetics, Boys Town National Research Hospital, Omaha, Nebraska

IT HAS LONG BEEN KNOWN THAT tissue injury often leads to the infiltration of interstitial spaces with plasma, resulting in the polymerization of fibrin as a provisional matrix to support the migration of cells that mediate healing process. When all goes well, during the course of tissue repair the fibrin is broken down through the liberation of the serine protease plasmin from plasminogen via cleavage by either tissue plasminogen activator (tPA) and/or urokinase plasminogen activator (uPA). Left unchecked, however, it has been assumed that persistence of the provisional fibrin matrix promotes the accumulation of extracellular matrix, promoting the development of fibrotic disease (1).

In addition to fibrin, plasmin can degrade fibronectin and laminin matrix and activate collagenases. Thus the regulation of plasmin activity has been an important topic in the field of fibrosis. The plasminogen activators uPA and tPA are inhibited by plasminogen activator inhibitor-1 (PAI-1), and once liberated, plasmin activity can be directly inhibited by 2-antiplasmin. Collectively, these molecules comprise a system for tight regulation of plasmin activity. Thus the effect of dysregulation of the system components on fibrogenesis might seem quite predictable. An increasing body of evidence indicates that this is not necessarily the case.

In the bleomycin-induced lung fibrosis model, for example, infusion of uPA into the lungs of mice following bleomycin treatment protects against fibrosis (9), plasminogen-deficient mice show increased fibrosis (10), and PAI-1 gene deletion protects against fibrosis (3). All of these effects seem predictable. When lung fibrosis in bleomycin-treated wild-type mice was compared with that in mice lacking the A chain of fibrin, however, no differences were observed (5). This unexpected finding challenged whether fibrin is required for the development of fibrosis this model.

Studies investigating the role of the fibrinolytic system in renal fibrosis have also provided vexing results. Most of this work has been done using the unilateral ureteral obstruction (UUO) model of renal fibrosis. Consistent with a role for the fibrin deposition in promoting fibrosis, PAI-1 was found to promote fibrosis (7, 8), while uPAR (the receptor for uPA) was found to attenuate fibrosis (14). Fibrosis was actually accelerated in plasminogen-deficient mice, a concept diametrically opposed to the fibrin/fibrosis link (2, 13). This might be partly explained by recent studies using cultured tubular epithelial cells showing that the plasmin directly influences ERK-mediated signaling, leading to epithelial-to-mesenchymal transition (13). Thus, in addition to its role as a fibrinolytic enzyme, plasmin appears to have profibrotic influences as well. It would follow that the profibrotic effect of PAI-1 and the antifibrotic effects of uPAR might be mediated via plasmin-independent mechanisms, consistent with what has been observed in the bleomycin-induced lung fibrosis model mentioned above. Similarly, fibrosis in tPA-deficient mice was attenuated, contrary to expectations (12). This was found to be due to the ability of tPA to activate MMP-9, which degrades tubular basement membranes and promotes epithelial-to-mesenchymal transition, providing a second example where a component of the fibrinolytic pathway can possess activities that both promote and attenuate fibrosis.

Given that uPAR attenuates fibrosis and PAI-1 promotes fibrosis in the UUO model, it would follow that uPA would be expected to attenuate fibrosis. As exemplified by the role of plasmin in this system, however, one does not always observe what one expects. Indeed, uPA has been shown to be profibrotic in some fibrosis systems and antifibrotic in others. In this issue of the journal, Yamaguchi et al. (11) address the role of uPA in the progression of renal fibrosis in UUO mice. Despite the fact that uPA is markedly induced in proximal tubular epithelial cells of fibrotic kidneys, no difference in the progression of fibrosis was observed in uPA-deficient UUO mice compared with wild-type mice. Thus it would appear that the antifibrotic effects of PAI-1 on renal fibrosis are completely independent of plasmin, tPA, and now uPA.

The findings that uPA does not influence renal fibrosis differ from similar experiments performed in the bleomycin-induced lung fibrosis model, where reduced uPA activity was associated with attenuated fibrosis, illustrating the organ-specific influence of uPA on fibrotic mechanisms (4, 9). In addition to organ specificity, one must also consider the nature of the fibrosis model. Studies in an acute fibrosis model of renal fibrosis associated with significant fibrin deposition showed reduced glomerular disease in uPA null mice compared with wild-type mice (6). This exemplifies the possibility that influences of the fibrinolytic system on fibrosis might be distinct for different renal diseases even though many still consider fibrosis as a common pathway.

Finally, it is worthwhile to remember that this fibrinolytic "system" has a historical context. Indeed, this system represents a tight and robust means of modulating plasmin activity, but we are finding that the serine proteases uPA, tPA, and plasmin possess a multitude of biological functions including regulation of growth factor and MMP activation and cell signaling influences. Considering this, the pleotrophic effects of these factors on different models and mechanisms of fibrosis are not so surprising and underscore how much more we need to know about this important class of molecules.

	FOOTNOTES

 

Address for reprint requests and other correspondence: D. Cosgrove, Dept. of Genetics, Boys Town National Research Hospital, Omaha, NE 68131

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This Article Full Text (PDF) All Versions of this Article: 293/1/F10    most recent 00143.2007v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Cosgrove, D. Search for Related Content PubMed PubMed Citation Articles by Cosgrove, D.