Published ahead of print on July 13, 2006, doi:10.1165/rcmb.2006-0006OC Am. J. Respir. Cell Mol. Biol., Volume 35, Number 6, December 2006, 705-713 A more recent version of this article appeared on December 1, 2006
Submitted on January 4, 2006 Plasminogen-mediated Activation and Release of Hepatocyte Growth Factor from Extracellular MatrixHiroto Matsuoka1,1 Department of Internal Medicine, Pulmonary/Critical Care Medicine Division, University of Michigan Health Sciences Center, Ann Arbor, MI, USA * To whom correspondence should be addressed. E-mail: richsimo{at}umich.edu.
Interventions that enhance plasminogen activation within the lung consistently limit the fibrosis that follows alveolar injury. However, this protective effect cannot be attributed solely to accelerated clearance of fibrin that forms as a provisional matrix following lung injury. To explore other mechanisms, we considered interactions between the plasminogen activation system and hepatocyte growth factor (HGF). HGF is known to have anti-fibrotic activity, but to do so, it must be both released from its sites of sequestration within extracellular matrix and activated by proteolytic cleavage. A recent study using bleomycin-exposed mice showed that manipulations of the plasminogen activation system influenced the amount of free HGF within bronchoalveolar lavage fluid without affecting total lung HGF mRNA or protein. To elucidate the mechanisms, we studied the role of plasminogen activation in fibroblast-mediated HGF release and activation. We found that NIH3T3 and mouse lung fibroblasts release extracellular matrix-bound HGF in a plasminogen-dependent fashion. The plasminogen effect was lost when lung fibroblasts from urokinase-type plasminogen activator (uPA)-deficient mice were used and increased by fibroblasts from plasminogen activator inhibitor-1 (PAI-1)-deficient mice. Plasminogen addition to NIH3T3 or mouse lung fibroblasts increased conversion of pro-HGF to its active form. The plasminogen effect on activation was lost when uPA-deficient fibroblasts were used and accentuated by PAI-1 deficient fibroblasts. In conjunction with the previous in vivo study, these results suggest that plasminogen activation can protect the lung against fibrosis by increasing the availability of active HGF.
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