Abstract
Extracellular matrix (ECM) deposition during wound healing is a physiological response
to an insult. Wound healing becomes deregulated in the setting of chronic injury or
long-standing metabolic disease, leading to the accumulation of ECM components and
fibrosis. Matrix protein turnover is determined by the rate of synthesis as well as
the rate of proteolytic degradation and clearance by matrix metalloproteinases (MMPs).
The persistent activation of interstitial myofibroblasts, coupled with defects in
matrix proteolysis, ultimately disrupts tissue architecture and leads to biochemical
and mechanical organ dysfunction with eventual organ failure. Plasminogen activator
inhibitor type-1 (PAI-1) regulates tissue homeostasis and wound healing by inhibiting
plasmin-mediated MMP activation. Multiple reports using models of liver, lung, and
kidney fibrosis suggest that PAI-1 deficiency or inhibition of PAI-1 activity attenuates
fibrosis. The disinhibition of plasmin-mediated MMP activation leads to collagen degradation
and its diminished accumulation, resulting in the reduction of fibrotic matrix deposition
in these organs. Paradoxically, homozygous deficiency of PAI-1 promotes age-dependent
spontaneous cardiac fibrosis, suggesting a protective role for PAI-1 in the heart.
It remains unclear whether PAI-1-deficient cardiac fibroblasts have increased proliferative,
migratory, or differentiation capabilities, that allow them to overcome increased
plasmin and MMP activity and matrix clearance. In this review, we examine the specific
roles of PAI-1 in fibrosis of different organs including the lung, liver, kidney,
and cardiovascular system.
Keywords
plasminogen - serpin - fibrosis - matrix - fibroblast
