The antifibrotic effects of plasminogen activation occur via prostaglandin E2 synthesis in humans and mice

Abstract

Plasminogen activation to plasmin protects from lung fibrosis, but the mechanism underlying this antifibrotic effect remains unclear. We found that mice lacking plasminogen activation inhibitor-1 (PAI-1), which are protected from bleomycin-induced pulmonary fibrosis, exhibit lung overproduction of the antifibrotic lipid mediator prostaglandin E 2 (PGE 2 ). Plasminogen activation upregulated PGE 2 synthesis in alveolar epithelial cells, lung fibroblasts, and lung fibrocytes from saline-and bleomycin-treated mice, as well as in normal fetal and adult primary human lung fibroblasts. This response was exaggerated in cells from Pai1 -/-mice. Although enhanced PGE 2 formation required the generation of plasmin, it was independent of proteinase-activated receptor 1 (PAR-1) and instead reflected proteolytic activation and release of HGF with subsequent induction of COX-2. That the HGF/COX-2/PGE 2 axis mediates in vivo protection from fibrosis in Pai1 -/-mice was demonstrated by experiments showing that a selective inhibitor of the HGF receptor c-Met increased lung collagen to WT levels while reducing COX-2 protein and PGE 2 levels. Of clinical interest, fibroblasts from patients with idiopathic pulmonary fibrosis were found to be defective in their ability to induce COX-2 and, therefore, unable to upregulate PGE 2 synthesis in response to plasmin or HGF. These studies demonstrate crosstalk between plasminogen activation and PGE 2 generation in the lung and provide a mechanism for the well-known antifibrotic actions of the fibrinolytic pathway.

Keratoconus: an inflammatory disorder?

“…Eye rubbing is a proven factor that triggers the onset and progression of the disease, through several effects including stimulation of inflammation. 112,113,119,120 Increasing evidence supports the fact that thinning and ectasia of the cornea are related to a degraded extracellular matrix involving inflammatory events (mainly increased levels of MMP-9, IL-6, and TNF-α) 10,[12][13][14]67,91 and increased oxidative stress. [143][144][145][146] However, the precise role of each of the identified molecular factors still needs to be defined in further studies.…”

“…PGE2 has been related to antifibrotic effects via inhibition of major pathobiologic functions of effector fibroblasts including chemotaxis, proliferation, collagen synthesis, and differentiation to myofibroblasts. 91 Dogru et al 92 found that corneal sensitivity was significantly lower in keratoconus patients compared with controls, especially in patients with severe keratoconus. They also found tear film break-up time values shorter in moderate and severe keratoconus, and fluorescein and rose bengal scores significantly higher in keratoconus patients.…”

Matrix Metalloproteinase-19 Is a Key Regulator of Lung Fibrosis in Mice and Humans

“…Fibroblasts derived from IPF lungs exhibit a relative deficiency of PGE2 production as well as reduced responsiveness to PGE2 (48)(49)(50). Several studies suggested that bleomycin-induced fibrosis is enhanced when PTGS2-derived PGE2 is low or absent (51-53), whereas others did not observe the effects to the same extent (54) or suggested alternative pathways to PGE2 production (55). Important to our findings, which demonstrated that silencing MMP-19 in alveolar epithelial cells reduced wound healing and transfection of MMP-19 increased cell migration, is the evidence that inhibiting PTGS2 results in a dose-dependent inhibition of wound closure in human and feline epithelial cells (56).…”

siRNA against plasminogen activator inhibitor-1 ameliorates bleomycin-induced lung fibrosis in rats

“…In a previous study, Senoo et al revealed that PAI-1 siRNA can inhibit lung fibrosis by inhibiting EMT induced by TGF-β in LA-4 cells [18] . Bauman et al observed that plasminogen activation promoted the release of hepatocyte growth factor to promote prostaglandin E 2 (PGE 2 ) synthesis and fibroblast apoptosis [27] .…”