MMP19 protein may be therapeutic target for IPF
Researchers examine MMP19's role in regulating cellular processes
The protein matrix metalloproteinase 19 (MMP19) plays an important role in regulating cellular processes in the lining of blood vessels that contribute to lung fibrosis occurring in idiopathic pulmonary fibrosis (IPF), a new study reveals.
“Vascular integrity regulated by MMP19 could be a promising therapeutic target for suppressing pulmonary fibrosis,” researchers wrote.
The study, “Endothelial cell-derived MMP19 promotes pulmonary fibrosis by inducing E(nd)MT and monocyte infiltration,” was published in the journal Cell Communication and Signaling.
IPF is a progressive disease characterized by the formation of scarring, or fibrosis, in the lungs, affecting their proper functioning and leading to several symptoms, such as shortness of breath, low blood oxygen levels, and chronic cough.
MMPs are molecules that play a key role in the molecular composition of the extracellular space. This space, or matrix, is heavily involved in the fibrotic processes of IPF, and that is why MMPs have been studied in the context of IPF, both as potential biomarkers and potential therapy targets.
One MMP, MMP19, was found in great quantities in lung epithelial cells (which line the airways) of IPF patients and appeared to have a role in a process called epithelial-to-mesenchymal transition. This process causes epithelial cells to transform into mesenchymal cells, which can migrate and participate in wound healing and fibrosis processes.
Beyond epithelial cells, endothelial cells, which line blood vessels, also are a source of mesenchymal cells by undergoing a similar process called endothelial-to-mesenchymal transition (EndMT).
A team of researchers in China noted the lack of studies on MMP19 in endothelial cells and set out to investigate if MMP19 is involved in endothelial cell function and endothelial-to-mesenchymal transition and whether it may contribute to fibrotic processes in IPF.
MMP19 in lung endothelial cells
First, the team assessed the presence of MMP19 in lung endothelial cells and whether its levels are affected by IPF. For this, they used tissue and data from IPF patients, as well as tissue from mice with lung fibrosis induced by the chemical bleomycin (bleomycin-induced mice).
Lung tissue of IPF patients had higher MMP19 levels than healthy lung tissue. Moreover, the activity of the gene responsible for MMP19 was increased in bronchoalveolar lavage fluid — collected after washing the lungs with a saline solution — of IPF patients.
Likewise, MMP19, both in gene activity (expression) and protein quantity, was increased significantly in the lungs, and in endothelial cells specifically, of bleomycin-induced mice compared with lungs from healthy animals.
Next, the researchers assessed whether MMP19 had a role in IPF, endothelial function, and endothelial-to-mesenchymal transition mechanisms. For this, they generated a mouse model with high levels of MMP19 (overexpression) in the lungs and a cellular model of human lung endothelial cells that also overexpressed MMP19.
Mice overexpressing MMP19 had exacerbated lung fibrosis in response to bleomycin, compared with control mice, as well as accumulation of immune cells in lung tissue. They also had significant weight loss and increased dry lung weight.
Cells overexpressing MMP19 showed clear molecular and morphological signs of transitioning to mesenchymal cells, as well as increased migration, compared with control cells. Additionally, MMP19 over-expressing cells showed higher permeability than control cells, indicating that increased levels of MMP19 were affecting the endothelial cells’ function as a barrier.
The influence of MMP19 overexpression on endothelial-to-mesenchymal transition was further confirmed in the mouse model. Mice overexpressing MMP19 had increased levels of mesenchymal cell markers and decreased levels of endothelial cell markers.
Some endothelial and mesenchymal markers colocalized in endothelial cells, further indicating that MMP19 was promoting these processes.
Endothelial function also was affected by MMP19 overexpression in mice, with significantly increased permeability in lung blood vessels in these animals, compared with control mice.
The final study step explored potential mechanisms behind MMP19’s actions in endothelial cells. The researchers focused on two targets known to be associated with MMPs and involved in endothelial processes: ET-1, a molecule known to promote endothelial-to-mesenchymal transition, and the signaling molecule SDF-1 and its receptor CXCR4, which regulate the activity of immune cells called monocytes. Monocytes, when activated, can interact with endothelial cells and infiltrate tissues, transforming into macrophages.
Compared with control mice, ET-1, SDF-1, and CXCR4 levels were increased significantly in the lung tissue of mice overexpressing MMP19 after bleomycin induction. Data from IPF patients showed that ET-1 and SDF-1 expression were positively correlated with MMP19 expression. Moreover, both ET-1 and SDF-1 were found to be physically associated with MMP19 in endothelial cells.
Additionally, increased interaction between monocytes and endothelial cells, as well as increased numbers of monocytes in the tissue and blood vessels of the lungs, were observed in mice overexpressing MMP19 after bleomycin induction.
Blocking the activity of ET-1 in mice overexpressing MMP19 inhibited the MMP19-promoted endothelial-to-mesenchymal transition and ameliorated the aggravated lung fibrosis seen in these animals after bleomycin induction. Blocking ET-1 activity also reduced the accumulation of macrophages in lung tissue.
Similarly, blocking the activity of CXCR4 in mice overexpressing MMP19 reduced the levels of monocyte interaction and accumulation in lung tissues and alleviated the aggravation of lung fibrosis induced by bleomycin.
Chain of interactions
Taken together, these findings illustrate a complex chain of interactions, where MMP19 in IPF and bleomycin-induced mice appears to promote ET-1 and SDF-1 activity — with ET-1 then increasing endothelial-to-mesenchymal transition and vascular permeability and SDF-1 promoting monocyte activation and accumulation in lung tissues. Both contributed to fibrosis damage.
“MMP19 plays an important role in microvascular endothelial cell injury, activation and remodeling, and pulmonary fibrosis and could be a promising therapeutic target for suppressing pulmonary fibrosis,” the researchers concluded.
About the Author
