Blocking 15-PGDH Enzyme Seen to Ease Inflammation, Fibrosis in Mouse Model

Blocking 15-PGDH Enzyme Seen to Ease Inflammation, Fibrosis in Mouse Model
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Blocking an enzyme — called 15-PGDH — in a mouse model of pulmonary fibrosis (PF) limited early-stage inflammation and the development of fibrosis in the lungs, aiding the animals’ survival, a study demonstrated. 

These findings support further work targeting 15-PGDH as a potential treatment option for people with PF. 

The study, “Therapeutic targeting of 15-PGDH in murine pulmonary fibrosis,” was published in the journal Nature Scientific Reports.

PF is characterized by the scarring of lung tissue. Myofibroblasts are a type of cell that plays a critical role in wound healing and is responsible for the production and buildup of proteins that form scar tissue (fibrosis) in patients’ lungs.

Myofibroblasts are activated by a signaling protein called TGF-beta. And a small molecule hormone known as prostaglandin E2 (PGE2) is known to disrupt TGF-beta signaling and suppress myofibroblast activation. 

However, natural PGE2 levels cannot block the disease progression TGF-beta induces because its receptors are produced at low levels in fibrotic lung tissue. 

Therapies that could increasing PGE2 levels may be an alternative way of  suppressing the activation of disease-related myofibroblasts. 

Recently, a team of researchers at Case Western University in Cleveland discovered a small molecule — called (+)SW033291 — that increased PGE2 levels by binding to and blocking the enzyme 15-PGDH (15-hydroxyprostaglandin dehydrogenase), which is responsible for the breakdown of PGE2.

In the current study, the team continued to investigate the potential of 15-PGDH in a PF mouse model, in which mice were exposed to bleomycin — a chemical that triggers inflammation and fibrosis. 

Initial experiments confirmed that 15-PGDH was produced and active in the lungs of healthy mice, which supported the “rationale for pharmacologic targeting of 15-PGDH,” the researchers wrote.

To study the effects of blocking 15-PGDH, bleomycin was administered intravenously to mice along with twice-daily  (+)SW033291 treatments to one group and a control vehicle to another. 

Blocking 15-PGDH helped to suppress lung inflammation early and limit systemic inflammation triggered by the bleomycin. After seven days of treatment, compared with control mice, levels of TGF-beta were lower and lung wall thickening was lesser in treated animals.

“These data indicate that inhibiting 15-PGDH in the context of bleomycin-induced lung injury may limit pathologic inflammation in the lung,” the researchers wrote.

Mice continued to be treated with (+)SW033291 for 35 days after bleomycin exposure. While control-group mice experienced severe weight loss in the first eight days after bleomycin administration (lost 26.8% of their body weight), treated mice lost less weight (16.0% body weight) and were stable thereafter. Notably, 35% of control mice died, compared with 10% of treated mice.

An examination of lung tissue found more fibrosis in control mice, and lesser in treated mice. Treated animals also showed fewer fibrotic lesions and accumulated collagen. Blocking PGDH also suppressed the negative impact of bleomycin on lung function. 

To identify specific cell types were affected by treatment, lung cells of healthy mice treated with (+)SW033291 were isolated. The cells most affected were immune cells known as macrophages — which are involved in PF progression — mast cells from connective tissue, and epithelial cells found on the surface of organs, including the lungs. 

These data “identify alveolar macrophages, mast cells, and to a lesser extent, endothelial cells, as the likely targets of PGDH [inhibition] therapy in [mouse] PF,” the researchers wrote.

To support this approach’s potential benefits for people, researchers also examined human lung tissue (isolated post-mortem). They found 15-PGDH was produced in all six samples tested, and localized in cells lining the blood vessels and alveoli, the tiny air sacs in the lungs. 

“The existence of PGDH+ cells in human lung tissue supports the notion that 15-PGDH inhibition may be a novel and effective therapy for IPF patients,” the researchers wrote. 

Overall, these results showed that long-term 15-PGDH inhibition “was well-tolerated, reduced the severity of pulmonary fibrotic lesions and extracellular matrix remodeling, and improved pulmonary function in bleomycin-treated mice. Moreover, PGDH [inhibition] attenuated both acute inflammation and weight loss, and decreased mortality,” the team concluded.

Steve holds a PhD in Biochemistry from the Faculty of Medicine at the University of Toronto, Canada. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases. Steve recently stepped away from the lab and into science communications, where he’s helping make medical science information more accessible for everyone.
Total Posts: 110
Patrícia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.
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Steve holds a PhD in Biochemistry from the Faculty of Medicine at the University of Toronto, Canada. He worked as a medical scientist for 18 years, within both industry and academia, where his research focused on the discovery of new medicines to treat inflammatory disorders and infectious diseases. Steve recently stepped away from the lab and into science communications, where he’s helping make medical science information more accessible for everyone.
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