Tests on cell cultures indicate a newly discovered signaling pathway can be blocked, making it a possible target for therapy
Physicians and scientists in the Center for Perinatal Research have identified a cellular signaling pathway that appears to be essential to progression of pulmonary hypertension associated with hypoxia.
Pulmonary hypertension (PH), which is high blood pressure in the lungs, is a common and dangerous complication of bronchopulmonary dysplasia, a chronic lung disease that affects newborns and infants; and chronic obstructive pulmonary dysplasia (COPD), a chronic lung disease that affects adults.
Low levels of oxygen, or hypoxia, in the lungs of patients with these diseases appears to trigger PH, which, through vasoconstriction and vascular remodeling restricts blood flow. The restricted flow raises blood pressure within the lungs and forces the heart to work harder, often leading to failure of the right heart.
PH significantly increases the risk of prolonged reliance on mechanical assistance to breathe, prolonged hospitalizations and death.
“The problem is there is no curative therapy for pulmonary hypertension in infancy, children or adults,” says Leif Nelin, MD, division chief of Neonatology and a principal investigator in the Center for Perinatal Research. “We’ve found a pathway that’s very important — it may very well be a clinical target.”
“In pulmonary hypertension, vasoconstriction makes a vessel smaller; vascular remodeling fills space inside the vessel with cells so there is even less room for blood flow; and proliferation of smooth muscle cells makes the constriction stronger,” says Dr. Nelin, who is also a professor of Pediatrics at The Ohio State University College of Medicine. “A curative therapy would remove these three things.”
Dr. Nelin’s team previously found that hypoxia-induced proliferation of human pulmonary microvascular endothelial cells depends upon the protein arginase II and that an increase in arginase II expression relies on epidermal growth factor receptor (EGFR). But it was unclear how the process works.
In this new research, published in Physiological Reports, the researchers performed several experiments on human pulmonary microvascular endothelial cell cultures and human pulmonary artery smooth muscle cells cultures. They found hypoxia induces epidermal growth factor (EGF) production, which in turn binds to and activates EGFR. Activated EGFR in turn leads to increased arginase II expression and cell proliferation.
They also showed that they could prevent arginase II expression and cell proliferation by either blocking the binding of EGF to EGFR or inhibiting EGF expression.
“Several ligands can bind with EGFR but we started with EGF,” Dr. Nelin says. “Importantly, there are already medicines in cancer that block EGF from binding with EGFR.”
If further studies support a clinical trial aimed at blocking the pathway in PH patients, having an approved drug already known to do this may speed the process, Dr. Nelin adds.
The investigators are starting to look at EGF and EGFR signaling in the lungs of children to see if the genes controlling the process change with BPD. They hope to determine if the genes are mutated and whether that leads to altered signaling.
They’ve also begun preliminary preclinical studies that suggest that blocking the interaction between EGF and EGFR works in an animal model of BPD, Dr. Nelin says.
“COPD has a lot of similarities to BPD so potentially this could be broadly applicable,” he says. In addition to infants and adults with the diseases, other potential beneficiaries may be people who live at high altitudes. They tend to suffer from PH as they age.
Citation: Pool CM, Jin Y, Chen B, Liu Y, Nelin LD. Hypoxic-induction of arginase II requires EGF-mediated EGFR activation in human pulmonary microvascular endothelial cells. Physiological Reports. 2018 May; 6(10): e13693.