Scientists ID promising therapeutic target for preventing CTEPH
Goal would be stopping clots from obstructing blood flow: Study
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Blocking a signaling pathway in certain white blood cells may prevent blood clots from obstructing blood flow in the pulmonary arteries — the cause of chronic thromboembolic pulmonary hypertension (CTEPH).
That’s according to a new study that investigated whether a certain immune signaling pathway in the body plays a role in converting resolvable blood clots into fibrous tissue in CTEPH. The researchers found that the pathway is, in fact, a potential therapeutic target for this rare form of pulmonary hypertension (PH), a disease characterized by abnormally high pressure in the blood vessels of the lungs.
“Targeting this pathway may represent a promising immunomodulatory strategy to limit [disease-causing blood clot formation],” the researchers wrote.
The study, “The MCP-1/CCR2-CD16⁺ monocyte axis drives thrombus fibrosis in Chronic Thromboembolic Pulmonary Hypertension,” was published in the Journal of Translational Medicine.
Acute pulmonary embolism (APE) is a condition marked by the sudden blockage of a lung artery by a blood clot. Most of these clots resolve within three months, but in rare cases, they fail to dissolve properly and become fibrous, or scar-like, tissue.
That tissue, in turn, permanently blocks blood flow and increases blood pressure, causing CTEPH, which strains the right side of the heart.
Researchers’ focus was on a subset of white blood cells
Now, researchers in China sought to determine whether an immune signaling pathway involving the protein MCP-1 and the cell-surface receptor CCR was involved in converting blood clots into fibrous tissue in CTEPH. The scientists focused on a subset of white blood cells, called CD16-positive monocytes, which have been found at higher levels in this PH type.
First, the team collected blood samples from 32 people with confirmed CTEPH and 30 with APE. Samples were also collected from 20 healthy people, matched for age and sex, and used as controls.
Testing revealed that CD16-positive monocytes accounted for a substantially larger share of all circulating monocytes in people with CTEPH than in healthy controls (mean 29.44% vs. 10.65%). Importantly, total monocyte counts did not differ between the groups, indicating the change was a shift within the monocyte population rather than an overall increase in monocytes, according to the researchers.
Compared with clinical data, a higher proportion of CD16-positive monocytes was strongly correlated with increased pulmonary vascular resistance (PVR), a measure of how hard the right heart must work to pump blood. Elevated levels of these monocytes were also tied to higher mean blood pressure in the pulmonary arteries.
In other blood tests, MCP-1 levels were highest in APE patients, intermediate in CTEPH patients, and lowest in healthy controls. MCP-1 levels in blood samples drawn directly from the pulmonary artery were significantly higher than in blood drawn from a vein in the extremities of the same CTEPH patients, suggesting that the protein accumulates specifically in the lungs’ arteries, per the team.
Further analysis suggested that MCP-1 influences CD16-positive monocytes levels rather than the other way around, which in turn affects PVR. In laboratory experiments using blood cells from healthy donors, adding MCP-1 boosted the proportion of these monocytes. And, MCP-1’s effect on CD16-positive monocytes depended on CCR2 signaling.
More work needed to validate potential of this therapeutic target
The researchers then examined gene activity in fresh clot tissue taken directly from the pulmonary arteries of five APE patients. The analysis found that CD16-positive monocytes accounted for most of the monocytes and showed higher activity in genes related to tissue remodeling, the process that leads to scar formation.
From CTEPH patients, tissue specimens were obtained during surgical procedures to remove clot material from the pulmonary arteries. The number of macrophages, the immune cells that develop from monocytes, increased progressively across the stages of clot formation. And MCP-1 staining co-localized with areas of macrophage infiltration, which were predominantly M2-type, the type that, when overactivated, forms scar tissue.
Lastly, the team studied mice in which a certain vein was surgically tied off to induce clot formation, allowing the researchers to observe clot fibrosis develop over time.
Blood clots progressed into densely fibrous tissue by day 14. M2 macrophages accumulated progressively within the clots, paralleling the increase in the deposition of collagen, the main protein in scar tissue. At the same time, the mouse equivalent of CD16-positive monocytes (Ly6C-negative monocytes) rose steadily from day five.
When the researchers blocked the MCP-1/CCR2 pathway with a drug called RS102895, the levels of Ly6C-negative monocytes and M2 macrophages decreased, along with the fibrotic area of the newly formed blood clot.
“These findings expand our understanding of the immunopathology of CTEPH and highlight the MCP-1/[CD16-positive] monocyte axis as a potential therapeutic target,” the researchers wrote. “Future longitudinal and mechanistic studies will be crucial to validate these findings and to translate them into precision immunomodulatory therapies for CTEPH.”
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