Understanding fibrin’s role in inflammation and tissue recovery

After intensive chemotherapy, the bone marrow must rebuild the cells that produce blood and support the immune system. Recovery depends on a carefully coordinated response to injury, including the formation and eventual removal of fibrin, a protein that helps stop bleeding and provides a temporary framework for tissue repair.

New research from Lakmali Silva, assistant professor of Oral Medicine, Infection, and Immunity at the Harvard School of Dental Medicine (HSDM), is shedding light on what happens when that process does not go as planned. Published in Blood Advances, the study found that when fibrin remained in the bone marrow instead of being cleared, it interfered with the tissue’s ability to regenerate. Silva conducted the study with Rafaela Ferrer, DMSc29, Betul Ogan, a postdoctoral fellow, and other collaborators.

The findings complement Silva’s broader research program at HSDM, where her laboratory investigates the mechanisms through which persistent fibrin contributes to inflammation and tissue damage in the oral cavity, particularly in periodontal (gum) disease.

“My research program at HSDM asks a broader question: how do proteins traditionally associated with blood clotting and clot removal influence the immune system and the way tissues respond to injury?” Silva said.

Fibrin is a normal part of the body’s response to injury. It helps form a blood clot and provides a temporary structure around damaged tissue while healing begins. As recovery progresses, the body breaks down and removes the fibrin.

In the bone marrow study, however, fibrin continued to accumulate when its clearance was impaired, disrupting the tissue’s ability to regenerate. To investigate whether specific interactions between fibrin and immune cells contributed to these harmful effects, Silva and her collaborators used experimental models to disrupt specific interactions between them. Doing so improved outcomes following chemotherapy, suggesting that specific fibrin–immune cell interactions contribute to the harmful consequences of impaired fibrin clearance.

“What was particularly exciting was that disrupting specific interactions between fibrin and immune cells improved survival and aspects of recovery following chemotherapy, without eliminating fibrin itself,” said Silva. “That distinction is important because fibrin also performs essential functions in controlling bleeding and initiating wound repair.”

Although the findings are still preclinical, they provide new insight into how the body's failure to remove fibrin and its interactions with immune cells can affect bone marrow recovery. They also offer a model for studying how persistent fibrin may influence inflammation in other tissues.

“The bone marrow and the oral cavity are very different environments, but they share a fundamental challenge,” Silva said. “Following injury or inflammation, the body needs to mount a protective response and then resolve that response appropriately so the tissue can return to a healthy state.”

Maintaining that balance is particularly important in the oral cavity, where tissues are constantly exposed to bacteria and other potential sources of inflammation. At HSDM, Silva’s lab investigates how persistent fibrin interacts with immune cells in the protective lining of the mouth and may contribute to chronic inflammation and tissue damage.

“Fibrin is known to influence immune cell responses beyond its traditional role in blood clotting. Building on this understanding, our research investigates how fibrin contributes to inflammation and tissue damage in the oral cavity and other tissues, and the molecular mechanisms that drive these responses,” she said. 

One area of particular interest is periodontal disease. In healthy tissue, inflammation helps the body respond to bacteria and protect against infection. When inflammation persists, however, it can begin to damage the tissues that support the teeth. Building on previous findings demonstrating that persistent fibrin contributes to periodontal inflammation and tissue destruction, Silva and her team are now investigating the molecular mechanisms through which fibrin influences immune responses and promotes tissue damage.

Silva’s lab is also exploring how interactions between oral microorganisms, fibrin, and the immune system influence periodontal inflammation and tissue damage.

“The formation and removal of fibrin are not simply processes that accompany tissue injury and repair. They can actively shape the inflammatory environment and influence whether tissues recover or progress toward chronic disease. Understanding how fibrin regulates these responses across different tissues is fundamental to our research,” Silva said.

By understanding these processes, Silva and her team hope to uncover why inflammation resolves in some tissues but persists in others, potentially identifying new approaches to support tissue repair and limit chronic inflammation.

This research was supported by the National Institutes of Health, the National Institute of Dental and Craniofacial Research, and institutional support from the Harvard School of Dental Medicine.