Abdominal surgery is quite exhausting. But each year, hundreds of thousands of patients undergo follow-up operations to remove the resulting internal scar tissue, which causes problems such as pain and intestinal blockages. Now, researchers have discovered that normally protective immune cells known as macrophages can cause this scar tissue to accumulate, offering a possible strategy to thwart it.
This postsurgical scarring “is a big problem,” says cell biologist and immunologist Daniel McVicar of the National Cancer Institute, who was not involved in the work. The study, he says, is “getting to the cellular mechanism of how that happens.”
Immunologist Paul Kubes of the University of Calgary and his colleagues found the connection between macrophages and the accumulation of abdominal scar tissue by chance. They were investigating the role of cells in the fluid-filled peritoneal cavity, which houses organs such as the liver and intestines. Macrophages there, like those in other parts of the body, eat bacteria and other microbial invaders. But 5 years ago, researchers found that peritoneal cells also appeared to promote healing from organ damage.
For the new study, Kubes’ team devised a way to spy on the cells of live mice. The researchers stretched the middle of the abdomen between the animals’ stomach muscles to create a hernia-like bulge. The scientists were able to observe the activities of the cells through a strip of translucent tissue in that part of the abdomen.
The team then used a laser to induce a small burn on the abdominal wall. The macrophages accumulated in the damaged area (hundreds of them arrived in a few minutes) and formed a cap. “We thought they could be like ants crawling through organs,” until the cells find where they are needed, Kubes says.
Instead, the peritoneal cells move and adhere to the injured tissue as they pass. Their style of going with the flow makes them different from typical macrophages, which focus on their targets, and rather platelets, the cell fragments that clump together in wounds to produce blood clots. By congregating, macrophages accelerate recovery, the team reports today in Sciences. When the researchers gave the mice a molecule that prevents cells from accumulating, their wounds healed about 50% slower.
“This is a brilliant and clear example of the role of macrophages in wound healing,” says immunologist David Mosser of the University of Maryland, College Park, who was unrelated to the study.
But macrophages apparently cannot cope with the severe tissue trauma caused by the surgery. When the team performed an abdominal operation on the mice, the cells reached the incision site, stacked in large clumps, and entwined with resistant protein fibers. This process produced structures that resemble peritoneal adhesions, belts of scar tissue that can be painful and sometimes fatal.
In humans, most peritoneal adhesions are the result of surgery, and their removal is the motivation for about 300,000 operations each year in the United States. “I suspect that adhesions are an inappropriate response” from macrophages, Kubes says. He and his team are now working with medicinal chemists to develop drugs that inhibit its formation.
However, Gwendalyn Randolph, an immunologist at Washington University School of Medicine in St. Louis, says she remains “very skeptical” that the team has determined the mechanism of how these macrophages heal and damage. To confirm the role of immune cells, he argues, researchers must test whether adhesions are reduced in genetically altered mice that lack the cells. Still, he says, the study could provide a boost by stimulating researchers to think more about this surgical complication.