Abdominal surgery is grueling enough. But every year, hundreds of thousands of patients undergo follow-up operations to carve away the internal scar tissue that results, which causes problems such as pain and intestinal blockages. Now, researchers have discovered that normally protective immune cells known as macrophages may provoke accumulation of this scar tissue, offering a possible strategy to thwart it.
This postsurgical scarring “is a huge issue,” says cell biologist and immunologist Daniel McVicar of the National Cancer Institute, who was not involved with the work. The study, he says, is “getting at the cellular mechanism for how that occurs.”
Immunologist Paul Kubes of the University of Calgary and colleagues chanced on the connection between macrophages and the buildup of abdominal scar tissue. They were investigating the cells’ roles in the fluid-filled peritoneal cavity, which houses organs such as the liver and the intestines. Macrophages there, like those elsewhere in the body, gobble bacteria and other microbial invaders. But 5 years ago, the researchers found that the peritoneal cells also appeared to promote healing of organ damage.
For the new study, Kubes’s team devised a way to spy on the cells in living mice. The researchers stretched out the middle of the abdomen between the animals’ stomach muscles to create a bulge a bit like a hernia. The scientists could observe the cells’ activities 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. Macrophages amassed on the damaged area—hundreds of them arrived within a few minutes—and formed a cap. “We thought they might be like ants crawling around on the organs,” until the cells find the site where they are needed, Kubes says.
Instead, the peritoneal cells drift around and latch onto wounded tissue as they pass by. Their go-with-the-flow style makes them unlike typical macrophages, which home in on their targets, and more like platelets, the cellular shards that cluster at wounds to produce blood clots. By congregating, the macrophages speed recovery, the team reports today in Science. When the researchers gave the mice a molecule that prevents the cells from gathering, their injuries healed about 50% slower.
“This is a clear and cool example of the role of macrophages in wound healing,” says immunologist David Mosser of the University of Maryland, College Park, who wasn’t connected to the study.
But the macrophages apparently can’t cope with the severe tissue trauma caused by surgery. When the team performed an abdominal operation on the mice, the cells arrived at the incision site, stacked into huge clumps, and interlaced with tough protein fibers. This process yielded structures that resemble peritoneal adhesions, belts of scar tissue that can be painful and sometimes lethal.
In humans, most peritoneal adhesions result from surgery, and removing them is the motivation for about 300,000 operations each year in the United States. “I suspect that the adhesions are an inappropriate response” by the macrophages, Kubes says. He and his team are now working with medicinal chemists to develop drugs that crimp their formation.
However, Gwendalyn Randolph, an immunologist at Washington University School of Medicine in St. Louis, says she remains “very skeptical” that the team has nailed down the mechanism of how these macrophages heal and harm. To confirm the role of the immune cells, she argues, researchers need to test whether adhesions are reduced in genetically altered mice that lack the cells. Still, she says, the study could provide a boost by stimulating researchers to think more about this surgical complication.