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Many Adhesion Mysteries Unraveled, but Questions Remain


 

PASADENA, CALIF. — Adhesion formation probably occurs within the first 3–5 days following surgery, when hypoxia triggers a cascade of cytokines, growth factors, and clotting factors that form a fibrinous, clotlike mass, Dr. Michael P. Diamond said at a meeting of the Obstetrical and Gynecological Assembly of Southern California.

Unless a high level of tissue plasminogen activator (TPA) in relation to plasminogen activator inhibitor-1 (PAI-1) can break up the mass, conditions become ripe for uniquely equipped fibroblasts to proliferate and amass at the site of injury.

Angiogenesis follows, and resilient adhesive bands of tissue are formed that are exceedingly difficult to permanently eradicate through adhesiolysis.

The scenario, based on years of research into the unique properties of adhesion tissue, explains why adhesions are so likely to recur after they are lysed. It also offers guidance in the quest for antiadhesion barriers or medications, since these evidently require only short-term action to prevent long-term problems, said Dr. Diamond, professor and associate chair of obstetrics and gynecology at Wayne State University in Detroit.

The fibroblasts in adhesion tissue and fibroblasts in normal peritoneal tissue differ in fundamental ways. Those differences are exaggerated in the face of hypoxia, Dr. Diamond said. “Years later, there are still molecular and biological differences in these tissues that predispose [patients with adhesions] to further adhesion formation.”

Adhesions form after about 60%–80% of laparotomies or laparoscopies, with no meaningful differences seen between the two. “They are not something unique to the work we do as obstetrician gynecologists. Name a surgical specialty and they will have a problem with adhesions,” said Dr. Diamond, who also directs the division of reproductive endocrinology and infertility at his university.

Compared with normal tissue, fibroblasts in adhesions have higher basal levels of collagen, fibronectin, transforming growth factor (TGF)-β1, TGF-β2, and PAI-1. Hypoxia—a result of tissue injury during surgery—heightens the disparity in most of these cytokines. Basal TPA levels, critical to breaking up early adhesion formation, are higher in fibroblasts in normal tissue. In adhesion tissue, they plummet to near zero with hypoxia.

Furthermore, fewer cytokines involved in programmed cell death are produced in adhesion tissue. “These cells are in a revved-up position to heal,” said Dr. Diamond.

In the face of further injury, such as adhesiolysis, the cells are preprogrammed to heal again, with even more vigor than when they first evolved in response to hypoxia.

Dr. Diamond said these studies may shed light on why patients with chronic pelvic pain may obtain significant pain relief following adhesiolysis, but often find that their pain returns to near-baseline levels within several months.

Roughly 10%–20% of patients do experience lasting pain relief following adhesiolysis, but no one has been able to distinguish them from other patients, he said.

Still other questions persist about the connection between adhesions and chronic pelvic pain. For example, Dr. Diamond noted that men develop adhesions at the same or higher rates as women after surgery, trauma, hemorrhage, and other hypoxic events. But the literature contains no studies about adhesions causing pelvic pain in men. He noted that the two approved products designed to prevent adhesions—Interceed and Seprafilm—consistently reduce adhesion formation about half the time. “Each of these help, but neither is a panacea,” he said. Importantly, neither device is approved for use in laparoscopic surgery.

Because hypoxia seems inexorably tied to adhesion formation, any surgical tool that causes injury—scalpel, laser, or coagulation device—is as likely as the others to cause adhesions, according to Dr. Diamond.

More promising than new adhesiolysis techniques may be new preventive agents, perhaps barriers infused with medications, liquids, or gels designed to stay in place at the site of injury for the 3–5 critical days after surgery. One intriguing possibility might be the use of cyclooxygenase-2 (COX-2) inhibitors, since COX-2 is expressed only in the context of hypoxia in fibroblast tissue, he said.

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