Stiffened cells lodge in lung capillaries.
When bacteria invade the body, white blood cells flock to the infection site, primed to engulf and kill. But getting there is only half the battle. Keeping these cells at the site long enough to conquer the infection is an essential part of the immune strategy.
Focusing on the lungs, researchers have discovered one reason why the body's most abundant white blood cells, called neutrophils, don't desert the battlefield. The finding, they say, might someday yield new ways to move neutrophils along in cases where the cells stay too long or fight too hard.
Too big to travel freely along the average lung capillary, neutrophils normally squeeze through like mice through a chink in a baseboard. when they reach an inflamed area, however, they slow to a standstill, staying where they're needed most. For decades, scientists have explained this ordinarily beneficial slowdown by noting that chemicals released during inflammation increase the cells' stickiness. Now they've added a new mechanism: cell stiffening.
Intrigued by basic research showing that when monoclonal antibodies prevent neutrophil stickiness, they still don't keep the cells from lodging in the lungs, G. Scott Worthen and his colleagues at Denver's National Jewish Center for Immunology and Respiratory Medicine, along with researchers at the Washington University School of Medicine in St. Louis, began looking for another explanation. Following up on a "farfetched" idea that mechanical properties of neutrophils might be important, they discovered that stiffening by itself can cause the cells to lodge in lung capillaries and in capillary-sized filter pores. The group reports its findings in the July 14 SCIENCE.
To stimulate neutrophils to stiffen, Worthens' team used a synthetic chemical with an action similar to certain blood-borne chemical mediators of inflammation. Neutrophils responded by internally assembling microfilaments and becoming stiff. Stimulated neutrophils lodged in the filters, while unstimulated ones squeezed through. When the researchers radioactively labeled the stimulated neutrophils and infused them into rabbits, they could see the cells had pooled in the lungs.
To separate the effects of stiffness and stickiness, the group blocked each effect chemically. Stimulated cells prevented from assembling microfilaments passed through filter pores and rabbits' lung capillaries, but cells prevented from getting sticky still lodged in the filters. "If we prevent the increase in stickiness with a monoclonal antibody," Worthen says, "we still get retention." In addition, the researchers measured cell stiffness directly with a "cell poker," gently denting neutrophils with a fine glass needle. Stiffness increased significantly with increasing chemical stimulation.
When capillary clogging follows severe injury, bacterial blood infections or massive burns, it can lead to adult respiratory distress syndrome -- an untreatable and often fatal result of neutrophils run amok. Releasing potent chemicals of their own, the amassed neutrophils can damage lungs so severely that a patient cannot breathe. If researchers can find a chemical that modifies neutrophil stiffening without affecting stickiness or infection-fighting effects, Worthen says, they may be able to produce the first treatment for this syndrome.