BUGS AND PLUGS: LUNG DAMAGE IN CYSTIC FIBROSIS

SEATTLE-By age 18, most patients with cystic fibrosis (CF) have been colonized with Pseudomonas aeruginosa. Pulmonary damage-caused in part by that organism-contributes greatly to decreased life expectancy in CF patients. But how and why this occurs has remained unclear. At least part of the answer may lie in the thickened, difficult-to-remove mucus commonly found in the airways of CF patients. Experts are beginning to suspect that mucosal abnormalities are even more likely than alterations in the airways' epithelial lining to hold the key to early bacterial colonization of CF lungs.

"We propose that bacteria bind with the mucosal layer and do not reach the epithelial cell layer," Gerd Doering, PhD, told the 13th Annual North American Cystic Fibrosis Conference. That fact, he added, has important implications for the development of new approaches to preventing and treating early lung infections in CF.

Dr. Doering, of the University of Tübingen, Germany, is president of the European Cystic Fibrosis Society. He and his colleagues studied the activity of Staphylococcus aureus in airway tissues and found that the organisms bind to the mucosal layer; there is little adhesion to airway cells (Figure). "Mucus is essential for the binding," Dr. Doering explained. "Most of the organisms are in the mucus of the obstructed airways, not . . . on the cell membrane."

This and similar findings suggest that the mucus in CF patients, compared with that in patients with normal airways, might preferentially bind bacteria. But this does not appear to be the case. Studies so far have shown that mucus from CF patients has no more receptors than does mucus from normal subjects, Dr. Doering noted. However, analyses of CF mucus have produced a number of other new findings, many of which involve the neutrophils.

MUCUS BINDING AND NEUTROPHIL BLINDING

In a normal lung, a pathogen assault is followed by neutrophil influx, mucus hypersecretion, and clearing of the invading organism. Dr. Doering's group asked why this defense did not eradicate the bacteria in CF patients.

The answer appears to be that in the lungs of CF patients, phagocytosis is defective because elastase released from the neutrophils clings to receptors, making the neutrophils essentially "blind"; as a consequence, they are unable to recognize invading pathogens. "Bacteria are not only sitting on the mucus, they are invisible [to the immune defenses]," according to Dr. Doering.

Bacterial success leads to the next stages in CF lung disease: the formation of mucus plugs and the change of bacterial phenotypes to more destructive forms. A key element in this process is that the neutrophils, recruited to fight the pathogens, die after failing to eradicate the initial infection, Dr. Doering noted.

The corpses of the neutrophils then plug up the small airways. These plugs are negatively charged and may absorb positively charged toxins or antibiotics. As a result, any antibiotics administered would not be available for eradicating bacteria.

"Oxygen is depleted in the plugs of CF airways," Dr. Doering added. This creates anaerobic conditions, in which both Pseudomonas and Staphylococcus organisms thrive. Neutrophils become less effective because they can find few oxygen radicals to reduce. "Oxygen radicals are very important in the fight against bacteria," Dr. Doering explained.

SOME IMPLICATIONS FOR THERAPY

Neutrophil failure and subsequent plug development have important implications for CF care. For example, the pathology supports the importance of regular chest physiotherapy to clear out mucus, even in very young and/or very healthy CF patients who still have normal lung function. Dr. Doering's work also suggests that antibiotics that do not work well in anaerobic conditions might be poor choices for the treatment of acute lung infections and exacerbations of chronic infections in patients with CF.

-Janis Kelly