Lung Inflammation Early in Cystic Fibrosis
Bugs Are Indicted, But the Defense Is Guilty

Melvin Berger, Ph.D.

Departments of Pediatrics and Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio

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In the early to mid 1990s, as bronchoscopy with lavage was used to study relatively healthy children and then very young infants with cystic fibrosis (CF), a series of papers appeared in these pages that changed our concepts of the onset of inflammation in this disease and its relation to infection. As summarized by Cantin in his 1995 editorial, "Cystic fibrosis lung inflammation: early, sustained, and severe" (1), it had become evident that the inflammatory process in the CF lung began much earlier than had previously been suspected. The concepts that the CF lung was simply colonized with harmless bacteria and that infection occurred only when recognized clinically as an exacerbation had to be discarded in favor of the understanding that we are really dealing with a continuous infectious/inflammatory process, which begins in the first months of life. One of Cantin's conclusions was that "the jury is still out as to whether the inflammatory component . . . may be initiated or at least amplified by the basic defect" (1). Two papers in this issue (2, 3), together with other recent studies, tell us the jury has come back. It should come as no great surprise, however, that the verdict is mixed and the question was not quite black versus white.

A paper published in this issue of the AJRCCM by Dakin and coworkers (pp. 904-910) demonstrates that inflammation is clearly related to infection (2). Using careful bronchoscopic technique to avoid contamination, three lobes, including the right upper lobe, were sampled in each patient. Although the study lacks healthy and non-CF control subjects, it quite clearly shows that the presence of > 10⁵ bacteria/ml of bronchoalveolar fluid is associated with a highly significant increase in the number of inflammatory cells and a marked increase in the concentration of interleukin-8. Of the children, 36% had negative fluid cultures (defined as < 100 colony-forming units/ ml). Although they had fewer neutrophils and less interleukin-8 than did children with positive cultures, these values were still much higher than in noninfected, non-CF control subjects in other studies. The authors' conclusion that "while the findings do not exclude the possibility of intrinsic inflammation, they do describe a very significant relationship between infection and inflammation" seems entirely appropriate.

The study by Muhlebach and Noah (pp. 911-915), also published in this issue of the AJRCCM, extends their previous reports, which showed that in both CF and non-CF patients, concentrations of neutrophils and interleukin-8 were proportional to the number of bacteria in lavage specimens (3). In CF patients, however, the neutrophils and interleukin-8 were on curves that were significantly higher at any number of bacteria than was the case for non-CF patients (4). The most likely explanation for the earlier findings is that CF patients have a more intense response to any given degree of stimulus than do non-CF patients. An alternative explanation is that the CF patients actually received a greater stimulus because they retained more lipopolysaccharide for any number of viable bacteria recovered. Using moderately large groups of infected CF (27 patients) and non-CF patients (25 patients), Muhlebach and Noah (3) show that the relationship between the concentration of lipopolysaccharide and the number of bacteria is the same in both types of patients. Interleukin-8 and neutrophils were positively correlated with the concentration of lipopolysaccharide. The slopes are quite similar in the CF and non-CF patients, but the intercepts are significantly higher in the CF patients. Thus, the increased inflammation in CF is more likely due to an exaggerated inflammatory response to a given stimulus rather than to a difference in the degree of stimulus provided by any given number of bacteria.

The findings that CF patients have increased inflammatory responses to any degree of stimulation are especially relevant in light of the paper by Dakin and coworkers (2). These findings suggest an inverse correlation between specific compliance and percentage of neutrophils and a direct correlation between hyperinflation and the percentage of neutrophils or the concentration of interleukin-8. Thus, the excessive inflammatory response is not just of concern to laboratory scientists, but also has a definite clinical impact.

The verdict can thus be stated clearly: bugs are guilty of stimulating the inflammatory response and that is harmful to the patient. Even if some degree of autonomous inflammation cannot be ruled out, these data clearly indict the excessive inflammatory response to bacteria as a major problem. Similar studies (5-8) all agree that interleukin-8, neutrophils, and free elastase are more elevated in lavage fluid of those CF patients with positive cultures than in those with negative cultures. The longitudinal study of Burns and colleagues suggests that 97.5% of infants with CF have been infected with Pseudomonas aeruginosa by their third birthday (9), so this problem is nearly universal, even in infants. Some insight into the problem of inflammation in babies with CF who have negative cultures is provided by the serial studies of Bonfield and coworkers (10). Although only a few babies were studied, the results showed that even after transient infection was cleared, which can occur in infants, interleukin-8 production and neutrophil influx continued (10). This suggests that the inflammatory response might not only be quantitatively excessive while bacteria are present, but might also be excessively prolonged and therefore persist even after bacteria have been eradicated. Thus, although it is clear that we need new strategies to prevent and/ or control the infectious stimulus, we must also understand why the inflammatory responses in CF are excessive. Reports that cftr/ (S489X) mice had excessive inflammatory responses and increased mortality in a model of P. aeruginosa infection (11) and that G551D mice have excessive responses to lipopolysaccharide (12), clearly suggest that defects in CF transmembrane regulator (CFTR) lead to dysregulation of inflammation. Many laboratories are now focusing on the I-B/ NF-B system as a major site of this dysregulation in CF, because NF-B controls transcription of interleukin-8 and other proinflammatory mediators that contribute to the neutrophil influx into the lung. Our challenge as investigators is to find new antiinflammatory therapies that can safely dampen the excessive inflammatory response in the CF lung before it becomes a vicious cycle that spins out of control.

	References

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