The Science Journal of the American Association for Respiratory Care

2000 OPEN FORUM Abstracts

Cystic Fibrosis: Lessons from the '90s

Dennis Nielson, MD PhD The Children's Medical Center, Dayton, Ohio

Although cystic fibrosis (CF) may have been around for over 50,000 years and it was talked about in nursery rhymes in the Middle Ages, it was not described or recognized by the medical world until this century. Various theories of the cause of CF came and went until 1983, when Paul Quinton clearly demonstrated chloride impermeability in CF epithelium. The CF gene was isolated in 1989, which brings us to the 90s, a remarkable decade of progress in our understanding of CF and its protean manifestations.
In 1990 it was thought that as many as 6 mutations might cause CF. As of this year over 850 disease-causing mutations of the CF gene have been described around the world. These are ethnic differences in the prevalence of specific mutations. Mutations have been classified into four to six different mechanistic categories. The most common mutation, DF508, a deletion of a single phenylalanine at position 508 of the CFTR protein, rarely reaches the cell membrane. Instead it is rapidly degraded before it leaves the endoplasmic reticulum because its abnormal folding signals the cell to reject and degrade it.
CG genotype correlates closely with pancreatic function. There is good correlation with (the non-CF phenotype) congenital bilateral absence of the vas deferens, an important cause of male infertility. In contrast, genotype correlates only in broad terms with severity of lung disease, the most lethal aspect of CF. We know that the CFTR gene interacts with a number of other genes, including a group of newly described modifier genes that might explain the complex relationship between genotype and pulmonary phenotype. In spite of the tremendous advances in our understanding of the genetics of CF, fulfilling the promise of gene therapy remains an elusive goal.
CF research has pursued many aspects. We now know that inflammation begins early in CF, and the products of unremitting inflammation account for much of the damage done to the lungs. A number of new therapies are directed at controlling inflammation and decreasing the damage it causes. CF research has led to the discovery of a new class of antibacterial molecules endogenous to the lung: the defensins. Exploitation of this discovery may result in more effective strategies at controlling lung infection. Prevention of lung infection with resistant bacteria is a goal of several lines of research, including the development of an anti-pseudomonal vaccine.
No stone is left unturned as researchers investigate virtually every aspect of CF care, including mucus clearance strategies, lung transplantation, patterns of antibiotic use, and so on. As a result of all this activity, survival and quality of life will continue to increase in steps both large and small.

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