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Cystic fibrosis (CF) is a frequent autosomal recessive genetic disease. The isolation of the gene at the CF locus assigned to the long arm of chromosome 7 band q 31 and defining description of its protein named CFTR (cystic fibrosis transmembrane conductance regulator) promoted understanding the basic biochemical defect. Brief review of relevant literature demonstrates that glycoprotein CFTR is a chloride channel and is activated by a combination of phosphorylation by protein kinase A and binding of ATP. Most common mutation of CF gene, a deletion of the three nucleotides encoding phenylalanine (Delta F508) results in disturbance of chloride transport through membrane of epithelial cells involved in pathomechanism of CF. The way for gene therapy in CF is open, however therapeutic progress is noted on both pharmacologic arena and on the gene cure front. Recombinant vectors utilizing the adenovirus system with high efficiency of CFTR gene transfer to airway epithelium demonstrated in a rat model look promising. The use of retroviruses for CFTR transfer is also advanced mode of somatic gene therapy. An alternative approach suggesting the use of germ line cells is prerequisite of the development of the preimplantation/preconception genetic CF diagnosis. A number of safety and efficacy issues have to be addressed for all approaches before human trials can be implemented.

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The isolation of cystic fibrosis gene at the CF locus assigned to the long arm of chromosome 7 band q31 and definition of its protein product named CFTR (cystic fibrosis transmembrane conductance regulator) permits to understand the basic defect in this inherited disorder known as cystic fibrosis (CF) or mucoviscidosis. A variety of mutations of CF gene was revealed and the most common, a deletion of the 3 nucleotides that encode phenylalanine (Delta F508) with the variable incidence among the different ethnic groups of CF patients was delineated. CF is a variable disease and genetic testing can be useful to explain this variation but to date the phenotype-genotype correlation is not clarified. Polymerase chain reaction (PCR) amplification is used to test CF gene in CF patients and their families but is not sufficiently genetically informative to population screening for carrier detections. Recently identified glycoprotein encoded by CF gene is responsible for the regulation of the membrane chloride channel of epithelial cells and the experiments used retro-virus-mediated gene transfer demonstrated complementation CF defect in vitro. The way for gene therapy in this disease is open. An alternative approach to use the germ line cells to CF gene therapy is prerequisite of the development of the preimplantation preconception genetic CF diagnosis. The researchers managed already to express human CFTR gene in vivo in cotton rats lungs through the viral delivery system. It will be generalized into the airways of CF patients with hope that normal CFTR will reverse the physiological defect in CF cells.

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The pathophysiology of cystic fibrosis (CF), the secretory properties of CF cells and conductance studies of CF cells and membranes suggest that the basic defect of CF is an abnormality of regulation affecting a broad spectrum of functions. Prolactin (PRL) was proposed as the putative regulatory factor, because the multifarious activities of PRL, especially the well documented osmo- and electrolyte regulatory effects, can be related to all of the symptoms of CF. These include salt loss in sweat, abnormal mucus production, impaired intestinal digestion and absorption, male infertility, delayed puberty, failure to thrive, etc. Additionally those tissues in lower vertebrates in which PRL activity has been demonstrated are phylogenetically related to many of the tissues affected in CF.

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1. The elevated (Cl) of sweat from cystic fibrosis (CF) skin reverted to normal after the skin had been grafted onto immunoincompetent, congenitally athymic mice [N'NIH(S)-NU]. 2. The sweat (Cl) of CF skin grafts unlike that from normal skin did not increase when the host mice were injected with antibodies to human prolactin (hPRL). 3. One explanation for the above observations postulated a structurally modified PRL in CF patients. Circulating PRL in CF appears to contain a larger amount of glycosylated variants than that of healthy individuals.

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A simple scheme for quantifying lung perfusion scintigrams was developed to evaluate the efficacy of a therapeutic regimen for the relief of airways obstruction in cystic fibrosis patients. Ten hospitalized patients were given conventional therapy including administration of intravenous antibiotics, mucolytic aerosols, chest physical therapy, and adequate nutrition and hydration as adjuncts to a single bronchoscopic bronchial washing procedure. Quantitative scoring of the lung scintigram was based upon the severity of the perfusion defects in equivalent upper and lower lung fields, as viewed from right and left posterior oblique projections. Seven to ten days following bronchoscopic washing, scintigraphic scores were found to correlate with changes in both the forced vital capacity and the one-second, time forced expiratory volume (r = 0.78, 0.70, respectively; P <.05). The severity of defective lung perfusion indicated the loss of lung volume and perfusion due to airways obstruction and secondary hypoxic vasoconstriction. Chest radiography was less reflective of improvement than lung scintigraphy. It was concluded that serial pulmonary perfusion scintigrams provide a sensitive tool for evaluating the relief of airways obstruction in cystic fibrosis.

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In order to assess the relationship between various factors influencing Pseudomonas (Ps) colonization of the respiratory tract of patients with cystic fibrosis (CF) and the appearance of various strains of Ps, two groups of CF patients were studied during a 5-year period. Group A consisted of 24 Ps-negative patients, and Group B consisted of 32 Ps-positive patients, including eight patients who expired. Several clinical and laboratory parameters were evaluated. Although the precise mechanism causing the appearance of Ps in the respiratory tract of CF patients remains elusive, we analyzed several biologic characteristics of both host and organism. This study indicates that frequent use of antibiotics combined with the eradication of Staphylococcus aureus from the respiratory tract heralds the onset of persistent Ps colonization and a subsequent downhill course for CF patients.

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The purpose of this study was to elucidate the possible relationship between defective PRL and elevated sweat Cl in CF patients. Full thickness human skin was grafted onto the back of immunoincompetent, nude congenitally athymic mice. This study indicated: 1) that when skin from CF patients with high sweat chloride concentrations was grafted, the chloride concentration of sweat from the grafts was the same as of sweat from grafts of normal skin; and 2) that administration of anti-hPRL to the mice bearing the CF grafts did not increase the chloride concentration of the sweat as it had in normal skin grafts. 3) that CF may involve defective PRL production leading to failure of regulation of Cl channels in affected epithelia, 4) that the athymic mouse is a useful model for studying PRL activity in the pathophysiology of sweating of CF patients.

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We investigated the role of Pseudomonas aeruginosa colonization in the respiratory tracts of cystic fibrosis (CF) patients to relate the effect of this colonization to progression of bronchial airway pathologic conditions and to the patients' clinical progress, and to identify predisposing factors to persistence of P aeruginosa colonization and bronchial tree damage. Half of 160 CF patients studied had persistent P aeruginosa respiratory tract colonization; the other half had none. Pseudomonas aeruginosa seems to have an exclusive propensity for the respiratory tract and may appear at any age. Treatment with antibiotics, including aminoglycosides, failed to eradicate P aeruginosa. The continuous use of antibiotics seemed to contribute to the persistence of P aeruginosa and the appearance of mucoid strains of P aeruginosa.

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Validation of rigid-tube bronchoscopy with small-volume (5-ml increments not to exceed 300 ml) bronchial washing as a therapeutic adjunct was performed on six patients with cystic fibrosis, using serial tests of pulmonary function as a yardstick for assessment of efficacy. Two patients did not undergo the procedure and served as control subjects. All patients were characterized as having varying severity of pulmonary involvement. Large central airways were severely obstructed, and older patients had more trapped gas in their lungs. Hypoxemia and large alveolar-arterial oxygen pressure differences [P(A-a)O2] were due to inhomogeneity of alveolar ventilation. Results indicated that up to ten days to two weeks, bronchoscopic bronchial washing may in some instances improve maximal expiratory flow-volume curves and specific airway conductance and decrease P(A-a)O2 towards normal. Distribution of alveolar gas P(A-a)O2 towards normal. Distribution of alveolar gas became more homogeneous. We conclude that bronchoscopic bronchial washing may be effective in the management of patients with cystic fibrosis, by augmentation of their inadequate cleansing function of the conducting airways.

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Twenty-seven adolescents and young adults with cystic fibrosis were studied to evaluate the phychological impact of this chronic illness. At first glance, most patients appeared to function adequately on a daily basis. However, four sources of psychological stress, leading to emotional disturbance, were identified: altered physical appearance causing distorted body images and denial of sexuality, strained interpersonal relationships resulting in isolation and mental strain, conflicts in upbringing, and increased awareness of the future and of death. Guidelines for the physician treating these young adults and their families include: (1) encouragement for greater involvement by the patient's father; (2) assisting the mother to find outside interests and to allow more independence to the patient; (3) stressing communication about cystic fibrosis within the home; (4) emphasizing outside activity for each patient; (5) repeated discussions of the patient's concerns while emphasizing his strengths; (6) anticipation of problems, specific to cystic fibrosis, such as sterility in males; and (7) encouragement of interpatient communication.

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