Cystic fibrosis: ultrastructural changes of nasal mucosa.

Cystic fibrosis (CF) is an inherited multisystemic disorder that results in a generalized dysfunction of exocrine glands. Besides chronic obstructive pulmonary diseases, chronic sinusitis, nasal polyposis and hypertrophy of the inferior turbinates with nasal airway obstruction are typical signs. Tissue samples of the inferior turbinates and nasal polyps were taken during nasal surgery from 21 children, ranging from 3 to 16 years of age. Light- and electron microscopical examination were carried out. Furthermore, specimens of nasal mucosa of patients without chronic inflammation as controls and specimens of duodenal mucosa of patients with CF were investigated. Under a thick layer of respiratory epithelium with a high proportion of goblet cells, the seromucous glands display abnormal morphological structures with wide mucous cells and cystic dilatation. The glandular cells show inhomogeneous glandular droplets in the supranuclear cell portion. The nucleus contains dispersed chromatin as a sign of increased activity and the structures of the Golgi apparatus are clearly detectable. Apart from investigations concerning nasal polyps in CF, studies on the different morphological changes of nasal mucosa at the electron microscopic level are rare. This histological study focuses on various morphological changes of nasal glands at the ultrastructural level in correlation with typical symptoms in CF. In addition, a comparison with electron microscopic findings of CF-enteropathies is proposed. These findings could help to bring information concerning new morphological aspects in the pathophysiology of patients with CF.

Basal-like cells constitute the proliferating cell population in cystic fibrosis airways.

RATIONALE: Cystic fibrosis airways are recurrently exposed to noxious stimuli, leading to epithelial injury. Previous reports suggest that cystic fibrosis airway epithelia may respond to injury by increasing proliferation. OBJECTIVES: We sought to determine the characteristics of the proliferating cell population in cystic fibrosis airways. METHODS: Six cystic fibrosis and six normal lung sections from lung transplant recipients or lung surgery were obtained from the Duke Hospital pathology archives. Sections containing bronchi were evaluated for epithelial cell proliferation using immunohistochemistry for a nuclear proliferation antigen, Ki-67, and image analysis; immunohistochemistry for basal cells using a cytokeratin 5/14 antibody; and immunohistochemistry for the epidermal growth factor receptor and ErbB2, two receptor tyrosine kinases implicated in epithelial proliferation and differentiation. RESULTS: Overall, cystic fibrosis sections had a greater proliferation index than control sections with 25.1 +/- 2.1% positively staining nuclei/total nuclei compared with control sections, 4.6 +/- 0.9% (p = 0.002). In cystic fibrosis sections only, there were areas of hyperplastic cuboidal cells adjacent to normal pseudostratified columnar epithelial sections; in these areas of epithelial hyperplasia, there was uniform Ki-67 staining, indicating a zone of proliferating cells. The proliferating cell population also expressed the basal cell cytokeratins 5/14 and epidermal growth factor receptor. Expression of ErbB2 was diminished in the proliferating cells. CONCLUSIONS: Our results suggest that basal-like cells, expressing the epidermal growth factor receptor, constitute the proliferating cell population in cystic fibrosis airways.

The ultrastructure of the nasal polyps in patients with and without cystic fibrosis.

Nasal polyps are commonly associated with cystic fibrosis (CF) and also with idiopathic allergies, asthma, and aspirin intolerance. The pathogenesis of nasal polyp formation is controversial. The present study investigates the ultrastructure of thirteen nasal polyps surgically removed from seven CF patients and six non-CF (NCF) patients with allergic diseases, asthma, and aspirin intolerance. All nasal polyps showed focal edema, hyperplasia, atrophy, or squamous metaplasia of the epithelium. The lamina propria was moderately populated with small blood vessels and mucous glands and showed focal accumulation of inflammatory cells. The CF nasal polyps, however, revealed several specific characteristics: 1) minimal damage to the surface epithelium, 2) presence of a mucus blanket lining the apical epithelium, 3) occasional intracytoplasmic lumens, 4) continuous and fenestrated type capillaries, 5) numerous degranulated mast cells, 6) many plasma cells, often with atypical morphology and intracisternal Russell bodies, and 7) a smaller number of eosinophils as compared to the NCF nasal polyps. The results indicate significant differences between CF and NCF nasal polyps and support the multifactorial pathways theory of nasal polyp formation.

Bacterial overgrowth in the cystic fibrosis transmembrane conductance regulator null mouse small intestine.

We recently reported the inflammation of the cystic fibrosis (CF) mouse small intestine, and we hypothesized bacterial overgrowth as a possible cause. Quantitative PCR of bacterial 16S genomic DNA in the CF mouse small intestine revealed an increase of greater than 40-fold compared to controls. Sequencing of 16S PCR products and Gram staining showed that the majority of bacteria in the CF mouse intestine were gram negative. Bacteria were observed to colonize the mucus that accumulates in the intestinal lumen of mice with CF. Impaired Paneth cell defenses were suggested by observation of partially dispersed Paneth granules in the mucus plugs of CF mouse intestinal crypts, and this mucus was strongly immunoreactive for Paneth cell bactericidal products. The role of bacterial overgrowth in intestinal inflammation in CF was tested by treating mice with oral antibiotics (ciprofloxacin and metronidazole) for 3 weeks, which reduced bacterial load in the CF mouse small intestine over 400-fold. Antibiotic treatment decreased the expression of the inflammation-related genes mast cell protease 2, leucine-rich alpha2 glycoprotein/leucine-rich high endothelial venule glycoprotein, suppressor of cytokine signaling 3, hematopoietic cell transcript 1, and resistin-like molecule beta/found in inflammatory zone 2, all of which were no longer expressed at levels significantly different from control levels. The reduction of intestinal bacteria also significantly improved the growth of CF mice but had no effect on the growth of wild-type mice. These data suggest that bacterial overgrowth in the CF mouse small intestine has a role in inflammation and contributes to the failure to thrive in this mouse model of CF.