[Lung transplantation in cystic fibrosis--a position paper]. / Lungentransplantation bei Mukoviszidose--ein Positionspapier.

Lung transplantation in cystic fibrosis is an established therapy, due to the fact that vast majority of adult CF patients will develop respiratory failure. Even adolescents and children can be transplanted successfully today. Lung transplantation in cystic fibrosis requires special consideration concerning candidate selection, surgery and postoperative follow-up care. Due to a donor shortage and increasing waiting time, early referral to transplant centres of potential candidates is crucial. In the process of candidate selection, assumed improvements in quality of life and survival benefit should be weighed against contraindications. Centre-based follow-up and close cooperation with local physicians are key factors for success. During follow-up care, the transplantation team should be contacted immediately in the case of any problem or change in medication.

Reactive oxygen intermediates are involved in IL-8 production induced by hyperosmotic stress in human bronchial epithelial cells.

Changes in the osmolarity of the airway surface fluid have been described to be involved in the pathogenesis of exercise induced asthma, and are suggested as the major cause of the lung disease in cystic fibrosis. In this study, we examined the signaling pathway of hyperosmotic challenge to interleukin-8 (IL-8). Hyperosmolarity (NaCl) caused a time- and concentration-dependent increase in IL-8 expression and secretion in bronchial epithelial cells. These effects could be blocked by antioxidants, such as DMSO, DMTU, DTT, and beta-mercaptoethanol, suggesting an involvement of reactive oxygen intermediates (ROI) in the signal transduction of hyperosmolarity-induced IL-8 synthesis. Since IL-8 is regulated by MAP kinases, we examined the influence of MAP kinase inhibitors on hyperosmolarity-induced IL-8 expression. The results show that this induction is regulated by p38 MAPK and not by ERK1/2. Furthermore, antioxidants blocked the activation of p38 MAPK induced by hyperosmolarity. These results suggest that ROIs are critical for p38 MAPK mediated IL-8 expression by hyperosmolarity.

Colonization with superantigen-producing Staphylococcus aureus is associated with increased severity of atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with colonization of the skin with Staphylococcus aureus known to produce toxins with superantigen (SAg) activity. Besides T-cell activation these toxins induce T-cell skin homing in vitro. This may contribute to the observed induction or enhancement of skin inflammation. OBJECTIVE: The aim of this study was to determine whether colonization with SAg-producing S. aureus isolates modulates the intensity of AD. If so, it was of interest whether this may be primarily due to the toxins' effects as SAgs or as allergens. METHODS: In AD patients, healthy controls, and atopic controls SAg production by S. aureus isolated from skin or mucous membranes was investigated and correlated to the severity of the disease. Total IgE, SAg-specific IgE, and T-cell activation and recirculation markers were analysed and correlated with SAg production. RESULTS: Fifty-seven percent of S. aureus strains isolated from AD patients produced SAgs. This frequency was higher compared to healthy controls (33%). SAg production by S. aureus was correlated with a significantly higher scoring of AD (SCORAD index, 58 +/- 19 in SAg-producing vs 41 +/- 7 in non-SAg-producing germs; P < 0.05). However, the severity of the disease was not associated with sensitization against the SAgs staphylococcal enterotoxin A (SEA) and staphylococcal enterotoxin B (SEB). Furthermore, SAg production by S. aureus was inversely correlated with total IgE concentration (P < 0.05) and positively correlated with T-cell activation (as measured by HLA-DR and CD69 expression) and the expression of the T-cell skin homing phenotype cutaneous lymphocyte-associated antigen. CONCLUSION: SAg production by S. aureus is suggested to be associated with an increased severity of atopic dermatitis. Since SAg production was found neither exclusively in AD patients nor in all patients, other pathogenic factors may be additionally effective.

Modulation of cystic fibrosis transmembrane conductance regulator gene - expression by elevation of intracellular cyclic AMP.

Cystic fibrosis (CF) is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Its product is a cyclic AMP-dependent Cl- channel, that is defective in CF. Since cAMP regulates the expression of many genes and since the 5'-flanking region of the CFTR gene contains cAMP response elements, we hypothesized that intracellular cAMP might modulate not only the cAMP-dependent Cl- channel CFTR, but also CFTR gene expression in epithelial cells. To accomplish this, we investigated Cl- secretion and CFTR-mRNA levels in HT-29 and T84 colon carcinoma epithelial cells before and after exposure to forskolin and 8-bromo-cAMP for 12 hr. While resting T84 cells increased Cl- secretion in response to forskolin strongly and immediately, HT-29 cells did not, although both cell lines showed highly increased Cl- efflux in response to A23187, a calcium ionophore. Interestingly, prolonged exposure to forskolin (12 hr) induced a clear decrease of CFTR-mRNA levels in T84 cells, but an increase of CFTR-mRNA levels in HT-29 cells, thus demonstrating different behaviour of CFTR gene regulation in different epithelial cells in response to intracellular cAMP. These results suggest that cells with an effective cAMP-dependent Cl- channel (CFTR) respond to prolonged stimulation of this channel with down-regulation of CFTR gene expression, while cells with no effective cAMP-dependent Cl--secretion respond with an up-regulation of CFTR gene expression.

Effect of cytokines and lipopolysaccharides on HIV infection of human macrophages.

Human blood-borne monocytes (MO) differentiating into mature macrophages (MAC) were cultured on hydrophobic Teflon membranes. The cells were infected with two different monocytotropic HIV isolates: HIV1D117III obtained from a perinatally infected child, and HIV2D194 obtained from an AIDS patient who suffered exclusively from neurological symptoms. Virus production monitored by reverse transcriptase activity and HIV-antigen ELISA in cell-free supernatant was of a high level and continued for several weeks. To investigate possible modulatory pathways interfering with HIV infection in MAC we tested various recombinant cytokines as well as bacterial lipopolysaccharides (LPS) in our culture system. Whereas interleukin-1 (IL1) accelerated and increased HIV replication in MO/MAC, the interferons (IFN) alpha, beta and gamma effectively suppressed or delayed infection depending on the concentration used. Suppression was seen at concentrations as low as 0.3 U/ml and was most effective when the IFN were given prior to infection. No effect was observed with IL6 up to 2,000 U/ml. LPS affected virus infection in a complex manner: at 1-100 ng/ml virus replication was inhibited, but it was enhanced at subnanogram concentrations (25-100 pg/ml).