The respiratory manifestations of cystic fibrosis (CF) are characterized by neutrophil-dominated airway inflammation. Since a variety of inflammatory stimuli are capable of inducing bronchial epithelial cells to express the gene for IL-8, a cytokine that attracts and activates neutrophils, mediators in respiratory epithelial lining fluid
Although circulating tumor necrosis factor (TNF)-alpha levels have been found to be increased in weight-losing patients with chronic obstructive pulmonary disease (COPD), the main causes for this phenomenon remain to be elucidated. Since hypoxia itself can enhance the production of the TNF-alpha in vitro, we studied the relationship between hypoxemia and activities of the TNF-alpha system, including circulating TNF-alpha and soluble TNF-receptors (sTNF-R; sTNF-R55 and -R75) levels, in 27 COPD patients and 15 age-matched healthy controls. The COPD patients showed a significant weight loss (body mass index = 18.1 +/- 2.8 versus 22.8 +/- 2.2 [mean +/- SD] kg/m(2); p < 0.0001. % fat = 16.3 +/- 5.9 versus 24.3 +/- 4.9 %; p < 0.001), and hypoxemia (Pa(O2 )= 62.2 +/- 9.5 versus 88.6 +/- 5.9 mm Hg; p < 0.0001) as compared with the healthy controls. Serum TNF-alpha (6.15 +/- 1.08 versus 5.41 +/- 1.60 pg/ml; p < 0.05) and plasma sTNF-R55 (1.15 +/- 0.49 versus 0.67 +/- 0.13 ng/ml; p < 0.0001) and sTNF-R75 (3.54 +/- 1.16 versus 2.25 +/- 0.43; p < 0.0001) levels were significantly higher in the COPD patients than in the healthy controls. There were inverse correlations between Pa(O(2)) and circulating TNF-alpha and sTNF-R levels in patients with COPD (TNF-alpha; r = -0.426, p = 0.0297; sTNF-R55: r = -0.587, p = 0.0027; sTNF-R75: r = -0.573, p = 0.0035). In addition, we found inverse correlations between sTNF-R levels and % fat in COPD patients (sTNF-R55: r = -0.442, p = 0.0272; sTNF-R75: r = -0. 484, p = 0.0155). TNF-alpha levels correlated well with sTNF-R levels (sTNF-R55: r = 0.488, p = 0.0127; sTNF-R75: r = 0.609, p = 0. 0019). These relationships were not observed in the healthy controls. These data suggest that systemic hypoxemia noted in patients with COPD is associated with activation of the TNF-alpha system in vivo, which may be a factor contributing to the weight loss in patients with the disease.
Based on the knowledge that neutrophil elastase (NE) in cystic fibrosis (CF) epithelial lining fluid (ELF) can induce human bronchial epithelial cells to express the gene for interleukin 8 (IL-8), an 8.5-kD neutrophil chemoattractant, we have evaluated CF ELF for the presence of IL-8, and investigated the ability of aerosolized recombinant secretory leukoprotease inhibitor (rSLPI) to suppress NE, and hence IL-8, levels on the respiratory epithelial surface in CF. Enzyme-linked immunoassay revealed 21.9±4.8 nM IL-8 in CF ELF compared with none in normals. Active NE was detectable in ELF of all individuals with CF and was significantly decreased (P < 0.03) after aerosolization of rSLPI. Human bronchial epithelial cells exposed to CF ELF recovered before rSLPI therapy expressed IL-8 mRNA transcripts, but ELF recovered after rSLPI therapy induced far less bronchial epithelial cell IL-8 gene expression. Consistent with this, rSLPI aerosol therapy caused a marked reduction in CF ELF IL-8 levels (P < 0.05) and neutrophil number (P < 0.02). There was also a clear association between CF ELF active NE and IL-8 levels (r = 0.94). These data suggest that rSLPI therapy not only suppresses respiratory epithelial NE levels, but also breaks a cycle of inflammation on the CF epithelial surface. (J. Clin. Invest. 1992. 90:1296-1301.) Key words: aerosol therapy * antiprotease * cytokinev neutrophil chemoattractant * neutrophil elastase
Consistent with the fact that the clinical disorder cystic fibrosis (CF) is manifested on epithelial surfaces, active transcription of the CF transmembrane conductance regulator (CFTR) gene and CFTR mRNA transcripts are detectable in a variety of epithelial cells, suggesting CFTR gene expression might be epithelial cell-specific. However, analysis of the CFTR gene promoter suggests it is a housekeeping gene, implying more widespread expression than only in epithelial cells. To evaluate the latter hypothesis, various human cells of non-epithelial origin, including lung fibroblasts, U-937 histiocytic lymphoma cells, K-562 erythroleukemia cells, HL-60 promyelocytic leukemia cells as well as freshly isolated blood lymphocytes, neutrophils, monocytes, and alveolar macrophages were examined for CFTR gene expression. Although Northern analysis failed to show CFTR mRNA transcripts in these cells, amplification of mRNA (after conversion to cDNA) by polymerase chain reaction combined with Southern analysis demonstrated the presence of CFTR mRNA transcripts at low levels in all cells evaluated except HL-60 cells. Comparative quantitative analysis showed fibroblasts contained 200-400 fold less CFTR mRNA transcripts than the T84 and HT-29 colon carcinoma epithelial cell lines, but had similar levels of CFTR transcripts to those of other epithelial cell lines. Nuclear transcription run-on analyses demonstrated very low level CFTR gene transcription in fibroblasts and U-937 cells, similar to that of other epithelial cells, but lower than the T84 and HT-29 colon carcinoma cell lines. Interestingly, while chromatin DNA of fibroblasts had no DNase I hypersensitivity sites in the 5' flanking region of the CFTR gene, HT-29 chromatin DNA exhibited four DNase I accessible sites in the same region, suggesting that these sites may be related to more active transcription of the CFTR gene in the intestinal epithelial cells than in fibroblasts.
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