Crohn's disease (CD) patients have an abnormal increase in intestinal epithelial permeability. The defect in intestinal tight junction (TJ) barrier has been proposed as an important etiologic factor of CD. TNF-alpha increases intestinal TJ permeability. Because TNF-alpha levels are markedly increased in CD, TNF-alpha increase in intestinal TJ permeability could be a contributing factor of intestinal permeability defect in CD. Our purpose was to determine some of the intracellular mechanisms involved in TNF-alpha modulation of intestinal epithelial TJ permeability by using an in vitro intestinal epithelial system consisting of filter-grown Caco-2 monolayers. TNF-alpha produced a concentration- and time-dependent increase in Caco-2 TJ permeability. TNF-alpha-induced increase in Caco-2 TJ permeability correlated with Caco-2 NF-kappa B activation. Inhibition of TNF-alpha-induced NF-kappa B activation by selected NF-kappa B inhibitors, curcumin and triptolide, prevented the increase in Caco-2 TJ permeability, indicating that NF-kappa B activation was required for the TNF-alpha-induced increase in Caco-2 TJ permeability. This increase in Caco-2 TJ permeability was accompanied by down-regulation of zonula occludens (ZO)-1 proteins and alteration in junctional localization of ZO-1 proteins. TNF-alpha modulation of ZO-1 protein expression and junctional localization were also prevented by NF-kappa B inhibitors. TNF-alpha did not induce apoptosis in Caco-2 cells, suggesting that apoptosis was not the mechanism involved in TNF-alpha-induced increase in Caco-2 TJ permeability. These results demonstrate for the first time that TNF-alpha-induced increase in Caco-2 TJ permeability was mediated by NF-kappa B activation. The increase in permeability was associated with NF-kappa B-dependent downregulation of ZO-1 protein expression and alteration in junctional localization.
Presumptive diagnosis may be made by a review of the peripheral blood smear after the onset of the cardiopulmonary phase. Critical care management includes the avoidance of fluid overload, pressors to maintain cardiac output, and the use of extracorporeal membrane oxygenation in the most severe cases, but treatment with intravenous ribavirin is probably not effective.
The immediate early (IE) genes
The fraction of exhaled nitric oxide (FeNO) is elevated in asthmatics compared to normal subjects. Many studies have demonstrated that FeNO correlates with other markers of airway inflammation. The purpose of this study was to assess the clinical utility of routine monitoring of FeNO in determining its ability to predict future asthma exacerbations compared with other standard clinical measures of spirometry, peak flows, quality of life score, medication usage, and symptoms. A convenience sample of 22 patients with moderate and severe-persistent asthma in the University of New Mexico Adult Asthma Clinic were evaluated during a routine clinic visit and then noted whether they had an exacerbation within 2 weeks of the initial appointment. Those with an exacerbation had a higher mean FeNO (29.67 ppb +/- 14.48) compared to those who did not (12.92 ppb +/- 5.17), p = 0.002. A nominal logistic regression model to determine those variables that predict asthma exacerbation found that FeNO was the only significant predictor, p = 0.03. Thus, FeNO appears to be a clinically useful tool to assess disease control in this population.
To determine whether alveolar macrophages from smokers have an abnormal interleukin 1 beta (IL-1) release, we obtained macrophages by bronchoalveolar lavage (BAL) of otherwise healthy volunteers in three groups: nonsmokers (NS; n = 11), light smokers (LS, less than 10 pack-yr smoking history; n = 4) and heavy smokers (HS, greater than 10 pack-yr smoking history; n = 9). After 24 h in culture, unstimulated macrophages (from each group) released negligible amounts of IL-1. Lipopolysaccharide (LPS) (1 micrograms/ml) caused release of 21.77 +/- 4.33 ng IL-1/10(6) cells at 24 h from NS macrophages; IL-1 release from HS macrophages was significantly decreased (5.52 +/- 1.66 ng/10(6) cells; P less than 0.05), whereas LS macrophages released intermediate amounts (15.07 +/- 6.15 ng/10(6) cells). Release of IL-1 from HS macrophages was also decreased after 48 and 72 h in culture and was observed over a wide range of concentrations of LPS. The decreased amount of IL-1 in HS macrophage supernatants appeared to be due to a defect in release of IL-1 from the cells and not due to a defect in production of the mediator, since total IL-1 (IL-1 present in the cell lysates plus that in the cell supernatants) was similar in the NS and HS groups. In addition, after 24 h in culture, LPS-stimulated HS macrophages released significantly less prostaglandin E2 (PGE2) (which can suppress IL-1 production) than did NS macrophages; in the presence of indomethacin, which abolished macrophage PGE2 release, no augmentation of LPS-stimulated IL-1 release was observed. Cell viability, as measured by lactate dehydrogenase release, was not different between HS and NS macrophages under any conditions. We conclude that there is a defect in release but not production of IL-1 from the alveolar macrophages of chronic smokers.
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