The pathological hallmark of cystic fibrosis (CF) chronic inflammatory response is the massive neutrophil influx into the airways. This dysregulated neutrophil emigration may be caused by the abnormal secretion of chemoattractants by respiratory epithelial cells and polarised lymphocyte T-helper response. Neutrophils from CF patients have a different response to inflammatory mediators than neutrophils from normal subjects, indicating that they are primed in vivo before entering the CF airways. CF neutrophils secrete more myeloperoxidase and elastase, mobilise less opsonin receptors and release less L-selectin than non-CF neutrophils. Moreover, they show altered cytokine production and a dysregulated chemotaxis response. Laboratory studies now suggest that CFTR is involved in regulating some neutrophil functions and indicate that altered properties of CF neutrophils may depend on genetic factors. Current gene therapy approaches are targeted to the respiratory epithelium, but many hurdles oppose an efficient and efficacious CFTR gene transfer. The possibility of CFTR gene therapy-based approach targeting CF neutrophils at the hematopoietic stem cell level is discussed.
Both trans- and cis-[PtCl(2)(NH(3))(L)] compounds have been synthesized, L representing either the imino ether HN=C(OMe)Me having a Z or E configuration at the C=N double bond, or the cyclic ligands N = C(OMe)CH2CH2CH2 and N = C(Me)OCH2CH2 (compounds 1-4 for trans geometry and 5-8 for cis geometry, respectively). The cyclic ligands mimic the imino ether ligands but, differently from imino ethers, cannot undergo change of configuration. In a panel of human tumor cells, trans compounds inhibit growth much more than transplatin. Moreover, compound 1 in most cases is less active than 2, and 1 and 2 are less active than 3 and 4, respectively. For cis compounds with imino ethers, the activity is reduced (5) or unaffected (6) with respect to cisplatin. Moreover, unlike trans compounds, substitution of cyclic ligands (7,8) for imino ethers (5,6) generally decreases the activity. This determines, for compounds with cyclic ligands, an unusual inversion of the cis geometry requirement for activity of platinum(II) species. Importantly,1-4 and 5-8 partially circumvent the multifocal cisplatin resistance of A2780cisR cells, and 1-4 also overcome resistance from reduced uptake of 41McisR cells. DNA interaction regioselectivity of 1-4 and 5-8 is not substantially modified with respect to transplatin and cisplatin. However, both imino ethers and cyclic ligands slow down the DNA interstrand cross-link reaction, ( E)-HN=C(OMe)Me and N = C(Me)OCH2CH2 decreasing also its extent. Therefore, DNA interaction of 1-4 and 5-8 appears to be characterized by persistent monoadducts (1-4), and by monoadducts and/or intrastrand cross-links structurally different from those of cisplatin (5-8). This study demonstrates that ligand configuration modulates the activity of both trans and cis compounds, and supports the development of platinum drugs based on their coordination chemistry to combat cisplatin resistance.
Hydrogen sulfide is a toxic metabolite released by several bacterial agents under anaerobic conditions. In the present paper, we investigated the effects of sulfide on polymorphonuclear cell (PMN) apoptosis, a mechanism suggested for limiting the toxic potential of neutrophils in inflammatory sites. We showed that 1 mM sulfide (concentration not conditioning PMN viability) is able to enhance the apoptotic fate of human granulocytes by increasing: i) the number of cells containing pyknotic nuclei, ii) the internucleosomal cleavage, and, iii) the intensity of tubulin immunofluorescence staining. The sulfide effect is partially prevented by ionomycin and this finding is consistent with the hypothesis of the inhibiting role played by high levels of cytosolic calcium in PMN apoptosis modulating.
Helicobacter pylori neutrophil-activating protein (HP-NAP) is a virulence factor that activates phagocytic NADPH-oxidase. The effect of HP-NAP on the production of tissue factor (TF), plasminogen activator inhibitor-2 (PAI-2), and urokinase-type plasminogen activator (u-PA) by human blood mononuclear cells (MNC) was evaluated by using functional and immunological assays and mRNA analysis. HP-NAP induced time- and dose-dependent increases in TF and PAI-2, with a maximal effect at 300 nmol/L (>15-fold increase in antigens). No changes in u-PA were observed. When whole bacteria were used, an H. pylori mutant lacking HP-NAP was significantly less active than the wild-type strain. MNC from a patient with chronic granulomatous disease behaved as do normal cells, which indicates that HP-NAP effects can occur independently of NADPH-oxidase. HP-NAP, by inducing the coordinate expression of cell procoagulant and antifibrinolytic activities, might favor fibrin deposition and contribute to the inflammatory reaction of gastric mucosa elicited by H. pylori.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.