Lung Inflammation as a Therapeutic Target in Cystic Fibrosis

Koehler, David R.; Downey, Gregory P.; Sweezey, Neil; Tanswell, A. Keith; Hu, Jim

doi:10.1165/rcmb.2004-0124tr

Cited by 98 publications

(84 citation statements)

References 60 publications

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“…CpG-DNA was detected in the absence of bacteria in tissues of patients with chronic inflammatory conditions, including cystic fibrosis (8) and unstable coronary angina (9). Such pathological conditions are also characterized by increased nitrotyrosine formation (10 -12), widespread PMN activation (13), and persisting PMN trafficking into inflamed tissues (14). The elevation in nitrotyrosine may reflect local formation of reactive nitrogen species, in particular peroxynitrite (ONOO Ϫ ) (15).…”

mentioning

confidence: 99%

Activation of TLR-9 Induces IL-8 Secretion through Peroxynitrite Signaling in Human Neutrophils

József

Khreiss

Kebir

et al. 2006

The Journal of Immunology

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Bacterial DNA containing unmethylated CpG motifs is emerging as an important regulator of functions of human neutrophil granulocytes (polymorphonuclear leukocytes (PMN)). These motifs are recognized by TLR-9. Recent studies indicate that peroxynitrite (ONOO−) may function as an intracellular signal for the production of IL-8, one of the key regulators of leukocyte trafficking in inflammation. In this study we investigated whether bacterial DNA (CpG-DNA) could induce ONOO− signaling in human PMN. Human whole blood, isolated PMN (purity, >95%), and high purity (>99%) PMN respond to CpG-DNA, but not to calf thymus DNA, with secretion of IL-8 and, to a lesser extent, IL-6 and TNF. Methylation of cytosines in CpG-DNA resulted in a complete loss of activity. The endosomal acidification inhibitors, bafilomycin A and chloroquine, inhibited CpG-DNA-induced cytokine release from PMN. CpG-DNA-induced IL-8 mRNA expression and release was also blocked by the NO synthase inhibitor Nω-nitro-l-arginine methyl ester. CpG-DNA evoked concomitant increases in intracellular superoxide and NO levels, leading to enhanced ONOO− formation and, consequently, nuclear accumulation of c-Fos and NF-κB. Pharmacological inhibition of NF-κB activation attenuated ∼75% of CpG-DNA-evoked IL-8 release. These results identify ONOO−-dependent activation of NF-κB and c-Fos as an important mechanism that mediates PMN responses, including IL-8 gene expression and release, to bacterial DNA and unmethylated CpG motifs in particular. Enhanced ONOO− formation represents a mechanism by which bacterial DNA may contribute to prolongation and amplification of the inflammatory response.

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mentioning

confidence: 99%

Activation of TLR-9 Induces IL-8 Secretion through Peroxynitrite Signaling in Human Neutrophils

József

Khreiss

Kebir

et al. 2006

The Journal of Immunology

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“…CF is an autosomal recessive monogenic disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which codes for an epithelial chloride channel. 1 The major cause of morbidity and mortality in CF patients is lung disease, and hence the most important aim of CF gene therapy is to treat the respiratory system. By far, CF gene therapy has garnered most research due to the feasibility of theoretically correcting the disease by providing a single copy of the CFTR gene to airway epithelial cells.…”

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confidence: 99%

Nacystelyn enhances adenoviral vector-mediated gene delivery to mouse airways

2007

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Adenoviral vector-mediated gene delivery has been vastly investigated for cystic fibrosis (CF) gene therapy; however, one of its drawbacks is the low efficiency of gene transfer, which is due to basolateral colocalization of viral receptors, immune responses to viral vectors and the presence of a thick mucus layer in the airways of CF patients. Therefore, enhancement of gene transfer can lead to reduction in the viral dosage, which could further reduce the acute toxicity associated with the use of adenoviral vectors. Nacystelyn (NAL) is a mucolytic agent with anti-inflammatory and antioxidant properties, and has been used clinically in CF patients to reduce mucus viscosity in the airways. In this study, we show that pretreatment of the airways with NAL followed by administration of adenoviral vectors in complex with DEAE-Dextran can significantly enhance gene delivery to the airways of mice without any harmful effects. Moreover, NAL pretreatment can reduce the airway inflammation, which is normally observed after delivery of adenoviral particles. Taken together, these results indicate that NAL pretreatment followed by adenoviral vector-mediated gene delivery can be beneficial to CF patients by increasing the efficiency of gene transfer to the airways, and reducing the acute toxicity associated with the administration of adenoviral vectors.

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“…In the treatment of chronic lung inflammation of CF patients, corticosteroids and NSAIDs have garnered the most attention, to date. Although traditional treatments with corticosteroids and ibuprofen have demonstrated potential benefits in CF patients, their use is limited by severe adverse effects, as for high doses of prednisone, or by a narrow pharmacological window, as www.intechopen.com in the case of ibuprofen (Birke, 2001;Koehler, 2004;Konstan, 2005). The endobronchial location makes CF pulmonary inflammation potentially amenable to inhaled therapies, thus achieving much higher concentrations in the airway epithelium and limiting the adverse effects of long term systemic use.…”

Section: Cf Bronchial Cells Seem To Be Resistant To the Treatment Witmentioning

confidence: 99%

Pharmacological Modulators of Sphingolipid Metabolism for the Treatment of Cystic Fibrosis Lung Inflammation

Dechecchi¹,

Nicolis²,

Mazzi³

et al. 2012

Cystic Fibrosis - Renewed Hopes Through Research

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Lung Inflammation as a Therapeutic Target in Cystic Fibrosis

Cited by 98 publications

References 60 publications

Activation of TLR-9 Induces IL-8 Secretion through Peroxynitrite Signaling in Human Neutrophils

Activation of TLR-9 Induces IL-8 Secretion through Peroxynitrite Signaling in Human Neutrophils

Nacystelyn enhances adenoviral vector-mediated gene delivery to mouse airways

Pharmacological Modulators of Sphingolipid Metabolism for the Treatment of Cystic Fibrosis Lung Inflammation

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