Enhancing Cystic Fibrosis Immune Regulation.

In cystic fibrosis (CF), sustained infection and exuberant inflammation results in debilitating and often fatal lung disease. Advancement in CF therapeutics has provided successful treatment regimens for a variety of clinical consequences in CF; however effective means to treat the pulmonary infection and inflammation continues to be problematic. Even with the successful development of small molecule cystic fibrosis transmembrane conductance regulator (CFTR) correctors and potentiators, there is only a modest effect on established infection and inflammation in CF patients.

HE3286, an oral synthetic steroid, treats lung inflammation in mice without immune suppression.

Background: 17α-Ethynyl-5-androsten-3β, 7β, 17β-triol (HE3286) is a synthetic derivative of an endogenous steroid androstenetriol (β-AET), a metabolite of the abundant adrenal steroid deyhdroepiandrosterone (DHEA), with broad anti-inflammatory activities. We tested the ability of this novel synthetic steroid with improved pharmacological properties to limit non-productive lung inflammation in rodents and attempted to gauge its immunological impact.

Methods And Results: In mice, oral treatment with HE3286 (40 mg/kg) significantly (p < 0.

Monitoring infection and inflammation in murine models of cystic fibrosis with magnetic resonance imaging.

Purpose: To evaluate magnetic resonance imaging (MRI) in assessing lung inflammation longitudinally in genetic mouse models of cystic fibrosis (CF). MRI is used to view soft tissues noninvasively, but the lung is challenging to image.

Materials And Methods: Cftr(+/+) (wildtype) and Cftr(-/-) (CF) mice were inoculated with agarose beads laden with Pseudomonas aeruginosa.

Peroxisome proliferator-activated receptor-gamma in cystic fibrosis lung epithelium.

The pathophysiology of cystic fibrosis (CF) inflammatory lung disease is not well understood. CF airway epithelial cells respond to inflammatory stimuli with increased production of proinflammatory cytokines as a result of increased NF-kappaB activation. Peroxisome proliferator-activated receptor-gamma (PPARgamma) inhibits NF-kappaB activity and is reported to be reduced in CF.

Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis.

Microbial lung infections are the major cause of morbidity and mortality in the hereditary metabolic disorder cystic fibrosis, yet the molecular mechanisms leading from the mutation of cystic fibrosis transmembrane conductance regulator (CFTR) to lung infection are still unclear. Here, we show that ceramide age-dependently accumulates in the respiratory tract of uninfected Cftr-deficient mice owing to an alkalinization of intracellular vesicles in Cftr-deficient cells. This change in pH results in an imbalance between acid sphingomyelinase (Asm) cleavage of sphingomyelin to ceramide and acid ceramidase consumption of ceramide, resulting in the higher levels of ceramide.

SERCA pump inhibitors do not correct biosynthetic arrest of deltaF508 CFTR in cystic fibrosis.

Deletion of phenylalanine 508 (deltaF508) accounts for nearly 70% of all mutations that occur in the cystic fibrosis transmembrane conductance regulator (CFTR). The deltaF508 mutation is a class II processing mutation that results in very little or no mature CFTR protein reaching the apical membrane and thus no cAMP-mediated Cl- conductance. Therapeutic strategies have been developed to enhance processing of the defective deltaF508 CFTR molecule so that a functional cAMP-regulated Cl- channel targets to the apical membrane.

Response to acute lung infection with mucoid Pseudomonas aeruginosa in cystic fibrosis mice.

Rationale: Cystic fibrosis is caused by defects in the cystic fibrosis transmembrane conductance regulator gene, which codes for a chloride channel, but the role of this chloride channel in inflammation induced by lung infection with Pseudomonas aeruginosa remains to be defined.

Objectives: We tested the hypothesis that loss of this chloride channel alone is sufficient to cause excessive inflammation in response to inflammatory stimuli.

Methods: We investigated the response of cystic fibrosis and wild-type mice to mucoid P.

Tissue inhibitor of metalloproteinase 1 regulates resistance to infection.

Tissue inhibitor of metalloproteinase 1 (TIMP-1)-deficient mice are resistant to Pseudomonas aeruginosa corneal infections. Corneas healed completely in TIMP-1-deficient mice, and infections were cleared faster in TIMP-1-deficient mice than in wild-type littermates. Genetic suppression studies using matrix metalloproteinase (MMP)-deficient mice showed that MMP-9, MMP-3, and MMP-7 but not MMP-2 or MMP-12 are needed for resistance.

Role of Cftr genotype in the response to chronic Pseudomonas aeruginosa lung infection in mice.

Patients with cystic fibrosis have a lesion in the cystic fibrosis transmembrane conductance regulator gene (CFTR), which is associated with abnormal regulation of other ion channels, abnormal glycosylation of secreted and cell surface molecules, and vulnerability to bacterial infection and inflammation in the lung usually leading to the death of these patients. The exact mechanism(s) by which mutation in CFTR leads to lung infection and inflammation is not clear. Mice bearing different mutations in the murine homolog to CFTR (Cftr) (R117H, S489X, Y122X, and DeltaF508, all backcrossed to the C57BL/6J background) were compared with respect to growth and in their ability to respond to lung infection elicited with Pseudomonas aeruginosa-laden agarose beads.

Role for cystic fibrosis transmembrane conductance regulator protein in a glutathione response to bronchopulmonary pseudomonas infection.

The lung maintains an elevated level of glutathione (GSH) in epithelial lining fluid (ELF) compared to serum. The mechanism(s) by which the lung maintains high levels of ELF GSH and factors that modulate them are largely unexplored. We hypothesized that lung cystic fibrosis transmembrane conductance regulator protein (CFTR) modulates GSH efflux in response to extracellular stress, which occurs with lung infections.

Nutritional effects on host response to lung infections with mucoid Pseudomonas aeruginosa in mice.

In cystic fibrosis, a recessive genetic disease caused by defects in the cystic fibrosis conductance regulator (CFTR), the main cause of death is lung infection and inflammation. Nutritional deficits have been proposed to contribute to the excessive host inflammatory response in both humans and Cftr-knockout mice. Cftr-knockout mice and gut-corrected Cftr-knockout mice expressing human CFTR primarily in the gut were challenged with Pseudomonas aeruginosa-laden agarose beads; they responded similarly with respect to bronchoalveolar lavage cell counts and levels of the acute-phase cytokines tumor necrosis factor alpha, interleukin-1beta (IL-1beta), and IL-6.

Delivery of CFTR by adenoviral vector to cystic fibrosis mouse lung in a model of chronic Pseudomonas aeruginosa lung infection.

In cystic fibrosis (CF) there is an excessive inflammatory response to lung infections with Pseudomonas aeruginosa, which causes significant morbidity and mortality. Mice deficient in the cystic fibrosis conductance transmembrane regulator homolog (Cftr) have exaggerated production of proinflammatory cytokines in epithelial lining fluid and increased mortality in response to chronic bronchopulmonary infection with mucoid P. aeruginosa, compared with infected wild-type littermates.

Murine models of chronic Pseudomonas aeruginosa lung infection.

The animal model of chronic bronchopulmonary infection using agarose beads laden with Pseudomonas aeruginosa is frequently utilized in cystic fibrosis research, though it is challenging to perform it in mice. This paper reports the most successful methods for the creation of this model. Transtracheal insertion of a 22 G 1" over-the-needle intravenous catheter to preferentially inoculate the right mainstem bronchus using tribromoethanol anaesthesia administered i.