Clinical Immunology, Endocrine & Metabolic Drugs (Discontinued) - Volume 3, Issue 2, 2016

Cystic fibrosis pulmonary disease is caused by dysfunctional electrolytes transport that severely impacts the lung environment. Abnormal chloride and carbonate transport by the CFTR favours recurrent bacterial infections which in turn stimulate an immune response that, while inadequate to eradicate infection, contributes to lung failure. Many different cell types are affected by dysfunctional CFTR including epithelial cells and macrophages; the latter being involved in the elimination of foreign particles and microbes and orchestration of the inflammatory response. Sputa and BAL of CF patients are characterized by large amount of proinflammatory mediators, ROS and proteases that contribute to lung failure. Macrophages express CFTR and show functional deficiencies at different levels. First, defective intracellular bacteria killing has been reported in the murine model and in humans; disproportional inflammatory response resulting in high level of cytokine production and defective removal of cellular debris has been documented as well. Microbicidal deficiency against CF pathogens such as Burkholderia cenocepacia or Pseudomonas aeruginosa was ascribed to defective autophagy and phagolysosome pH, respectively. Looking at the causes of inflammation, a hyper responsiveness to LPS has been ascribed to defective AKT/miR-199a-5p/CAV1 pathway governing the feedback loop that shuts down TLR4 signalling. Moreover, abnormal activation of the IRE1a/XBP-1 arm of the unfolded protein response was shown to contribute to inflammation. Overall it appears that bacteria clearance and hyperinflammation may be improved by targeting CF macrophage deficiencies.

Cystic fibrosis (CF) lung disease is nowadays appreciated as a complex trait, characterised by dysfunction of the CF Transmembrane Conductor (CFTR) protein, opportunistic bacterial infections, chronic inflammation and remodelling of the airways. In this review, we have analysed the usefulness of biomarkers of inflammation and remodelling for their ability in predicting and assessing the onset of a pulmonary exacerbation, its evolution with time and its response to therapeutic interventions. Studies concerning sputum, bronchoalveolar lavage fluid, exhaled breath condensate and blood were considered. Our conclusions are: I) although their validity has been proven across different clinical settings, presently there is no biomarker which can be “promoted” to the status of surrogate end-point; II) longitudinal studies at different ages will be needed for assessing this issue; and III) different therapies should consider not only one biomarker but a constellation of them aiding in the evaluation of the complex pathogenesis of CF lung disease.

Cystic fibrosis (CF) is a complex genetic chloride channelopathy, manifesting clinically as a multisystem disorder. Patients with CF have significant morbidity and decreased life expectancy, primarily due to respiratory disease, which is characterised by frequent pulmonary exacerbations and decline in lung function. The pathogenesis of pulmonary disease in CF is explained in part by dehydration of airway surface liquid with reduced mucociliary clearance leading to accumulation of thick inspissated mucus in the airways. This results in airway obstruction, and provides a suitable environment for pathogens to grow and colonize, giving rise to a cycle of recurrent airway inflammation in the CF lung. Multiple therapeutic interventions in CF care are aimed at improving mucus clearance. These include improved chest physiotherapy techniques, recombinant DNase, and more recently nebulised hypertonic saline (HTS). Treatment with HTS has been shown to improve mucus clearance in CF and decrease exacerbations, with subsequent improvements in quality of life, and lung function. While the mechanisms by which HTS elicits these improvements are likely related to increase in mucociliary clearance, there is increasing evidence to suggest that HTS also exerts significant anti-inflammatory and anti-microbial effects in the CF lung. This review will describe these effects of HTS looking at the interaction between HTS and neutrophils, the major inflammatory cell in the CF lung, and the effects of HTS on the antimicrobial peptides found in the airways.

Abnormal functioning of the Cystic Fibrosis (CF) Transmembrane Conductance Regulator (CFTR) channel impairs mucociliary clearance and promotes chronic bacterial infections in the lung of CF patients. Progressive lung destruction leads to lung failure, the main cause of premature death in CF patients. However, impaired CFTR functioning affects also the pancreas and the liver with well recognized gastrointestinal manifestations that often develop early in life and contribute to the clinical deterioration. Novel therapies are under evaluation in the context of the extensive research on CF liver and gastrointestinal pathophysiology. In this review, pathological mechanisms and clinical manifestations of liver disease and pancreatic insufficiency are described with attention to future therapeutic development.

The research on the biological activity of natural products and biomaterials is becoming year by year more competitive and complex, and involves experts in different research fields, including chemists, biochemists, molecular biologists, immunologists and bioinformatics. While unfractionated natural products exhibit “per se” biological properties relevant for alternative therapeutic treatments of human diseases, the identification of lead compounds within these products, the characterization of molecular targets and studies of structurally-related molecules are key processes to develop novel therapeutic strategies. Cystic fibrosis is a genetic disease caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. It is well established that three major fields of therapeutic intervention should be considered, targeting CFTR, bacterial infection and inflammation. In this review, we describe natural products reported to be very useful tools for correction of pathological conditions related to cystic fibrosis. The main topics are (a) CFTR potentiation and correction using natural products, (b) natural products as antibacterial agents and (c) natural products exhibiting anti-inflammatory activity. The recent issues of waste utilization and drug repurposing are also discussed in the context of the development of possible therapeutic approaches for cystic fibrosis.

Cystic fibrosis (CF) is a multiorgan genetic disease caused by defective function of CFTR, a plasma membrane chloride channel particularly expressed in epithelial cells. CF mutations have been grouped in six classes according to the mechanism through which they affect CFTR function: premature translation termination, impaired folding and stability, altered channel gating, reduced single channel conductance, aberrant RNA splicing, reduced persistence on cell surface. Each type of CFTR defect can be targeted by specific small molecules (correctors, potentiators, or readthrough agents) in order to restore CFTR function. Novel in vitro assays, based on intestinal organoids or nasal epithelial cells, can be used to identify the most appropriate treatment for each genotype. This approach paves the way for the development of personalized treatments for CF patients.

Cystic fibrosis (CF) is a lethal congenital disease for which no efficient treatment exists currently. CF is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). After cloning of the CFTR gene, huge clinical interest has emerged in the transfer of the wild-type CFTR gene directly to the airways for the treatment of pulmonary disease. For this purpose a considerable number of viral and plasmid containing non-viral vectors have been developed, many clinical studies proved the concept of correcting the underlying chloride transport defect in CF patients. However, severe immune responses and low-efficient gene transfection hampered both approaches to be translated into routine clinical practices. The transfer of in vitro transcribed (IVT) mRNA for specific transgene expression could be used as an alternative approach once the challenges associated with IVT mRNA delivery were resolved. Apart from a brief overview of the development of gene therapy for CF in previous decades, the application of IVT mRNA as a potential novel therapy for CF treatment as well as their topical administration into the airways are discussed in this review.

Cystic fibrosis (CF) is an autosomal recessive inherited disorder that affects ~80,000 individuals worldwide. Mutations in the CF transmembrane conductance regulator gene (CFTR) cause dysfunction of the CFTR protein, a cAMP- and PKA-activated chloride channel. Decades of research and development have made great progress in molecular understanding and clinical care of this disease, which has dramatically extended the patient median life expectancy to over 40 years. However, this devastating disease remains incurable, with lung pathology the most common cause of morbidity and mortality. Stem cells maintain the capacity of self-renewal and induced differentiation, thus holding promise for CF therapy. While early studies generated the excitement of lung engraftment and regeneration by different origins of stem cells, several encountered obstacles impede viable development of this strategy into a feasible therapy. This review article will provide an update of the research and discuss the major challenges facing the field. Moreover, new emerging technologies, such as CRISPR/Cas9 genomic editing, make possible the precise correction of the CFTR defect in situ. Potential impacts of these advancements on future prospects of CF stem cell therapy will be highlighted.