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Cystic Fibrosis
01 Apr 2006-
TL;DR: Advances in understanding and treatment of cystic fibrosis are summarized, focusing on pulmonary disease, which accounts for most morbidity and deaths.
Abstract: Cystic fibrosis is the most common autosomal recessive disorder in white people, with a frequency of about 1 in 2500 livebirths. Discovery of the mutated gene encoding a defective chloride channel in epithelial cells--named cystic fibrosis transmembrane conductance regulator (CFTR)--has improved our understanding of the disorder's pathophysiology and has aided diagnosis, but has shown the disease's complexity. Gene replacement therapy is still far from being used in patients with cystic fibrosis, mostly because of difficulties of targeting the appropriate cells. Life expectancy of patients with the disorder has been greatly increased over past decades because of better notions of symptomatic treatment strategies. Here, we summarise advances in understanding and treatment of cystic fibrosis, focusing on pulmonary disease, which accounts for most morbidity and deaths.
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TL;DR: This work discusses how P. aeruginosa evolves from a state of early, recurrent intermittent colonization of the airways of patients with CF to a chronic infection state, and how this process offers opportunities to study bacterial evolution in natural environments.
Abstract: The airways of patients with cystic fibrosis (CF) are nearly always infected with many different microorganisms. This environment offers warm, humid and nutrient-rich conditions, but is also stressful owing to frequent antibiotic therapy and the host immune response. Pseudomonas aeruginosa is commonly isolated from the airways of patients with CF, where it most often establishes chronic infections that usually persist for the rest of the lives of the patients. This bacterium is a major cause of mortality and morbidity and has therefore been studied intensely. Here, we discuss how P. aeruginosa evolves from a state of early, recurrent intermittent colonization of the airways of patients with CF to a chronic infection state, and how this process offers opportunities to study bacterial evolution in natural environments. We believe that such studies are valuable not only for our understanding of bacterial evolution but also for the future development of new therapeutic strategies to treat severe chronic infections.
640 citations
TL;DR: This Review focuses on human HDPs and explores the diverse immunomodulatory effects of HDPs from a systems biology perspective, which highlights the interconnected nature of the effect (or effects) ofHDPs on the host.
Abstract: Host defence peptides (HDPs) are short, cationic amphipathic peptides with diverse sequences that are produced by various cells and tissues in all complex life forms. HDPs have important roles in the body's response to infection and inflammation. This Review focuses on human HDPs and explores the diverse immunomodulatory effects of HDPs from a systems biology perspective, which highlights the interconnected nature of the effect (or effects) of HDPs on the host. Studies have demonstrated that HDPs are expressed throughout the body and mediate a broad range of activities, which explains their association with various inflammatory diseases and autoimmune disorders. The diverse actions of HDPs, such as their roles in wound healing and in the maintenance of the microbiota, are also explored, in addition to potential therapeutic applications.
632 citations
University of Texas MD Anderson Cancer Center1, University of North Carolina at Chapel Hill2, University of Colorado Denver3, University of Nebraska Medical Center4, Texas A&M University5, University of Houston–Downtown6, University of California, San Francisco7, University of Manchester8, University of Texas Health Science Center at Houston9
TL;DR: It is shown that mouse Muc5b (but not MUC5ac) is required for MCC, for controlling infections in the airways and middle ear, and for maintaining immune homeostasis in mouse lungs, whereas Muc 5ac is dispensable.
Abstract: Respiratory surfaces are exposed to billions of particulates and pathogens daily. A protective mucus barrier traps and eliminates them through mucociliary clearance (MCC). However, excessive mucus contributes to transient respiratory infections and to the pathogenesis of numerous respiratory diseases. MUC5AC and MUC5B are evolutionarily conserved genes that encode structurally related mucin glycoproteins, the principal macromolecules in airway mucus. Genetic variants are linked to diverse lung diseases, but specific roles for MUC5AC and MUC5B in MCC, and the lasting effects of their inhibition, are unknown. Here we show that mouse Muc5b (but not Muc5ac) is required for MCC, for controlling infections in the airways and middle ear, and for maintaining immune homeostasis in mouse lungs, whereas Muc5ac is dispensable. Muc5b deficiency caused materials to accumulate in upper and lower airways. This defect led to chronic infection by multiple bacterial species, including Staphylococcus aureus, and to inflammation that failed to resolve normally. Apoptotic macrophages accumulated, phagocytosis was impaired, and interleukin-23 (IL-23) production was reduced in Muc5b(-/-) mice. By contrast, in mice that transgenically overexpress Muc5b, macrophage functions improved. Existing dogma defines mucous phenotypes in asthma and chronic obstructive pulmonary disease (COPD) as driven by increased MUC5AC, with MUC5B levels either unaffected or increased in expectorated sputum. However, in many patients, MUC5B production at airway surfaces decreases by as much as 90%. By distinguishing a specific role for Muc5b in MCC, and by determining its impact on bacterial infections and inflammation in mice, our results provide a refined framework for designing targeted therapies to control mucin secretion and restore MCC.
596 citations
TL;DR: It is shown that markers of classical activation are absent on ATMs from obese humans but are readily detectable on airway macrophages of patients with cystic fibrosis, a disease associated with chronic bacterial infection, and PPARγ and p62/SQSTM1 are identified as two key proteins that promote lipid metabolism and limit inflammation in metabolically activated macrophage
582 citations
TL;DR: The authors review recent progress in organoid derivation and applications and outline how advances in other disciplines might lead to more physiologically relevant organoids.
Abstract: Tissue and organ biology are very challenging to study in mammals, and progress can be hindered, particularly in humans, by sample accessibility and ethical concerns. However, advances in stem cell culture have made it possible to derive in vitro 3D tissues called organoids, which capture some of the key multicellular, anatomical and even functional hallmarks of real organs at the micrometre to millimetre scale. Recent studies have demonstrated that organoids can be used to model organ development and disease and have a wide range of applications in basic research, drug discovery and regenerative medicine. Researchers are now beginning to take inspiration from other fields, such as bioengineering, to generate organoids that are more physiologically relevant and more amenable to real-life applications.
579 citations
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TL;DR: It is now clear that CFTR genotype alone does not account for the wide diversity in CF pulmonary phenotype and evidence is accumulating that secondary genetic factors separate from the CFTR locus significantly influence the severity of CF lung disease.
87 citations
72 citations