Cystic fibrosis is a life-threatening, wide spread genetic disease diagnosed in 1 to 3000 livebirths of the Caucasian population. Here a mouse model for this disease is described and optimized using the CFTR-channel selective inhibitor CFTR(inh 172). The target parameter was mucociliary clearance measured using microdialysis of the transported fluorescent dye rhodamine in the mouse trachea in situ . The impact of Ap 4 A (diadenosine tetraphosphate) as a potential drug was investigated. Its inhalation was effective at low concentrations; established compounds such as Salbutamol and UTP increased mucociliary clearance as well. Our data show a functioning model of cystic fibrosis and the effectiveness of the newly tested Ap 4 A.
B. Marcet and J. M. Boeynaems, “Relationships between Cystic Fibrosis Transmembrane Conductance Regulator, Extracellular Nucleotides and Cystic Fibrosis,” Pharmacology & Therapeutics, Vol. 112, No. 3, 2006, pp. 719- 732. doi:10.1016/j.pharmthera.2006.05.010
M. T. Clunes and R. C. Boucher, “Front-Runners for Pharmacotherapeutic Correction of the Airway Ion Transport Defect in Cystic Fibrosis,” Current Opinion in Pharmacology, Vol. 8, No. 3, 2008, pp. 292-299. doi:10.1016/j.coph.2008.04.006
P. T. Bye and M. R. Elkins, “Other Mucoactive Agents for Cystic Fibrosis,” Paediatric Respiratory Reviews, Vol. 8, No. 1, 2007, pp. 30-39. doi:10.1016/j.prrv.2007.02.008
D. Kellerman, et al., “Inhaled P2Y2 Receptor Agonists as a Treatment for Patients with Cystic Fibrosis Lung Disease,” Advanced Drug Delivery Reviews, Vol. 54, No. 11, 2002, pp. 1463-1474. doi:10.1016/S0169-409X(02)00154-0
B. R. Yerxa, et al., “Potency and Duration of Action of Synthetic P2Y2 Receptor Agonists on Schirmer Scores in Rabbits,” Advances in Experimental Medicine and Biology, Vol. 506, 2002, pp. 261-265.
D. Kellerman, et al., “Denufosol: A Review of Studies with Inhaled P2Y(2) Agonists that Led to Phase 3,” Pulmonary Pharmacology & Therapeutics, Vol. 21, No. 4, 2008, pp. 600-607. doi:10.1016/j.pupt.2007.12.003
M. R. Knowles, et al., “Extracellular ATP and UTP Induce Chloride Secretion in Nasal Epithelia of Cystic Fibrosis Patients and Normal Subjects in Vivo,” Chest, Vol. 101, No. 3, 1992, pp. 60-63. doi:10.1378/chest.101.3_Supplement.60S
M. R. Knowles, et al., “Pharmacological Treatment of Abnormal Ion Transport in the Airway Epithelium in Cystic Fibrosis,” Chest, Vol. 107, No. 2, 1995, pp. 71-76. doi:10.1378/chest.107.2_Supplement.71S
S. Yamamoto, et al., “Regulation of Extracellular UTP- Activated Cl? Current by P2Y-PLC-PKC Signaling and ATP Hydrolysis in Mouse Ventricular Myocytes,” The Journal of Physiology, Vol. 57, No. 2, 2007, pp. 85-94. doi:10.2170/physiolsci.RP011406
B. R. Yerxa, et al., “Pharmacology of INS37217 [P(1)- (Uridine 5')-P(4)-(2'-deoxycytidine 5')tetraphosphate, Tetrasodium Salt], a Next-Generation P2Y(2) Receptor Agonist for the Treatment of Cystic Fibrosis,” Journal of Pharmacology and Experimental Therapeutics, Vol. 302, No. 3, 2002, pp. 871-880. doi:10.1124/jpet.102.035485
R. R. Deterding, et al., “Phase 2 Randomized Safety and Efficacy Trial of Nebulized Denufosol Tetrasodium in Cystic Fibrosis,” American Journal of Respiratory and Critical Care Medicine, Vol. 176, No. 4, 2007, pp. 362- 369. doi:10.1164/rccm.200608-1238OC
S. Storey and G. Wald, “Novel Agents in Cystic Fibrosis,” Nature Reviews Drug Discovery, Vol. 7, 2008, pp. 555-556. doi:10.1038/nrd2603
F. Ratjen, “New Pulmonary Therapies for Cystic Fibrosis,” Current Opinion in Pulmonary Medicine, Vol. 13, No. 6, 2007, pp. 541-546. doi:10.1097/MCP.0b013e3282efbc56
R. Schreiber and K. Kunzelmann, “Purinergic P2Y6 Receptors Induce Ca2+ and CFTR Dependent Cl? Secretion in Mouse Trachea,” Cell Physiol Biochem, Vol. 16, 2005, pp. 99-108. doi:10.1159/000087736
M. Taira, et al., “Adenosine A3 Receptor-Mediated Potention of Mucociliary Transport and Epithelial Ciliary Motility,” American Journal of Physiology—Lung Cellular and Molecular Physiology, Vol. 282, 2002, pp. 556- 562.
S. T. Ballard, et al., “Liquid Secretion Inhibitors Reduce Mucociliary Transport in Glandular Airways,” American Journal of Physiology—Lung Cellular and Molecular Physiology, Vol. 283, 2002, pp. 329-335.
T. Ma, et al., “Thiazolidinone CFTR Inhibitor Identified by High-Throughput Screening Blocks Cholera Toxin- Induced Intestinal Fluid Secretion,” Journal of Clinical Investigation, Vol. 110, 2002, pp. 1651-1658.
J. R. Thiagarajah, et al., “Prevention of Toxin-Induced Intestinal Ion and Fluid Secretion by a Small-Molecule CFTR Inhibitor,” Gastroenterology, Vol. 123, No. 2, 2004, pp. 511-519. doi:10.1053/j.gastro.2003.11.005
A. Perez, et al., “CFTR Inhibition Mimics the Cystic Fibrosis Inflammatory Profile,” American Journal of Physiology—Lung Cellular and Molecular Physiology, Vol. 292, No. 2, 2006, pp. 383-395. doi:10.1152/ajplung.00403.2005
B. R. Grubb, et al., “Mucociliary Transport Determined by in Vivo Microdialysis In the Airways of Normal and CF Mice,” American Journal of Physiology—Lung Cellular and Molecular Physiology, Vol. 286, No. 3, 2004, pp. 588-595. doi:10.1152/ajplung.00302.2003
N. Wienk?tter, et al., “The Effect of Thyme Extract on Beta2-Receptors and Mucociliary Clearance,” Planta Medica, Vol. 73, No. 7, 2007, pp. 629-635. doi:10.1055/s-2007-981535
F. Begrow, et al., “Effect of Myrtol Standardized and Other Substances on the Respiratory Tract: Ciliary Beat Frequency and Mucociliary Clearance as Parameters,” Advances in Therapy, Vol. 29, No. 4, 2012, pp. 350-358. doi:10.1007/s12325-012-0014-z
A. T. Kimoto, et al., “A New, Simple Method of Measuring Mucociliary Clearance in Guinea—Pigs,” Pulmonary Pharmacology & Therapeutics, Vol. 12, No. 1, 1999, pp. 49-54. doi:10.1006/pupt.1999.0169
H. Engler and I. Szelenyi, “Tracheal Phenol Red Secretion, a New Method for Screening Mucosecretolytic Compounds,” Journal of Pharmacological Methods, Vol. 11, No. 3, 1984, pp. 151-157. doi:10.1016/0160-5402(84)90033-0
W. H. Colledge, et al., “Generation and Characterization of a DeltaF508 Cystic Fibrosis Mouse Model,” Nature Genetics, Vol. 10, 1995, pp. 445-452. doi:10.1038/ng0895-445
J. N. Snouwaert, et al., “An Animal Model for Cystic Fibrosis Made by Gene Targeting,” Science, Vol. 257, No. 5073, 1992, pp. 1083-1088. doi:10.1126/science.257.5073.1083
K. A. Becker, et al., “Zystische Fibrose—Pathophysiologische Konzepte,” Biospektrum, Vol. 15, 2009, pp. 383- 385.
M. Mall, et al., “Increased Airway Epithelial Na+ Absorption Produces Cystic Fibrosis-Like Lung Disease in Mice,” Nature Medicine, Vol. 10, 2004, pp. 487-493. doi:10.1038/nm1028
G. Adam, et al., “Increase in Intracellular Cl? Concentration by cAMP- and Ca2+-Dependent Stimulation of M1 Collecting Duct Cells,” Pflugers Archiv, Vol. 449, No. 5, 2005, pp. 470-478. doi:10.1007/s00424-004-1356-4
Z. Cai, et al., “Inhibition of Heterologously Expressed Cystic Fibrosis Transmembane Conductance Regulator Cl? Channels by Non-Sulphonylurea Hypoglycaemic Agents,” British Journal of Pharmacology, Vol. 128, No. 1, 1999, pp. 108-118. doi:10.1038/sj.bjp.0702748
P. C. Zamecnik, et al., “Analogues of Diadenosine 5’,5’’’-P1,P4-Tetraphosphate (AP4A) as Potential Anti- Platelet-Aggregation Agents,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 89, No. 6, 1992, pp. 2370-2373. doi:10.1073/pnas.89.6.2370
E. J. Verspohl and B. Johannwille, “Diadenosine Polyphosphates in Insulin Secreting Cells: Their Interaction with Specific Receptors and Their Degradation,” Diabetes, Vol. 47, No. 11, 1998, pp. 1727-1734. doi:10.2337/diabetes.47.11.1727
S. A. Felicetti, et al., “Comparison of Tracheal Mucous Transport in Rats, Guinea Pigs, Rabbits, and Dogs,” Journal of Applied Physiology, Vol. 51, No. 6, 1981, pp. 1612-1617.