The lab of Kevin Foskett, PhD, the Isaac Ott Professor of Physiology1 at the University of Pennsylvania School of Medicine, has found a possible new target for fighting cystic fibrosis (CF囊胞性纤维症) that could compensate2 for the lack of a functioning ion channel in affected3 CF-related cells. Their finding appears in the Journal of Clinical Investigation4. The team explored the role of CFTR, the chloride ion(氯根离子) channel mutated in CF patients, in fluid secretion5(分泌物) by mucous6(黏液的) gland7 cells. They used a recently developed transgenic pig model, in which the CFTR gene8 has been knocked out. The CFTR gene provides instructions for making a channel that transports negatively charged particles called chloride ions into and out of cells. The flow of chloride ions helps control the movement of water in tissues, which is necessary for the production of thin, freely flowing mucous.
CF researchers had been held back because existing animal models did not fully9 mimic10 the problems seen in people with CF. In people, faulty mucous glands11 may contribute to airway12 dehydration13(脱水) and the problems associated with CF. Mucous glands found in the airways14 of the lung are important to breathing because they help clear inhaled15 irritants(刺激物) and bacteria. They are also the sites where important macromolecules(大分子) critical for lung defense16 against pathogens(病原体) are made.
CF is the most common genetic17 disease in the United States, affecting about 30,000 children and adults and about 70,000 worldwide. The CF mutation18 makes certain organs of the body susceptible19 to obstruction20 due to thick mucus secretions21(粘液分泌) , especially in the lung where thick secretions lead to chronic22 infections. This requires a daily regimen of drugs and physical therapy to help clear airway secretions.
"We discovered, first, that the ion transport and signal transduction mechanisms23 in the pig cells appear to be precisely24 the same as those used in human cells, indicating that the pig is an excellent model for studies of human lung function and a valuable tool for elucidating25(阐明,说明) pathology of lung disease in CF," notes Foskett.
The team also discovered that fluid secretion by the mucous cells -- in response to neurotransmitters -- requires CFTR. This secretion was absent in the pigs lacking CFTR. However, the same cells that lacked the CFTR chloride ion channel, mimicking26 the condition in human CF, expressed another, different chloride ion channel that could be activated28 by elevating intracellular(细胞内的) calcium29 by the same neurotransmitters. The presence of both channels in the same mucous cells suggests that the calcium-activated chloride channel could be targeted therapeutically31 to compensate for lack of CFTR functioning channels in CF-harmed cells.
"This crosstalk between the signaling pathways that activate27 the two different chloride ion channels now gives us a completely new therapeutic30 strategy to think about," says Foskett. For example, the presence of the calcium-activated chloride channel would enable CF mucous cells to secrete32 in response to stimulation33 that would have normally required the CFTR channel. Drugs that could enhance the magnitude of the calcium response might also enable activation34 of calcium-activated chloride channel-mediated secretion in CF cells. Importantly, such agents might be able to lead to secretion only during times of physiological35 stimulus36, utilizing37 the appropriate neural38 regulation of secretion that likely remains39 intact in CF.