囊胞性纤维症新疗法或将问世

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.