More tales from the cystic fibrosis pig

The cystic fibrosis (CF) pig generated by the Welsh Group in Iowa continues to deliver insight into the mechanistic basis of CF lung disease. Perhaps the most salient of the lessons that this model has provided to date is the importance of airway pH and its critical influence on the early bacterial colonisation of the lungs. The latest instalment of the story highlights the role of the non-gastric proton pump, ATP12A, in the airway and how in the absence of normal CFTR function, it drives acidification and the compromised ability of the lung to defend itself (Science. 2016 351(6272): 503-507).

Prior to the generation of the CFTR-/- pig it had been appreciated that the airway mucosa of CF patients was relatively acidic when compared to healthy controls although the putative implications for the disease were unknown. Early studies with the pig highlighted that within hours of birth, the bacterial load in the airways was higher in the CF animals (Sci Transl Med. 2010 2(29):29ra31). Follow-up studies demonstrated that the airway surface liquid (ASL) of the CF pigs was lacking a bactericidal capacity that was evident in the littermate controls. It transpired that the acidic pH of the ASL attenuated the activity of a number of innate defence molecules including lysozyme and lactoferrin and this likely conferred the susceptibility to early bacterial colonisation (Nature. 2012 487(7405):109-13).

Studies in the pig and also primary human airway epithelial cells are now demonstrating that in the absence of CFTR-mediated bicarbonate secretion, it is H+ secretion via the non-gastric H+/K+ ATPase (ATP12A) that leads to an unchecked acidification of the mucosa. Inhibition of apical ATP12A with oubain partially alkalinised the ASL and restored the anti-bacterial activity of mucosal innate defence proteins in cultured human and porcine airway epithelial cells. Furthermore, adenoviral-mediated expression of Atp12a in mouse airway epithelium induced a ‘CF-like’ acidic / immunocompromised phenotype. Of note, endogenous expression of Atp12a in mouse airways was significantly lower than observed in human and pig, a finding that may contribute to the protection of the various CF mouse models of cystic fibrosis, all of which fail to develop any signs of lung disease.

ATP12A is a cAMP activated H+ pump. To this end, Welsh and colleagues raise the intriguing question as to the risk-benefit balance of using agents that can elevate cAMP in the lung epithelium. Inhaled β2-receptor agonists will unquestionably relax airway smooth muscle and offer the potential to bronchodilate the airways. However, could there also be a downside to this elevation in cAMP in terms of an acidification of the ASL and increased susceptibility to infection? Of note, similar theoretical risks regarding the use of cAMP-elevating agents in CF have been previously raised in respect to their potential to elevate ENaC function and therefore further dehydrate the airway mucosa (Science. 1983 221(4615):1067-70).

ATP12A does therefore offer the potential to be a new drug target whereby inhibitors would be predicted to boost innate defence in the CF lung. In view of the low airway pH in additional respiratory diseases that are associated with increased infection risk, could this mechanism and therapeutic benefit be extended beyond cystic fibrosis?


Blog written by Henrey Danahay

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