Swine as an Animal Model... for Cystic Fibrosis

Cystic fibrosis (CF) is an autosomal recessive disease resulting from a variety of mutations in the cftr gene, which codes for the cystic fibrosis transmembrane conductance regulator anion channel. The disease dramatically affects multiple organs, but the main cause morbidity and mortality in humans is failure of the lungs as a result of chronic inflammation and secondary infection. Despite intensive study, available therapies for CF are inadequate and the disease still has no cure. One of the main obstacles in CF research has been the lack of good animal models as mice expressing defective cftr genes fail to develop lung disease. In search of a better model in which to study CF pathogenesis and potential therapeutics, researchers have recently been focusing on swine. [2,10]

Swine have a lifespan amenable to the study of a disease like CF where lung deterioration progresses over a relatively long period of time and potential novel therapeutics would need to be tested over time as well. In contrast to mice, swine lungs are anatomically, physiologically, histologically, and biochemically very similar to human lungs. Further, swine have already been established as reliable animal models for a variety of lung-related studies including lung development, injury (hypoxia-, toxin-, or reperfusion-induced), growth after lobectomy, transplantation, airway hyper-responsiveness, asthma, surfactant biology, and many other aspects of lung pathophysiology. [10]

Transgenic swine bearing mutations in the cftr gene have recently been innovated and characterized as developing lung disease that very closely approximates clinical observations. Wild-type human and swine CFTR proteins display 93% identical amino acid sequences that are translated in the endoplasmic reticulum (ER), glycosylated in the Golgi, and transported to the apical membrane of airway epithelia where they function as anion channels controlled by phosphorylation. While human mutant CFTR protein is nearly completely retained within the ER and degraded, a very small portion of swine mutant CFTR escapes and can be detected on the apical membrane. Despite this low level CFTR presence, swine expressing mutant CFTR show aberrant airway epithelial electrolyte transport similar to humans. [10]

The lungs of patients suffering from CF easily become infected by a wide variety of pathogens and though humans and swine are not susceptible to precisely the same subset of viral or bacterial species, the resulting immune response and chronic inflammatory state that ensues is very comparable. Swine possess airway host defense mechanisms that are notably similar to humans including resident phagocytes expressing the full complement of pattern recognition receptors, soluble bioactive peptides and proteins including defensins, collectins, and others, and a wide variety of pro-inflammatory cytokines, chemokines, and their respective receptors. How CFTR dysfunction adversely affects host defense making sufferers more susceptible to infection is not known, but increasing ionic strength of human and swine airway surface liquid is known to reduce its antimicrobial capability. [10]

References

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10.Rogers, C.S. et al. (2008) The porcine lung as a potential model for cystic fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 295:L240-L263.

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12.Kuluz, J.W. et al. (2007) New pediatric model of ischemic stroke in infant piglets by photothrombosis – acute changes in cerebral blood flow, microvasculature, and early histopathology. Stroke 38:1932-1937.

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