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Published ahead of print on August 3, 2006, doi:10.1165/rcmb.2006-0184TR
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American Journal of Respiratory Cell and Molecular Biology. Vol. 36, pp. 1-7, 2007
© 2007 American Thoracic Society
DOI: 10.1165/rcmb.2006-0184TR

Translational Review

Cystic Fibrosis Mouse Models

Claudine Guilbault, Zienab Saeed, Gregory P. Downey and Danuta Radzioch

McGill Centre for the Study of Host Resistance, McGill University Health Center Research Institute, Montreal, Quebec; and Division of Respirology, Department of Medicine, University of Toronto, and Toronto General Hospital Research Institute of the University Health Network, Toronto, Ontario, Canada

Correspondence and requests for reprints should be addressed to Danuta Radzioch, Ph.D., McGill University Health Center, Montreal General Hospital Research Institute, 1650 Cedar Avenue, Room L11-218, Montreal, PQ, H3G 1A4 Canada. E-mail: danuta.radzioch{at}muhc.mcgill.ca


   Abstract
Top
 Abstract
CYSTIC FIBROSIS
 GENOTYPES
 PHENOTYPES
 MURINE MODELS OF CF...
 NOVEL TREATMENT APPROACHES
 References
 
Animal models of cystic fibrosis (CF) are powerful tools that enable the study of the mechanisms and complexities of human disease. Murine models have several intrinsic advantages compared with other animal models, including lower cost, maintenance, and rapid reproduction rate. Mice can be easily genetically manipulated by making transgenic or knockout mice, or by backcrossing to well-defined inbred strains in a reasonably short period of time. However, anatomic and immunologic differences between mice and humans mean that murine models have inherent limitations that must be considered when interpreting the results obtained from experimental models and applying these to the pathogenesis of CF disease in humans. This review will focus on the different CF mouse models available that represent diverse phenotypes observed in humans with CF and that can help researchers elucidate the diverse functions of the CFTR protein.


   CYSTIC FIBROSIS
Top
 Abstract
 CYSTIC FIBROSIS
GENOTYPES
 PHENOTYPES
 MURINE MODELS OF CF...
 NOVEL TREATMENT APPROACHES
 References
 
Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene located on human chromosome 7. These mutations either result in malfunction or complete absence of the CFTR protein, leading to multi-organ dysfunction. The manifestations of CF disease are diverse and include meconium ileus and peritonitis, failure to thrive, nasal polyposis, pancreatitis, malabsorption, cirrhosis, and recurrent and persistent pulmonary infection with bacteria such as Staphylococcus aureus and Pseudomonas aeruginosa. Because the mutations give rise to such a varied spectrum of disease manifestations, it has been difficult to create an animal model that mimics the human disease with a high degree of accuracy. However, several attempts have been made, with varying degrees of success. The following review will evaluate different mouse models, and how they help researchers to understand the many functions of the CFTR protein.


   GENOTYPES
Top
 Abstract
 CYSTIC FIBROSIS
 GENOTYPES
PHENOTYPES
 MURINE MODELS OF CF...
 NOVEL TREATMENT APPROACHES
 References
 
In 1989 the CFTR gene was identified and cloned, and just three years later the generation of the first CF mouse model was reported (1). To date, eleven CF mouse models have been characterized and reported (Table 1). Several CF mouse models have been generated using a method of gene targeting in embryonic stem cells to disrupt the endogenous CFTR gene. These models have established animal models for the two most common human mutations, {Delta}F508 and G551D, among others.


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  		TABLE 1. CYSTIC FIBROSIS MOUSE MODELS

 
The first CF mouse model was generated at the University of North Carolina in 1992 (1, 2). The endogenous CFTR gene in murine embryonic stem-cell lines was targeted leading to disruption of the CFTR gene by introducing a stop codon in exon 10. The targeted cell lines were introduced into early C57BL/6/129 mouse embryos and transferred to B6D2/129 pseudo-pregnant foster mothers. The resulting offspring were mated to B6D2/129, C57BL/6/129, or BALB/C/129 mice to generate heterozygotes, which were crossed to produce homozygous offspring, termed CFTRtm1UNC knockout (KO) mice. The survival rate of these mice was very low; less than 5% survived to maturity.

Kent and colleagues postulated that the mixed genetic background of the original strain of CFTRtm1UNC mice influenced the development of lung pathology (3). To test this notion, CFTRtm1UNC mice heterozygous at the Cftr locus were backcrossed onto the C57BL/6 background. The novel congenic strain was designated B6-CFTRtm1UNC/CFTRtm1UNC knockout mouse (3). This mouse model has been exploited to characterize the multi-organ involvement related to dysfunction of CFTR (4), as well the pulmonary inflammatory response to bacterial infection using a less invasive infection technique (5).

About the same time as the CFTRtm1UNC knockout mice were produced, Dorin and colleagues generated another strain of knockout mice on an MF1/129 genetic background, designated CFTRtm1HGU, by insertion mutagenesis targeted to exon 10 of the Cftr gene (6, 7). However, because of the targeting strategy used, exon skipping and aberrant splicing produced ~ 10% normal Cftr mRNA, resulting in a much milder disease phenotype. In fact, ~ 95% of these mice survived to maturity.

Another strain of Cftr mutant mice was created by Ratcliff and colleagues, on a mixed genetic background of MF1/129 and C57BL/6/129, resulting in a null mutation (8). The phenotype of these mice, designated CFTRtm1CAM, is very similar to that of the CFTRtm1UNC knockout mice except that these mice also exhibit lacrimal gland pathology.

Researchers in Texas and Iowa generated a CF mouse on a mixed C57BL/6/129 background, designated CFTRtm1BAY, by duplication of exon 3 in the mouse Cftr gene. These mice produce less than 2% of normal levels of wild-type (WT) mRNA and exhibit a severe phenotype with a high mortality rate; only 40% of the Cftr-KO mice survive past Day 7 (9). Two years later, Hasty and colleagues, by replacement of exon 2, created another null mutation in mice, designated CFTRtm3BAY. The CFTRtm3BAY knockout mice showed a 40% survival rate at 1 mo of age (10).

Rozmahel and colleagues generated another strain of Cftr-deficient mice, designated CFTRtm1HSC knockout mice, by disruption of exon 1 of the Cftr gene. Initially, these mice were generated on a mixed genetic background and displayed a severe phenotype with only 30% survival (11). In subsequent studies, the original founder mouse was crossed with different inbred strains to generate F1 mice of different genetic backgrounds, and the heterozygous F1 mice were intercrossed to produce homozygous CFTRtm1HSC/CFTRtm1HSC knockout mice. According to their genetic background, these knockout mice expressed different degrees of disease severity and survival rates.

In general, most CFTR mutations in humans result in loss of function due to abnormal processing of the protein and failure to insert CFTR into the plasma membrane (12). Murine models of the most common human CF mutation, {Delta}F508, have been generated by introducing this mutation into the endogenous mouse Cftr gene. The {Delta}F508 mouse model was generated by van Doorninck and colleagues by inserting the mutation into exon 10 using a double homologous recombination technique (13). The mice, generated on a FVB/129 background and designated CFTRtm1EUR, were viable but did not show severe disease, possibly because the mutant CFTR protein was expressed at near normal levels, and could thus provide enough residual function to ameliorate adverse phenotypic changes (14). Several studies have shown that the {Delta}F508 CFTR protein exhibits partial function as a Cl– channel, with a similar level of conductance but a decrease in open channel probability (15). Colledge and colleagues also generated {Delta}F508 knockout mice by replacement of exon 10 on a C57BL/6/129 background. In contrast to the null mutants (CFTRtm1CAM) that displayed only 20% survival, these {Delta}F508 mutants, designated CFTRtm2CAM, exhibited ~ 65% survival (16). This higher rate of survival was most likely due to the fact that CFTRtm2CAM mice express ~ 30% of the normal level of mutant Cftr mRNA (8). Zeiher and collaborators generated {Delta}F508 knockout mice by replacement of exon 10 on a C57BL/6/129 background, using the same method as Colledge and colleagues. However, the knockout mice, designated CFTRtm1KTH, had a survival rate of only 40%, and expressed nearly no mutant mRNA levels in the intestinal tract (17).

The G551D mutation is a class III mutation, affecting the regulatory domain of the CFTR protein (18, 19). CFTRtm1G551D was generated by replacement of exon 11 in CD1/129 mice, and these mice displayed 27% survival. The mutant Cftr mRNA expression resulted in a residual activity of ~ 4%.

The most recent mouse model was developed to mimic the human G480C mutation (20). Dickinson and colleagues generated a G480C mouse model by inserting the mutation into exon 10 using a double homologous recombination technique. The mice, designated CFTRtm2HGU, were generated on a C57BL/6/129 background and survive to maturity under usual animal housing conditions. As with the CFTRtm1EUR strain, their high rate of survival could be related to the use of the "hit and run" technique, resulting in expression of normal levels of the mutant CFTR protein.

Survival of the different mouse models has been shown to be influenced both by diet and housing conditions (3, 21, 22). Placing the CFTRtm1UNC KO mice on a nutrient-rich liquid diet to minimize intestinal obstruction greatly increased their survival (21). Additionally, placing CFTRtm1G551D mice under SPF conditions limited their intestinal obstruction and improved their survival rate from 27% in a conventional animal facility to ~ 60% under SPF conditions (18).


   PHENOTYPES
Top
 Abstract
 CYSTIC FIBROSIS
 GENOTYPES
 PHENOTYPES
MURINE MODELS OF CF...
 NOVEL TREATMENT APPROACHES
 References
 
Intestinal Disease
An intestinal phenotype appears to be the hallmark of most CF mouse models. With the exception of CFTRtm1HGU, CFTRtm1EUR and CFTRtm2HGU, all models display a fairly severe pathology. Most murine models express abnormal electrophysiological profiles, runting and failing to thrive, goblet cell hyperplasia, mucin accumulation in the crypts of Lieberkuhn, crypt dilatation, intestinal obstruction with resultant perforation, peritonitis and mortality (1, 9–11, 13, 18, 22). Intestinal obstruction is physiologically very similar to the meconium ileus observed in humans with CF. Overall it seems that murine CF models display the intestinal disease observed in humans.

Recently, Walker and colleagues investigated the effects of talniflumate (LOMUCIN) in CF mice (CFTRtm1UNC and CFTRtm1Kth) with distal intestinal obstructive syndrome (DIOS). DIOS involves the insufficient hydration of mucus and debris at mucosal surfaces, due to abnormal transepithelial electrolyte and water transport resulting from diminished or absent CFTR activity (23). They observed that oral talniflumate had beneficial effects on the survival of CF mice by decreasing small intestinal NaCl absorption through the inhibition of apical membrane Formula exchangers (24).

Pancreatic Disease
Snouwaert and coworkers reported a relative lack of pathologic changes in the pancreas of CFTRtm1UNC mice (1). Another study of CFTRtm1UNC/CFTRtm1UNC mice reported luminal dilatation and the accumulation of zymogen granules at the apical pole of the ductal epithelial cells (25). The CFTRtm1CAM CF mouse exhibits blockage of some of the small pancreatic ducts in ~ 50% of the mice examined, although the lesions were not considered severe enough to alter pancreatic function (8). Mice with the CFTRtm1BAY and CFTR tm3BAY mutations exhibited acinar atrophy that became more severe as the mice aged. Mice with the CFTRtm1HGU mutation exhibit no pancreatic pathology, probably as a result of expression of a significant amount of WT CFTR. In addition, these mice demonstrate no evidence of malabsorption or other gastrointestinal problems. Furthermore, none of the {Delta}F508 or the G551D models exhibit any obvious pancreatic pathology (6, 7, 13, 16–18). The milder pancreatic pathology observed in CF mice models compared with patients with CF appears to depend on two factors. First, certain mouse models express enough CFTR residual activity to have a normal Cl– secretory pathway. Second, it has been suggested that the murine pancreas contains an alternative channel to CFTR, a Ca2+-mediated Cl– conductance channel, that is expressed in both WT and CF mice (14, 26).

Hepatobiliary Disease
In most of the CF mouse models, there is no obvious liver pathology. However, most of the mice studied were young and might have developed hepatic disease if they had been studied later in life, as is the case for humans. In the CFTRtm1G551D mouse, 20% of the mice are reported to exhibit hyperplasia of the bile duct epithelium (23). The CF mouse gallbladder seems to exhibit more abnormalities than seen in the liver. However, the pathology is quite variable. Some CF mouse models (CFTRtm1G551D, CFTRtm1UNC, and CFTRtm1Bay) have distended gallbladders. CFTRtm1UNC and CFTRtm1G551D mice have their gallbladder filled with black bile (1, 18) and the gallbladder wall infiltrated with neutrophils, suggesting an ongoing inflammatory response. Understanding the gallbladder pathology seen in CF mice might help to find a treatment for the frequent formation of gallstones and gallbladder malformations observed in the human patients with CF.

Lung Disease and Inflammation
The first CFTRtm1UNC KO mice displayed pathologic changes in the upper airways but there were no signs of either inflammation or bacterial infection in the lungs (1). It was hypothesized that the mixed genetic background of the original strain influenced the development of lung pathology. Modifier genes could possibly code for an alternative Cl– channel that could compensate for defective CFTR (3). Therefore, Kent and colleagues reported the development of a congenic strain designated B6-CFTRtm1UNC/CFTRtm1UNC. Although no spontaneous infection of the lungs occurred, B6-CFTRtm1UNC/CFTRtm1UNC mice maintained in specific pathogen–free (SPF) conditions developed spontaneous and progressive lung disease, as we further confirmed in our more recent studies (3, 5, 27). The major features of the lung disease included failure of effective mucociliary clearance, postbronchiolar hyperinflation of alveoli, and parenchymal interstitial thickening, with evidence of fibrosis and inflammatory cell recruitment (3). Acinar and alveolar hyperinflation are consistent with obstructive small airway disease, which is a characteristic early feature of human CF (28, 29). The CFTRtm1HGU KO mice showed no gross lung disease at birth, but displayed cytokine abnormalities when maintained in standard animal facilities (30). Further studies have demonstrated significantly impaired mucociliary transport of inert particles in vivo and altered submucosal glands (31, 32). In the mice harboring the G551D mutation, about one-third of the animals exhibit inspissated eosinophilic material in the lumen of the pharyngeal submucosal glands. Up to one-third of mice homozygous for the CFTRtm1G551D mutation developed abnormal regulation of inflammation in the lungs. Furthermore, mice with the CFTRtm1G551D mutation display impaired pulmonary clearance and initial increased susceptibility to P. aeruginosa (33). Another interesting phenotype observed in CF mice is a decrease in pulmonary levels of iNOS, which has been implicated in the pathogenesis of CF lung disease. The expression of iNOS is significantly reduced in the mixed background strain of homozygous CFTRtm1KTH and CFTRtm1UNC KO mice (34, 35). All of the other mouse models examined had normal lung histology and absence of mucus plugging, displaying no sign of lung pathology. Therefore, apart from the B6-CFTRtm1UNC mice, no other CF mouse models develop spontaneous lung inflammation and none developed "spontaneous" chronic bacterial infections and/or inflammation as observed in human patients with CF. The reasons for this discrepancy are not known, but may be related in part to the relative paucity of submucous glands in the murine trachea and major bronchi compared with the human large airways, and in part to the expression of alternate (non-CFTR) chloride channels in the murine airway epithelia.

Nasal and Tracheal Electrophysiologic Profiles
The murine nasal mucosa is composed of ~ 40% olfactory epithelia and 60% respiratory epithelia. By comparison, the human nasal mucosa is made of more than 95% respiratory epithelia (36). Nevertheless, the nasal mucosa of CF mouse models accurately replicates the human profile, also showing hyper-absorption of Na+ and the Cl– transport defect (36). Na+ hyperabsorption is detected by a significantly negative baseline nasal potential difference (PD) in vivo and a response to amiloride, a drug that blocks the epithelial sodium channel ENaC. In response to amiloride, all the CF mouse models showed an increased potential difference compared with non-CF controls (11, 13, 17, 18, 37, 38). In human airway tissue, Cl– secretion is mediated almost equally by the CFTR channel and an alternative Ca2+-regulated channel in the apical membrane (39). In human CF tissue, although the cAMP-stimulated CFTR pathway is defective, the Ca2+-mediated Cl– secretory pathway is functional, and in fact sometimes upregulated (39–42). Also, nasal potential difference studies in patients with severe CF genotypes also showed that A2 adenosine (Ado) receptors, in CFTR-corrected CFBE41o- airway cells and human subjects, were CFTR-dependent (43). These results indicate that Ado is a potent Cl– secretagogue, with small effects on cAMP levels even with strong effects on CFTR-dependent short circuit current and nasal Cl– transport.

In the normal murine nasal mucosa, CFTR is the dominant Cl– secretory pathway. In CF nasal mucosa that expresses no CFTR, there is an upregulation of the Ca2+-mediated Cl– secretory pathway. With the exception of mice harboring the CFTRtm1HGU and CFTRtm1EUR mutations, all CF mice show a decrease in the cAMP-mediated Cl– response and an increase in the Ca2+-mediated Cl– secretory response (44).

Other Manifestations of the Disease
Several studies using various CF mouse models have reported normal fertility in males, and no pathology in the male reproductive tract. It was speculated that normal fertility in CF male mice is due to the presence of a Ca2+-mediated Cl– secretory pathway in the epididymis and seminal vesicles (45). Interestingly, B6-CFTRtm1UNC mice do not express an alternative Cl– channel, resulting in infertility in 90% of the males (our unpublished results). CF female mice also have no apparent pathology in the reproductive tract. However, CFTRtm1UNC female mice required more time than normal littermates to become pregnant, indicating a possible reduction in fertility (10), and CF knockout females in B6-CFTRtm1UNC have been almost completely infertile (unpublished observations).

Patients with CF are often of smaller than average height and have difficulty regaining weight once it is lost. In addition to the malabsorption of fats and proteins, other factors such as increased caloric demands for combating infection and labored breathing may also contribute to this weight loss. All CF mouse models except CFTRtm1HGU and CFTRtm2HGU display a lower body weight than their WT littermates. The lower body weight of CF mice is thought to be due to intestinal disease, since CF mice in which the defect has been corrected by tissue-specific CFTR transgenesis are of the same weight as non-CF littermate controls (46, 47).

With advances in CF research, treatments have helped to extend the median age of survival for patients with CF. Reduced bone mineral density and compression fractures of the vertebra leading to kyphosis are further complications that have become apparent with increased in survival of patients with CF (48). These phenotypes cause pathologic fractures in both children and adults. The link between CFTR dysfunction and ostenopenia/osteoporosis has yet to be established because it could depend on a number of accompanying disease factors, including pancreatic insufficiency, calcium or vitamin D nutritional deficiency, reduced exercise capacity, glucocorticoid therapy, delayed puberty, and chronic lung infection. A study using histomorphometric analysis of the bones of a mouse genetic model of CF found that the CFTR mutation is associated with severe osteopenia (49). Bone mineral density (BMD) of total body and of individual bones is significantly lowered compared with that of littermate controls. CFTR mutants display a 50% reduction of cortical bone width and thinner trabeculae, a significant reduction of bone formation, and a concomitant strong increase in bone resorption.


   MURINE MODELS OF CF AND PULMONARY INFECTION
Top
 Abstract
 CYSTIC FIBROSIS
 GENOTYPES
 PHENOTYPES
 MURINE MODELS OF CF...
NOVEL TREATMENT APPROACHES
 References
 
CF mice models have shown that CFTR mutant carriers are more resistant to certain bacteria, namely Vibrio cholerae and Salmonella typhii (16, 36, 50). This increased resistance to infectious diseases might maintain mutant CFTR alleles at high levels in selected populations, giving them a "heterozygote advantage."

For patients with CF, the bulk of morbidity and mortality is caused by an increased susceptibility to infection with certain bacteria, particularly P. aeruginosa, S. aureus, and Burkholderia cepacia. Mimicking these infections in mice models has increased our understanding of how patients with CF can increase their resistance to and better fight their infections.

P. aeruginosa
Human patients with CF are commonly colonized by P. aeruginosa in childhood, whereas spontaneous colonization with the typical CF pathogens has not been detected in CF mice. Initial studies examining the effect of exposure to P. aeruginosa in CFTRtm1HGU, CFTRtmUNC, and CFTRtm1KTH mice showed no increase in susceptibility to P. aeruginosa. These results may have been attributable to the methods of instillation used and also to the genetic background of the CF mice used in the study (44). Administration of free P. aeruginosa causes acute, not chronic, lung infection, with either rapid clearance of the bacteria or sepsis leading to rapid death (23, 51). Specific techniques such as intratracheal inoculation of bacteria with immobilizing agents such as agar, agarose, or seaweed alginate have to be used to mimic more chronic infection with P. aeruginosa. Using agar beads laden with P. aeruginosa to mimic colonization has proven more successful in revealing defects in bacterial clearance and the ensuing inflammatory response in CFTRtm1UNC mice (52). Our laboratories have infected B6-CFTRtm1UNC KO mice (53) by delivering mucoid P. aeruginosa in agar beads intratracheally to both lungs. While both the WT and the Cftr-KO mice developed severe bronchopneumonia after infection by this method, CF mice demonstrated defective clearance of bacteria from the lungs and higher mortality. Homozygous CFTRtm1G551D mice were also infected with entrapped mucoid strains of P. aeruginosa. After 3 d, these CF mice demonstrated defective bacterial clearance with a higher bacterial load and enhanced levels of proinflammatory mediators, showing excessive inflammation (33).

In another study, pulmonary infection in CF mice with non–alginate-producing P. aeruginosa resulted in rapid expression of alginate by the bacteria when they were exposed to anaerobic conditions, or were inoculated into murine lungs embedded in agar beads (54). van Heeckeren and colleagues sought to determine if absence of chloride channel activity alone was sufficient to cause excessive inflammation in response to infection with agar-encased P. aeruginosa. They observed that the absence of a Cl– channel was sufficient for exaggerated inflammation and excess mortality mice in CF compared with WT controls (55). The same group also found that application of mucoid P. aeruginosa intranasally significantly increases lung inflammation (56). Oceandy and colleagues also showed that reconstitution of the CFTR in airway epithelium, but not macrophages, is sufficient to correct P. aeruginosa–induced inflammation in the lung (57). Also, a recent report of intra-tracheal infection of CF mice using a strain of P. aeruginosa that expresses a stable mucoid phenotype (due to a deletion in mucA) resulted in pulmonary infection without the need for agar embedding (58). This was done successfully in Cftrtm1Unc–/– and BALB/c mice as assessed by bacterial counts in lung homogenates 7 d after infection. Histologic analysis revealed the presence of bacteria within alginate biofilms surrounded by polymorphonuclear leukocytes in the alveoli. This model has distinct advantages (e.g., no need for agar beads) and merits further characterization.

An intranasal immunization strategy in mice was also developed to block pilin-mediated binding of P. aeruginosa to airway epithelial cells (59). Vaccinations were performed using ntPEpilinPAK, a protein chimera made of a nontoxic form of P. aeruginosa exotoxin A (ntPE). Intranasal immunization with ntPEpilinPAK in BALB/c mice generated immune responses in both serum and saliva. Importantly, this method of immunization induced both mucosal and systemic immune responses that are beneficial for blocking early stage adhesion and/or infection after epithelial cell–P. aeruginosa interactions on oropharyngeal surfaces. This method holds great potential since a number of transmissible P. aeruginosa strains have been identified that potentially constitute an emerging threat to patients with CF (60).

S. aureus
Using single or repetitive intranasal infection with S. aureus, Snouwaert and coworkers reported that CFTRtm1UNC mice cleared bacteria as efficiently as CFTR heterozygous mice (61). In contrast, intratracheal instillation of S. aureus induced an acute inflammatory reaction but did not result in chronic lung disease (62). Davidson and colleagues, using daily aerosol challenges with S. aureus in CFTRtm1HGU mice, reported higher bacterial loads and more pronounced disease in the lungs of CF mice compared with their littermate controls, although no infectious dose was reported. CF mice showed a higher incidence of goblet cell hyperplasia, mucus retention, and bronchiolitis when compared with control mice (30).

B. cepacia
Establishing bacterial infection in rodent lungs is more difficult for B. cepacia than for S. aureus. Davidson and coworkers infected CFTRtm1HGU mice with aerosolized B. cepacia daily for a period of 1 mo. CF mice exhibited distinctive pathology as compared with control mice. As compared with WT mice, CF mice demonstrated more extensive areas of pneumonia and mucus retention, destruction of small airways, and edema. We have also studied B. cepacia infection in CFTRtm1UNC mice using repetitive intranasal instillation (63). Nine days after the last instillation, CF knockout mice displayed persistence of viable bacteria with chronic severe bronchopneumonia. The mortality in this experiment was low. The CFTRtm1UNC mice demonstrated an enhanced pulmonary inflammatory response characterized by infiltration of neutrophils and macrophages into the peribroncholear and perivascular space. Neutrophils and macrophages from CF mice manifest impaired activation, which may have contributed to bacterial persistence. Furthermore, enhanced pulmonary inflammation and injury were dependent on bacterial virulence based on infection with strains of B. cepacia of varying virulence.

Toll-Like Receptor Involvement
The intestinal epithelium is exposed to a high level of microbes and microbial products, and therefore has a huge impact on the inflammatory response. Mucosal immunity involves Toll-like receptors (TLRs), which line the polarized epithelium and accumulate within the lumen, where large numbers of neutrophils migrate to when there is an inflammatory response (64). The TLRs recognize microbial components and activate an innate inflammatory response. The distribution and function of TLRs in airway cells were studied to identify which are available to signal the presence of inhaled pathogens in the context of CF. TLRs 1–10, MD2, and MyD88 were expressed in CF and normal cells. TLR2 was predominantly at the apical surface of airway cells and TLR4 was present in a more basolateral distribution in airway cells (65). The increased TLR2 expression at the apical surfaces of CF epithelial cells is consistent with the increased inflammatory responses seen in CF airways and involves the participation of TLRs in the airway mucosa. Suppression of these TLR responses may reduce excessive inflammation in chronic diseases like CF.


   NOVEL TREATMENT APPROACHES
Top
 Abstract
 CYSTIC FIBROSIS
 GENOTYPES
 PHENOTYPES
 MURINE MODELS OF CF...
 NOVEL TREATMENT APPROACHES
References
 
Various strategies are used to manage airway inflammation and other pathologies associated with CF (66), but the challenge persists in finding drugs that combine effective anti-inflammatory activity in the CF lung with an acceptable risk of adverse effects.

There is strong evidence that nutritional status is important in determining the clinical course in patients with CF. Imbalance of fatty acids such as docosahexanoic acid (C22:6(n-3); DHA), arachidonic acid (C20:4(n-6); AA) and other important lipids could ultimately lead to increased severity of disease. While van Heeckeren and colleagues showed that DHA had no effect on the host response to P. aeruginosa (67), Freedman and coworkers showed that DHA decreased eicosanoids and neutrophils in cftr–/– mice, concluding that the lipid imbalance played an important role in pathogenesis of pulmonary inflammation (25, 68). Interestingly, treatments with antioxidants (vitamins A, C, E, beta-carotene, and linolenic acid) have been shown to improve neutrophil recruitment and gas exchange in CF lungs that endure increased oxidative stress. Therefore, enhancing the antioxidant defences in the airway surface liquid by dietary modification may decrease oxidative damage to the lung (69). Further, treatment strategies can be designed to enhance CFTR protein production. For example, {Delta}F508 CFTR maturation could be ameliorated by using chaperones, such as genistein, to help the protein target to the apical surface of the cell (70–72).

A recent study has also demonstrated that type I collagen induces murine embryonic stem (ES) cells to differentiate into nonciliated secretory Clara cells and that when cultured at the air–liquid interface, ES cells give rise to a fully differentiated airway epithelium (73). These results open new perspectives for cell therapy of injured epithelium in airway diseases. Overall, early preventive treatment combining nutritional therapy, physiotherapy, and pharmaceutical therapy may help improve the prognosis in patients with CF.

CONCLUSION
It is evident that animal models have contributed significantly to a better understanding of many aspects of human genetic diseases. Cystic fibrosis is a complex disease with more than one thousand reported mutations in the Cftr gene, which in turn present with different phenotypes and affect multiple organs. Thus, no single animal model can represent all aspects of this disease. Some animals are closer to humans phylogenically with respect to the genomic sequence of the CFTR gene, while others more faithfully reflect the phenotypes observed in specific organs in humans. These models should be exploited as powerful tools that will enable a better understanding of this devastating genetic disease.


   Footnotes
 
Originally Published in Press as DOI: 10.1165/rcmb.2006-0184TR on August 3, 2006

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form May 26, 2006

Accepted in final form July 27, 2006


   References
Top
 Abstract
 CYSTIC FIBROSIS
 GENOTYPES
 PHENOTYPES
 MURINE MODELS OF CF...
 NOVEL TREATMENT APPROACHES
 References
 

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