SUMMARY Almost two decades after identification of the CFTR gene, we lack answers to many questions about the pathogenesis of cystic fibrosis (CF), and it remains a lethal disease. Mice with a disrupted CFTR gene have greatly facilitated CF studies, but they fail to develop the characteristic pancreatic, lung, intestinal, liver, and other CF manifestations. Therefore, we produced pigs with a targeted disruption of both CFTR alleles. These animals exhibited defective chloride transport. They also developed meconium ileus, exocrine pancreatic destruction, and focal biliary cirrhosis, replicating abnormalities seen in newborn patients with CF. This swine model may provide opportunities to address persistent questions about CF pathogenesis and accelerate discovery of treatments and preventions.

NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptLung disease causes most of the morbidity and mortality in cystic fibrosis (CF). However, understanding its pathogenesis has been hindered by lack of an animal model with characteristic features of CF. To overcome this problem, we recently generated pigs with targeted CFTR genes. We now report that, within months of birth, CF pigs spontaneously develop hallmark features of CF lung disease including airway inflammation, remodeling, mucus accumulation, and infection. Their lungs contained multiple bacterial species, suggesting an equal opportunity host defense defect. In humans, the temporal and causal relationships between inflammation and infection have remained uncertain. To investigate these processes, we studied newborn pigs. Their lungs showed no inflammation, but were less often sterile than controls. Moreover, after intrapulmonary bacterial challenge, CF pigs failed to eradicate bacteria as effectively as wild-type pigs. These results suggest that impaired bacterial elimination is the pathogenic event that initiates a cascade of inflammation and pathology in CF lungs. Finding that CF pigs have a bacterial host defense defect within hours of birth provides an opportunity to further investigate pathogenesis and to test therapeutic and preventive strategies before secondary consequences develop.

Objectives There is limited literature on acute pancreatitis (AP), acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) in children. The INSPPIRE (International Study group of Pediatric Pancreatitis: In search for a cure) consortium was formed to standardize definitions, develop diagnostic algorithms, investigate disease pathophysiology and design prospective multicenter studies in pediatric pancreatitis. Methods Subcommittees were formed to delineate definitions of pancreatitis and a survey was conducted to analyze current practice. Results Acute pancreatitis (AP) was defined as requiring 2 of: (1) abdominal pain compatible with AP, (2) serum amylase and/or lipase values ≥3 times upper limits of normal, (3) imaging findings of AP. ARP was defined as: ≥2 distinct episodes of AP with intervening return to baseline. CP was diagnosed in the presence of: (1) typical abdominal pain plus characteristic imaging findings or; (2) exocrine insufficiency plus imaging findings or; (3) endocrine insufficiency plus imaging findings. We found that children with pancreatitis were primarily managed by pediatric gastroenterologists. Unless the etiology was known, initial investigations included serum liver enzymes, triglycerides, calcium, and abdominal ultrasound. Further investigations (usually for ARP and CP) included magnetic resonance or other imaging, sweat chloride, and genetic testing. Respondents’ future goals for INSPPIRE included: (1) determining natural history of pancreatitis; (2) eveloping algorithms to evaluate and manage pancreatitis; and (3) validating diagnostic criteria. Conclusions INSPPIRE represents the first initiative to create a multicenter approach to systematically characterize pancreatitis in children. Future aims include creation of patient database and biologic sample repository.

Mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel cause the autosomal recessive disease, cystic fibrosis (CF). The most common mutation is ΔF508, which deletes phenylalanine508. In vitro studies indicate that CFTR-ΔF508 is misprocessed, though in vivo consequences of the mutation are uncertain. To better understand effects of the ΔF508 mutation, we produced CFTRΔF508/ΔF508 pigs. Our biochemical, immunocytochemical and electrophysiological data on CFTR-ΔF508 in newborn pigs paralleled in vitro results. They also indicated that CFTRΔF508/ΔF508 airway epithelia retain a small residual CFTR conductance; maximal stimulation produced ~6% of wild-type function. Interestingly, cAMP agonists were less potent at stimulating current in CFTRΔF508/ΔF508 epithelia, suggesting that quantitative tests of maximal anion current may overestimate transport under physiological conditions. Despite residual CFTR function, four older CFTRΔF508/ΔF508 pigs developed lung disease strikingly similar to human CF. These results suggest that this limited CFTR activity is insufficient to prevent lung or gastrointestinal disease in CF pigs. These data also suggest that studies of recombinant CFTR-ΔF508 misprocessing predict in vivo behavior, which validates its use in biochemical and drug discovery experiments. These findings help elucidate the molecular pathogenesis of the common CF mutation and will guide strategies for developing new therapeutics.

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Objective To determine the clinical presentation, diagnostic variables, risk factors and disease burden in children with chronic pancreatitis. Study design We performed a cross-sectional study of data from INSPPIRE (International Study Group of Pediatric Pancreatitis: In search for a cuRE), a registry of children with acute recurrent pancreatitis and chronic pancreatitis. Between-group differences were compared using Wilcoxon rank-sum test. Results Among 170 subjects in the registry, 76 (45%) had chronic pancreatitis; 57% were female, 80% were Caucasian, median age at diagnosis was 9.9 years. Pancreatitis-predisposing genetic mutations were identified in 51 (67%) and obstructive risk factors in 25 (33%). Toxic/metabolic and autoimmune factors were uncommon. Imaging demonstrated ductal abnormalities and pancreatic atrophy more commonly than calcifications. Fifty-nine (77%) reported abdominal pain within the past year; pain was reported as constant and receiving narcotics in 28%. Children with chronic pancreatitis reported a median of 3 emergency room visits and 2 hospitalizations in the last year. Forty-seven subjects (70%) missed one day of school in the past month due to chronic pancreatitis; 26 (34%) missed 3 or more days. Children reporting constant pain were more likely to miss school (p=0.002), visit emergency room (p=0.01) and experience hospitalizations (p=0.03) compared with children with episodic pain. Thirty-three children (43%) underwent therapeutic ERCP; one or more pancreatic surgeries were performed in 30 (39%). Conclusions Chronic pancreatitis occurs at a young age with distinct clinical features. Genetic and obstructive risk factors are common, and disease burden is substantial.

This clinical report represents the first English-language recommendations for the management of pediatric AP. Future aims should include prospective multicenter pediatric studies to further validate these recommendations and optimize care for children with AP.

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