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Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), a multiorgan disease that is characterized by diverse metabolic defects. However, other than specific CFTR mutations, the factors that influence disease progression and severity remain poorly understood. Aberrant metabolite levels have been reported, but whether CFTR loss itself or secondary abnormalities (infection, inflammation, malnutrition, and various treatments) drive metabolic defects is uncertain. Here, we implemented comprehensive arteriovenous metabolomics in newborn CF pigs, and the results revealed CFTR as a bona fide regulator of metabolism. CFTR loss impaired metabolite exchange across organs, including disruption of lung uptake of fatty acids, yet enhancement of uptake of arachidonic acid, a precursor of proinflammatory cytokines. CFTR loss also impaired kidney reabsorption of amino acids and lactate and abolished renal glucose homeostasis. These and additional unexpected metabolic defects prior to disease manifestations reveal a fundamental role for CFTR in controlling multiorgan metabolism. Such discovery informs a basic understanding of CF, provides a foundation for future investigation, and has implications for developing therapies targeting only a single tissue., Introduction Cystic fibrosis (CF) is an autosomal recessive disease caused by loss-of-function mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) anion channel (1-4). The clinical phenotype is [...]

C3 glomerulopathy (C3G) defines a group of untreatable ultra-rare renal diseases caused by uncontrolled activation of the alternative complement pathway. Nearly half of patients progress to end stage renal failure within 10 years. Cp40, a second-generation compstatin analog in clinical development, is a 14 amino-acid cyclic peptide that selectively inhibits complement activation in humans and non-human primates by binding to C3 and C3b. We hypothesized that by targeting C3 Cp40 would provide an effective treatment for C3G. By investigating its effects in vitro using multiple assays of complement activity, we show that Cp40 prevents complement-mediated lysis of sheep erythrocytes in sera from C3G patients, prevents complement dysregulation in the presence of patient-derived autoantibodies to the C3 and C5 convertases, and prevents complement dysregulation associated with disease-causing genetic mutations. In aggregate, these data suggest that Cp40 may offer a novel and promising therapeutic option to C3G patients as a disease-specific, targeted therapy. As such, Cp40 could represent a major advance in the treatment of this disease. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) is a genetic disorder characterized by recurrent airway infections, inflammation, impaired mucociliary clearance, and progressive decline in lung function. The disease may start in the small airways; however, this is difficult to prove due to the limited accessibility of the small airways with the current single-photon mucociliary clearance assay. Here, we developed a dynamic positron emission tomography assay with high spatial and temporal resolution. We tested that mucociliary clearance is abnormal in the small airways of newborn cystic fibrosis pigs. Clearance of [ 68 Ga]-tagged macroaggregated albumin from small airways started immediately after delivery and continued for the duration of the study. Initial clearance was fast but slowed down a few minutes after delivery. Cystic fibrosis pigs' small airways cleared significantly less than non-CF pigs' small airways (non-CF 25.1 ± 3.1% vs. CF 14.6 ± 0.1%). Stimulation of the cystic fibrosis airways with the purinergic secretagogue uridine-5'-triphosphate (UTP) further impaired clearance (non-CF with UTP 20.9 ± 0.3% vs. CF with UTP 13.0 ± 1.8%). None of the cystic fibrosis pigs treated with UTP ( n = 6) cleared more than 20% of the delivered dose. These data indicate that mucociliary clearance in the small airways is fast and can easily be missed if the assay is not sensitive enough. The data also indicate that mucociliary clearance is impaired in the small airways of cystic fibrosis pigs. This defect is exacerbated by stimulation of mucus secretions with purinergic agonists. NEW & NOTEWORTHY We developed a novel positron emission tomography scan assay with unprecedented temporal and spatial resolution to measure mucociliary clearance in the small airways. We proved a long-standing but unproven assertion that mucociliary clearance is inherently abnormal in the small airways of newborn cystic fibrosis piglets that are otherwise free of infection or inflammation. This technique can be easily extended to other airway diseases such as asthma, idiopathic pulmonary fibrosis, or chronic obstructive pulmonary disease.

Systemic inflammatory response syndrome (SIRS) is a common clinical condition in patients in intensive care units that can lead to complications, including multiple organ dysfunction syndrome (MODS). MODS carries a high mortality rate, and it is unclear why some patients resolve SIRS, whereas others develop MODS. Although oxidant stress has been implicated in the development of MODS, several recent studies have demonstrated a requirement for NADPH oxidase 2 (NOX2)-derived oxidants in limiting inflammation. We recently demonstrated that NOX2 protects against lung injury and mortality in a murine model of SIRS. In the present study, we investigated the role of NOX2-derived oxidants in the progression from SIRS to MODS. Using a murine model of sterile systemic inflammation, we observed significantly greater illness and subacute mortality in gp91(phox-/y) (NOX2-deficient) mice compared with wild-type mice. Cellular analysis revealed continued neutrophil recruitment to the peritoneum and lungs of the NOX2-deficient mice and altered activation states of both neutrophils and macrophages. Histological examination showed multiple organ pathology indicative of MODS in the NOX2-deficient mice, and several inflammatory cytokines were elevated in lungs of the NOX2-deficient mice. Overall, these data suggest that NOX2 function protects against the development of MODS and is required for normal resolution of systemic inflammation., (Copyright © 2014 the American Physiological Society.)