HSP90 inhibitor geldanamycin reverts IL-13- and IL-17-induced airway goblet cell metaplasia.

Goblet cell metaplasia, a disabling hallmark of chronic lung disease, lacks curative treatments at present. To identify novel therapeutic targets for goblet cell metaplasia, we studied the transcriptional response profile of IL-13-exposed primary human airway epithelia in vitro and asthmatic airway epithelia in vivo. A perturbation-response profile connectivity approach identified geldanamycin, an inhibitor of heat shock protein 90 (HSP90) as a candidate therapeutic target.

Postnatal airway growth in cystic fibrosis piglets.

Mutations in the gene encoding the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) anion channel cause CF. The leading cause of death in the CF population is lung disease. Increasing evidence suggests that in utero airway development is CFTR-dependent and that developmental abnormalities may contribute to CF lung disease.

Repurposing tromethamine as inhaled therapy to treat CF airway disease.

In cystic fibrosis (CF), loss of CF transmembrane conductance regulator (CFTR) anion channel activity causes airway surface liquid (ASL) pH to become acidic, which impairs airway host defenses. One potential therapeutic approach is to correct the acidic pH in CF airways by aerosolizing HCO and/or nonbicarbonate pH buffers. Here, we show that raising ASL pH with inhaled HCO increased pH.

Electrolyte transport properties in distal small airways from cystic fibrosis pigs with implications for host defense.

While pathological and clinical data suggest that small airways are involved in early cystic fibrosis (CF) lung disease development, little is known about how the lack of cystic fibrosis transmembrane conductance regulator (CFTR) function contributes to disease pathogenesis in these small airways. Large and small airway epithelia are exposed to different airflow velocities, temperatures, humidity, and CO2 concentrations. The cellular composition of these two regions is different, and small airways lack submucosal glands.

Glycaemic regulation and insulin secretion are abnormal in cystic fibrosis pigs despite sparing of islet cell mass.

Diabetes is a common and significant co-morbidity in cystic fibrosis (CF). The pathogenesis of cystic fibrosis related diabetes (CFRD) is incompletely understood. Because exocrine pancreatic disease is similar between humans and pigs with CF, the CF pig model has the potential to contribute significantly to the understanding of CFRD pathogenesis.

Air trapping and airflow obstruction in newborn cystic fibrosis piglets.

Rationale: Air trapping and airflow obstruction are being increasingly identified in infants with cystic fibrosis. These findings are commonly attributed to airway infection, inflammation, and mucus buildup.

Objectives: To learn if air trapping and airflow obstruction are present before the onset of airway infection and inflammation in cystic fibrosis.

Intestinal CFTR expression alleviates meconium ileus in cystic fibrosis pigs.

Cystic fibrosis (CF) pigs develop disease with features remarkably similar to those in people with CF, including exocrine pancreatic destruction, focal biliary cirrhosis, micro-gallbladder, vas deferens loss, airway disease, and meconium ileus. Whereas meconium ileus occurs in 15% of babies with CF, the penetrance is 100% in newborn CF pigs. We hypothesized that transgenic expression of porcine CF transmembrane conductance regulator (pCFTR) cDNA under control of the intestinal fatty acid-binding protein (iFABP) promoter would alleviate the meconium ileus.

Expression of human paraoxonase 1 decreases superoxide levels and alters bacterial colonization in the gut of Drosophila melanogaster.

Paraoxonases (PON) are a family of proteins (PON1, 2 and 3) with multiple enzymatic activities. PON1 interferes with homoserine lactone-mediated quorum sensing in bacteria and with reactive oxygen species (ROS) in humans and mice. PON1 gene mutations have been linked to multiple traits, including aging, and diseases of the cardiovascular, nervous and gastrointestinal system.

Pancreatic and biliary secretion are both altered in cystic fibrosis pigs.

The pancreas, liver, and gallbladder are commonly involved in cystic fibrosis (CF), and acidic, dehydrated, and protein-rich secretions are characteristic findings. Pancreatic function studies in humans have been done by sampling the jejunal fluid. However, it has been difficult to separately study the function of pancreatic and biliary systems in humans with CF, because jejunal fluid contains a mixture of bile and pancreatic fluids.

CFTR is required for maximal transepithelial liquid transport in pig alveolar epithelia.

A balance between alveolar liquid absorption and secretion is critical for maintaining optimal alveolar subphase liquid height and facilitating gas exchange in the alveolar space. However, the role of cystic fibrosis transmembrane regulator protein (CFTR) in this homeostatic process has remained elusive. Using a newly developed porcine model of cystic fibrosis, in which CFTR is absent, we investigated ion transport properties and alveolar liquid transport in isolated type II alveolar epithelial cells (T2AECs) cultured at the air-liquid interface.

The ΔF508 mutation causes CFTR misprocessing and cystic fibrosis-like disease in pigs.

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. The most common CF-associated mutation is ΔF508, which deletes a phenylalanine in position 508. In vitro studies indicate that the resultant protein, CFTR-ΔF508, is misprocessed, although the in vivo consequences of this mutation remain uncertain.

Glucose depletion in the airway surface liquid is essential for sterility of the airways.

Diabetes mellitus predisposes the host to bacterial infections. Moreover, hyperglycemia has been shown to be an independent risk factor for respiratory infections. The luminal surface of airway epithelia is covered by a thin layer of airway surface liquid (ASL) and is normally sterile despite constant exposure to bacteria.

Cystic fibrosis pigs develop lung disease and exhibit defective bacterial eradication at birth.

Lung disease causes most of the morbidity and mortality in cystic fibrosis (CF). Understanding the pathogenesis of this disease has been hindered, however, by the lack of an animal model with characteristic features of CF. To overcome this problem, we recently generated pigs with mutated CFTR genes.

Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs.

Almost two decades after CFTR was identified as the gene responsible for cystic fibrosis (CF), we still lack answers to many questions about the pathogenesis of the disease, and it remains incurable. Mice with a disrupted CFTR gene have greatly facilitated CF studies, but the mutant mice do not develop the characteristic manifestations of human CF, including abnormalities of the pancreas, lung, intestine, liver, and other organs. Because pigs share many anatomical and physiological features with humans, we generated pigs with a targeted disruption of both CFTR alleles.

Drosophila are protected from Pseudomonas aeruginosa lethality by transgenic expression of paraoxonase-1.

Pseudomonas aeruginosa uses quorum sensing, an interbacterial communication system, to regulate gene expression. The signaling molecule N-3-oxododecanoyl homoserine lactone (3OC12-HSL) is thought to play a central role in quorum sensing. Since 3OC12-HSL can be degraded by paraoxonase (PON) family members, we hypothesized that PONs regulate P.

Hemodialysis-related steal syndrome: predictive factors and response to treatment with the distal revascularization-interval ligation procedure.

Hand ischemia due to steal causes major disability in affected members of the hemodialysis population. Between February 2000 and March 2007, 24 patients aged 37-77 years were identified who developed hand ischemia distal to a hemodialysis access and required a distal revascularization-interval ligation (DRIL) procedure. Of the 24 patients, 22 (92%) were diabetic, 14 (58%) were women, 7 (29%) had prosthetic grafts, and 17 (71%) had fistulas, all originating from the brachial artery.

Bronchoscopic imaging of pulmonary mucosal vasculature responses to inflammatory mediators.

In current clinical practice, the initial stage in the detection of pulmonary airway disease is the clinician's interpretation of a bronchoscopy procedure. Due to the nature of this form of detection, diseases are often well advanced upon discovery. This paper proposes a new method for examining the pulmonary airway microcirculatory system via fluorescein imaging techniques similar to those used extensively in ophthalmology.

Lysozyme secretion by submucosal glands protects the airway from bacterial infection.

Submucosal glands are abundant (approximately 1 gland/mm2) secretory structures in the tracheobronchial airways of the human lung. Because submucosal glands express antibacterial proteins, it has been proposed that they contribute to lung defense. However, this concept is challenged by the fact that mice do not have submucosal glands in their bronchial airways, yet are quite resistant to bacterial lung infection.

Xylitol enhances bacterial killing in the rabbit maxillary sinus.

Objectives: Factors that alter airway surface liquid (ASL) ionic concentrations may influence the course of sinusitis. Xylitol has been shown to effect ASL ionic composition in vitro and to reduce nasal bacterial carriage, otitis media, and dental caries in vivo. We examined the effect of xylitol on experimental sinusitis in the rabbit model.

Nonoperative management of acute spontaneous renal artery dissection.

Isolated spontaneous renal artery dissection is a rare condition that can result in renal parenchymal loss and severe hypertension. Although several risk factors have been identified in association with renal artery dissection, the natural history is not well defined. The rarity and nonspecific presentation of the disease often lead to diagnostic delay.

A study to assess the efficacy of chemoprophylaxis in the prevention of endoscopy-related bacteraemia in patients aged 60 and over.

Five hundred and fifteen patients aged 60 and over (mean age 74.7; 278 men and 237 women) underwent routine endoscopic procedures (gastroscopy, bronchoscopy and cystoscopy). Alternate patients were given antibiotics before the procedure, as currently recommended, and blood was taken for culture from all patients within five minutes of completion of the procedure.

Correlation of ascitic fluid cytology with histologic findings before and after treatment of ovarian cancer.

One hundred thirteen specimens of ascitic fluid from 97 patients with primary, persistent, or recurrent ovarian cancer were examined cytologically. Advanced stage of disease, involvement of the ovarian surface, a moderate or large volume of fluid, and nonbloody serous ascites were factors that correlated with a high rate of positive findings in ascites in these patients. Other factors influencing the positive rate appeared to be the invasive as opposed to borderline malignant histology of the tumor.

Peritoneal fluid cytology in patients with ovarian cancer.

Peritoneal fluid was examined for the presence of tumor cells in 94 patients with ovarian cancer. The findings were correlated with the type, grade, and stage of the tumor. Fluids that were positive for malignant cells were associated with serous and endometrioid carcinomas more often than with carcinomas of other types.

Bile cytology. A routine addition to percutaneous biliary drainage.

Exfoliative cytology of bile aspirated from percutaneously placed combined external/internal biliary drainage catheters yielded positive results in 34% of 100 cases. There were no false-positive results. Bile cytology is a simple, inexpensive, and useful method which can establish a diagnosis of malignant biliary obstruction after catheter decompression.