Kalpaj R. Parekh

Human cystic fibrosis airway epithelia have reduced Cl− conductance but not increased Na+ conductance

Loss of cystic fibrosis transmembrane conductance regulator (CFTR) anion channel function causes cystic fibrosis (CF) lung disease. CFTR is expressed in airway epithelia, but how CF alters electrolyte transport across airway epithelia has remained uncertain. Recent studies of a porcine model showed that in vivo, excised, and cultured CFTR−/− and CFTRΔF508/ΔF508 airway epithelia lacked anion conductance, and they did not hyperabsorb Na+. Therefore, we asked whether Cl− and Na+ conductances were altered in human CF airway epithelia. We studied differentiated primary cultures of tracheal/bronchial epithelia and found that transepithelial conductance (Gt) under basal conditions and the cAMP-stimulated increase in Gt were markedly attenuated in CF epithelia compared with non-CF epithelia. These data reflect loss of the CFTR anion conductance. In CF and non-CF epithelia, the Na+ channel inhibitor amiloride produced similar reductions in Gt and Na+ absorption, indicating that Na+ conductance in CF epithelia did not exceed that in non-CF epithelia. Consistent with previous reports, adding amiloride caused greater reductions in transepithelial voltage and short-circuit current in CF epithelia than in non-CF epithelia; these changes are attributed to loss of a Cl− conductance. These results indicate that Na+ conductance was not increased in these cultured CF tracheal/bronchial epithelia and point to loss of anion transport as key to airway epithelial dysfunction in CF.

Isoform-Specific Regulation and Localization of the Coxsackie and Adenovirus Receptor in Human Airway Epithelia

Adenovirus is an important respiratory pathogen. Adenovirus fiber from most serotypes co-opts the Coxsackie-Adenovirus Receptor (CAR) to bind and enter cells. However, CAR is a cell adhesion molecule localized on the basolateral membrane of polarized epithelia. Separation from the lumen of the airways by tight junctions renders airway epithelia resistant to inhaled adenovirus infection. Although a role for CAR in viral spread and egress has been established, the mechanism of initial respiratory infection remains controversial. CAR exists in several protein isoforms including two transmembrane isoforms that differ only at the carboxy-terminus (CAREx7 and CAREx8). We found low-level expression of the CAREx8 isoform in well-differentiated human airway epithelia. Surprisingly, in contrast to CAREx7, CAREx8 localizes to the apical membrane of epithelia where it augments adenovirus infection. Interestingly, despite sharing a similar class of PDZ-binding domain with CAREx7, CAREx8 differentially interacts with PICK1, PSD-95, and MAGI-1b. MAGI-1b appears to stoichiometrically regulate the degradation of CAREx8 providing a potential mechanism for the apical localization of CAREx8 in airway epithelial. In summary, apical localization of CAREx8 may be responsible for initiation of respiratory adenoviral infections and this localization appears to be regulated by interactions with PDZ-domain containing proteins.

The effect of lung size mismatch on complications and resource utilization after bilateral lung transplantation

BACKGROUND Oversizing the lung allograft, as estimated by a donor-to-recipient predicted total lung capacity (pTLC) ratio > 1.0, was associated with improved long-term survival after lung transplantation (LTx) but could be associated with increased post-operative complications and higher resource utilization. METHODS The prospectively maintained LTx database at The Johns Hopkins Hospital was retrospectively reviewed for bilateral LTx patients in the post-Lung Allocation Score (LAS) era. Patients were grouped by pTLC ratio ≤ 1.0 (undersized) or > 1.0 (oversized). Post-operative complications and hospital charges were analyzed. RESULTS The pTLC ratio was available for 70 patients: 31 were undersized and 39 oversized. Undersized patients had a higher LAS (40.4 vs 35.8, p = 0.009), were more often in the intensive care unit (ICU) pre-LTx (35% vs 10%, p = 0.01), and had a higher occurrence of primary graft dysfunction (PGD; 25% vs 5%, p = 0.013) and tracheostomy (32% vs 10%, p = 0.02), longer index hospitalizations (20 [interquartile range (IQR), 10-46] vs 16 [IQR, 12-25] days, p = 0.048), and higher index hospitalization charges (

O2⋅− and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate

176,247 [IQR,

Lung Phenotype of Juvenile and Adult Cystic Fibrosis Transmembrane Conductance Regulator–Knockout Ferrets

137,646-

CGRP induction in cystic fibrosis airways alters the submucosal gland progenitor cell niche in mice

284,012] vs

Gastrointestinal pathology in juvenile and adult CFTR-knockout ferrets.

158,492 [IQR,

Lung Size Mismatch and Survival After Single and Bilateral Lung Transplantation

136,250-

Kaizen Method for Esophagectomy Patients: Improved Quality Control, Outcomes, and Decreased Costs

191,301], p = 0.04). After adjusting for LAS and pre-LTx ICU stay, a lower pTLC ratio remained associated with higher hospital charges (p = 0.049). Airway complications were more frequent and severe in undersized patients. CONCLUSION Oversized allografts were not associated with an increase in post-LTx complications. However, LTx recipients of undersized allografts were more likely to experience PGD, tracheostomy, and had higher resource utilization. Higher acuity in the undersized group might explain these findings; however, multivariate models suggest an independent association between undersizing, PGD, and resource utilization.

Sox2 modulates Lef-1 expression during airway submucosal gland development

Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H2O2; however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O2⋅- and H2O2 are capable of disrupting intracellular iron metabolism, thereby selectively sensitizing non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox-active labile iron and H2O2. In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.