The cystic fibrosis transmembrane conductance regulator CFTR gene is found on chromosome 7 [Kerem, B., Rommens, J.M., Buchanan, J.A., Markiewicz, D., Cox, T.K., Chakravarti, A., Buchwald, M., Tsui, L.C., 1989. Identification of the cystic fibrosis gene: genetic analysis. Science 245, 1073-1080; Riordan, J.R., Rommens, J.M., Kerem, B., Alon, N., Rozmahel, R., Grzelczak, Z., Zielenski, J., Lok, S., Plavsic, N., Chou, J.L., et al., 1989. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245, 1066-1073] and encodes for a 1480 amino acid protein which is present in the plasma membrane of epithelial cells [Anderson, M.P., Sheppard, D.N., Berger, H.A., Welsh, M.J., 1992. Chloride channels in the apical membrane of normal and cystic fibrosis airway and intestinal epithelia. Am. J. Physiol. 263, L1-L14]. This protein appears to have many functions, but a unifying theme is that it acts as a protein kinase C- and cyclic AMP-regulated Cl(-) channel [Winpenny, J.P., McAlroy, H.L., Gray, M.A., Argent, B.E., 1995. Protein kinase C regulates the magnitude and stability of CFTR currents in pancreatic duct cells. Am. J. Physiol. 268, C823-C828; Jia, Y., Mathews, C.J., Hanrahan, J.W., 1997. Phosphorylation by protein kinase C is required for acute activation of cystic fibrosis transmembrane conductance regulator by protein kinase A. J. Biol. Chem. 272, 4978-4984]. In the superficial epithelium of the conducting airways, CFTR is involved in Cl(-) secretion [Boucher, R.C., 2003. Regulation of airway surface liquid volume by human airway epithelia. Pflugers Arch. 445, 495-498] and also acts as a regulator of the epithelial Na(+) channel (ENaC) and hence Na(+) absorption [Boucher, R.C., Stutts, M.J., Knowles, M.R., Cantley, L., Gatzy, J.T., 1986. Na(+) transport in cystic fibrosis respiratory epithelia. Abnormal basal rate and response to adenylate cyclase activation. J. Clin. Invest. 78, 1245-1252; Stutts, M.J., Canessa, C.M., Olsen, J.C., Hamrick, M., Cohn, J.A., Rossier, B.C., Boucher, R.C., 1995. CFTR as a cAMP-dependent regulator of sodium channels. Science 269, 847-850]. In this chapter, we will discuss the regulation of these two ion channels, and how they can influence liquid movement across the superficial airway epithelium.

Adenosine (ADO) signaling is altered in both asthma and chronic obstructive pulmonary disease, and the A 2B adenosine receptor (A 2B -R) may drive pulmonary inflammation. Accordingly, it has been proposed that specific inhibition of the A 2B -R could treat inflammatory lung diseases. However, stimulation of the cystic fibrosis transmembrane conductance regulator (CFTR) by ADO may be crucial in permitting the superficial epithelium to maintain airway surface liquid (ASL) volume, which is required to ensure hydrated and clearable mucus. Our goal was to determine which ADO receptor (ADO-R) underlies ASL volume regulation in bronchial epithelia. We used PCR techniques to determine ADO-R expression in bronchial epithelia and used nasal potential difference measurements, Ussing chambers studies, and XZ-confocal microscopy to look at Cl -secretion and ASL volume regulation. The A 2B -R was the most highly expressed ADO-R in donor specimens of human bronchial epithelia, and inhibition of ADO-R in vivo prevented activation of CFTR. A 2B -R was the only ADO-R detected in cultured human bronchial epithelial cells and inhibition of this receptor with specific A 2B -R antagonists resulted in ASL height collapse and a failure to effect ASL height homeostasis. Removal of ADO with ADO deaminase and replacement with 59N-ethylcarboxamide adenosine resulted in dosedependent changes in ASL height, and suggested that the cell surface (ADO) may be in excess of 1 mM, which is sufficient to activate A 2B -R. A 2B -R are required for ASL volume homeostasis in human airways, and therapies directed at inhibiting A 2B -R may lead to a cystic fibrosis-like phenotype with depleted ASL volume and mucus stasis.

BACKGROUND: Orthotopic heart transplantation (OHT) recipients may be particularly vulnerable to coronavirus disease 2019 (COVID-19). OHT during the pandemic presents unique challenges in terms of feasibility and safety. METHODS: Chart review was performed for consecutive OHT recipients with COVID-19 and waitlisted patients who underwent OHT from March 1, 2020 to May 15, 2020. RESULTS: Of the approximately 400 OHT recipients followed at our institution, 22 acquired COVID-19. Clinical characteristics included median age 59 (range, 49−71) years, 14 (63.6%) were male, and median time from OHT to infection was 4.6 (2.5−20.6) years. Symptoms included fever (68.2%), gastrointestinal complaints (55%), and cough (46%). COVID-19 was severe or critical in 5 (23%). All patients had elevated inflammatory biomarkers. Immunosuppression was modified in 85% of patients. Most (n = 16, 86.4%) were hospitalized, 18% required intubation, and 14% required vasopressor support. Five patients (23%) expired. None of the patients requiring intubation survived. Five patients underwent OHT during the pandemic. They were all males, ranging from 30 to 59 years of age. Two were transplanted at United Network of Organ Sharing Status 1 or 2, 1 at Status 3, and 2 at Status 4. All were successfully discharged and are alive without allograft dysfunction or rejection. One contracted mild COVID-19 after the index hospitalization. CONCLUSION: OHT recipients with COVID-19 appear to have outcomes similar to the general population hospitalized with COVID-19. OHT during the pandemic is feasible when appropriate precautions are taken. Further study is needed to guide immunosuppression management in OHT recipients affected by COVID-19.

Throughout the body, the epithelial Na+ channel (ENaC) plays a critical role in salt and liquid homeostasis. In cystic fibrosis airways, for instance, improper regulation of ENaC results in hyperabsorption of sodium that causes dehydration of airway surface liquid. This dysregulation then contributes to mucus stasis and chronic lung infections. ENaC is known to undergo proteolytic cleavage, which is required for its ability to conduct Na+ ions. We have previously shown that the short, palate lung and nasal epithelial clone (SPLUNC1) binds to and inhibits ENaC in both airway epithelia and in Xenopus laevis oocytes. In this study, we found that SPLUNC1 was more potent at inhibiting ENaC than either SPLUNC2 or long PLUNC1 (LPLUNC1), two other PLUNC family proteins that are also expressed in airway epithelia. Furthermore, we were able to shed light on the potential mechanism of SPLUNC1's inhibition of ENaC. While SPLUNC1 did not inhibit proteolytic activity of trypsin, it significantly reduced ENaC currents by reducing the number of ENaCs in the plasma membrane. A better understanding of ENaC's regulation by endogenous inhibitors may aid in the development of novel therapies designed to inhibit hyperactive ENaC in cystic fibrosis epithelia.

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