The life of patients with Cystic fibrosis (CF) continues to be shortened by progressive lung disease. Recently, the development of specific small molecules that rescue mutation specific CFTR function have made remarkable impacts on patient care, but they are not available for many patients. In addition, ongoing airway inflammation may reduce their effectiveness, at least in some patients. In this context, TGF-b1, a cytokine associated with worse pulmonary outcome in CF, decreases airway surface liquid (ASL) volume in CF cells in vitro by impairing the function of calcium activated chloride channels (CaCCs) and the apical potassium channel BK, both crucial for maintaining ASL volume in CF. TGF-b1 also reduced mucociliary clearance in sheep. We therefore propose that airway inflammation in general and TGF-b1 in particular worsens mucociliary function in CF patients. If this hypothesis is correct, novel anti-inflammatory medications could improve CF outcomes in patients currently not eligible for CFTR recovery therapy on which we focus here, but might also improve the function of small molecules. Clinically used Angiotensin II Receptor Blockers (ARBs) inhibit TGF-b signaling, independent of their angiotensin receptor blocking ability. Losartan, one widely used ARB, exerts these latter effects through one of its major metabolites, EXP3179. Thus, ARBs could present a ?fast track approach? for improving mucociliary dysfunction in CF. The preclinical, in vitro proof of concept aim 1 will test the hypothesis that losartan reverses the negative effects of TGF-b1 on CaCC and BK function (BK mainly through preventing decreases in LRRC26, the g regulatory subunit of BK required for its function in non- excitatory cells). Mechanisms of losartan's actions on CaCC and BK function will be explored using Ussing chambers as well as ASL volume and mucus transport measurements in fully differentiated airway epithelial cells from CF patients in the presence or absence of TGF-b1, losartan, and its metabolites EXP3174 and 3179. The preclinical, in vivo animal model aim 2 will test the hypothesis that inhaled or oral losartan improves CF- related mucociliary dysfunction in sheep induced by inhaled CFTRinh172 and human neutrophil elastase (HNE) or TGF-b1, which is downstream of HNE. We will measure tracheal mucus velocity, determine key pharmacokinetic parameters of losartan, and explore mechanisms that induce mucociliary dysfunction. Finally, the clinical in vivo aim 3 will test the hypothesis that oral losartan improves mucociliary dysfunction and decreases airway and systemic inflammation in CF patients who are not on small molecule treatment. The proposed experiments will test the ability of available anti-inflammatory medications, namely losartan and its metabolites, to improve parameters of mucociliary function in CF in vitro and in vivo and delineate their mode of action, thereby potentially identifying a ?low-hanging-fruit? intervention for CF airway inflammation.

Public Health Relevance

Some patients suffering from the most common, life shortening genetic disease called cystic fibrosis, have seen a drastic improvement of new treatment options that directly address the basic defect in CF, namely the CF transmembrane conductance regulator or CFTR channel. However, ongoing airway inflammation has hampered the success of the latest therapies to preserve lung function and some patients are not eligible for these medications. Novel anti-inflammatory therapies are needed and this project seeks to address airway inflammation in vitro, in animal models and in patients to improve therapies for CF by examining the effectiveness of well-known medications currently used for hypertension and cardiac diseases and deploy them for CF patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL133240-02
Application #
9701008
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Sheridan, John T
Project Start
2017-07-18
Project End
2021-05-31
Budget Start
2018-08-01
Budget End
2019-05-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Kansas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
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Sailland, Juliette; Grosche, Astrid; Baumlin, Nathalie et al. (2017) Role of Smad3 and p38 Signalling in Cigarette Smoke-induced CFTR and BK dysfunction in Primary Human Bronchial Airway Epithelial Cells. Sci Rep 7:10506
Schmid, Andreas; Sailland, Juliette; Novak, Lisa et al. (2017) Modulation of Wnt signaling is essential for the differentiation of ciliated epithelial cells in human airways. FEBS Lett 591:3493-3506