# Anti-inflammatory therapy to augment CFTR rescue in CF patients

> **NIH NIH R01** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2020 · $647,107

## Abstract

Project Summary
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 air...

## Key facts

- **NIH application ID:** 9962470
- **Project number:** 5R01HL133240-04
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Matthias A Salathe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $647,107
- **Award type:** 5
- **Project period:** 2017-07-18 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962470

## Citation

> US National Institutes of Health, RePORTER application 9962470, Anti-inflammatory therapy to augment CFTR rescue in CF patients (5R01HL133240-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9962470. Licensed CC0.

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