Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Cystic fibrosis transmembrane regulator correction attenuates heart failure-induced lung inflammation

Uhl, Franziska E LU ; Vanherle, Lotte LU and Meissner, Anja LU (2022) In Frontiers in Immunology 13.
Abstract

Heart failure (HF) affects 64 million people worldwide. Despite advancements in prevention and therapy, quality of life remains poor for many HF patients due to associated target organ damage. Pulmonary manifestations of HF are well-established. However, difficulties in the treatment of HF patients with chronic lung phenotypes remain as the underlying patho-mechanistic links are still incompletely understood. Here, we aim to investigate the cystic fibrosis transmembrane regulator (CFTR) involvement in lung inflammation during HF, a concept that may provide new mechanism-based therapies for HF patients with pulmonary complications. In a mouse model of HF, pharmacological CFTR corrector therapy (Lumacaftor (Lum)) was applied systemically... (More)

Heart failure (HF) affects 64 million people worldwide. Despite advancements in prevention and therapy, quality of life remains poor for many HF patients due to associated target organ damage. Pulmonary manifestations of HF are well-established. However, difficulties in the treatment of HF patients with chronic lung phenotypes remain as the underlying patho-mechanistic links are still incompletely understood. Here, we aim to investigate the cystic fibrosis transmembrane regulator (CFTR) involvement in lung inflammation during HF, a concept that may provide new mechanism-based therapies for HF patients with pulmonary complications. In a mouse model of HF, pharmacological CFTR corrector therapy (Lumacaftor (Lum)) was applied systemically or lung-specifically for 2 weeks, and the lungs were analyzed using histology, flow cytometry, western blotting, and qPCR. Experimental HF associated with an apparent lung phenotype characterized by vascular inflammation and remodeling, pronounced tissue inflammation as evidenced by infiltration of pro-inflammatory monocytes, and a reduction of pulmonary CFTR+ cells. Moreover, the elevation of a classically-activated phenotype of non-alveolar macrophages coincided with a cell-specific reduction of CFTR expression. Pharmacological correction of CFTR with Lum mitigated the HF-induced downregulation of pulmonary CFTR expression and increased the proportion of CFTR+ cells in the lung. Lum treatment diminished the HF-associated elevation of classically-activated non-alveolar macrophages, while promoting an alternatively-activated macrophage phenotype within the lungs. Collectively, our data suggest that downregulation of CFTR in the HF lung extends to non-alveolar macrophages with consequences for tissue inflammation and vascular structure. Pharmacological CFTR correction possesses the capacity to alleviate HF-associated lung inflammation.

(Less)
Please use this url to cite or link to this publication:
author
; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Animals, Cystic Fibrosis/genetics, Cystic Fibrosis Transmembrane Conductance Regulator/genetics, Heart Failure/drug therapy, Humans, Inflammation, Mice, Pneumonia/drug therapy, Quality of Life
in
Frontiers in Immunology
volume
13
article number
928300
publisher
Frontiers Media S. A.
external identifiers
  • pmid:35967318
  • scopus:85135867577
ISSN
1664-3224
DOI
10.3389/fimmu.2022.928300
language
English
LU publication?
yes
additional info
Copyright © 2022 Uhl, Vanherle and Meissner.
id
ce18685f-6e4e-4bea-827e-31f8ab602111
date added to LUP
2022-08-20 05:55:22
date last changed
2024-02-18 07:30:44
@article{ce18685f-6e4e-4bea-827e-31f8ab602111,
  abstract     = {{<p>Heart failure (HF) affects 64 million people worldwide. Despite advancements in prevention and therapy, quality of life remains poor for many HF patients due to associated target organ damage. Pulmonary manifestations of HF are well-established. However, difficulties in the treatment of HF patients with chronic lung phenotypes remain as the underlying patho-mechanistic links are still incompletely understood. Here, we aim to investigate the cystic fibrosis transmembrane regulator (CFTR) involvement in lung inflammation during HF, a concept that may provide new mechanism-based therapies for HF patients with pulmonary complications. In a mouse model of HF, pharmacological CFTR corrector therapy (Lumacaftor (Lum)) was applied systemically or lung-specifically for 2 weeks, and the lungs were analyzed using histology, flow cytometry, western blotting, and qPCR. Experimental HF associated with an apparent lung phenotype characterized by vascular inflammation and remodeling, pronounced tissue inflammation as evidenced by infiltration of pro-inflammatory monocytes, and a reduction of pulmonary CFTR+ cells. Moreover, the elevation of a classically-activated phenotype of non-alveolar macrophages coincided with a cell-specific reduction of CFTR expression. Pharmacological correction of CFTR with Lum mitigated the HF-induced downregulation of pulmonary CFTR expression and increased the proportion of CFTR+ cells in the lung. Lum treatment diminished the HF-associated elevation of classically-activated non-alveolar macrophages, while promoting an alternatively-activated macrophage phenotype within the lungs. Collectively, our data suggest that downregulation of CFTR in the HF lung extends to non-alveolar macrophages with consequences for tissue inflammation and vascular structure. Pharmacological CFTR correction possesses the capacity to alleviate HF-associated lung inflammation.</p>}},
  author       = {{Uhl, Franziska E and Vanherle, Lotte and Meissner, Anja}},
  issn         = {{1664-3224}},
  keywords     = {{Animals; Cystic Fibrosis/genetics; Cystic Fibrosis Transmembrane Conductance Regulator/genetics; Heart Failure/drug therapy; Humans; Inflammation; Mice; Pneumonia/drug therapy; Quality of Life}},
  language     = {{eng}},
  publisher    = {{Frontiers Media S. A.}},
  series       = {{Frontiers in Immunology}},
  title        = {{Cystic fibrosis transmembrane regulator correction attenuates heart failure-induced lung inflammation}},
  url          = {{http://dx.doi.org/10.3389/fimmu.2022.928300}},
  doi          = {{10.3389/fimmu.2022.928300}},
  volume       = {{13}},
  year         = {{2022}},
}