Cystic Fibrosis Transmembrane Conductance Regulator in Sarcoplasmic Reticulum of Airway Smooth Muscle. Implications for Airway Contractility

Daniel P Cook; Michael V Rector; Drake C Bouzek; Andrew S Michalski; Nicholas D Gansemer; Leah R Reznikov; Xiaopeng Li; Mallory R Stroik; Lynda S Ostedgaard; Mahmoud H Abou Alaiwa; Michael A Thompson; Y S Prakash; Ramaswamy Krishnan; David K Meyerholz; Chun Y Seow; David A Stoltz

doi:10.1164/rccm.201508-1562OC

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Cystic Fibrosis Transmembrane Conductance Regulator in Sarcoplasmic Reticulum of Airway Smooth Muscle. Implications for Airway Contractility

Journal article

Open access

Peer reviewed

Cystic Fibrosis Transmembrane Conductance Regulator in Sarcoplasmic Reticulum of Airway Smooth Muscle. Implications for Airway Contractility

Daniel P Cook, Michael V Rector, Drake C Bouzek, Andrew S Michalski, Nicholas D Gansemer, Leah R Reznikov, Xiaopeng Li, Mallory R Stroik, Lynda S Ostedgaard, Mahmoud H Abou Alaiwa, …

American journal of respiratory and critical care medicine, Vol.193(4), pp.417-426

02/15/2016

DOI: 10.1164/rccm.201508-1562OC

PMCID: PMC4803085

PMID: 26488271

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https://doi.org/10.1164/rccm.201508-1562OCView

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Abstract

An asthma-like airway phenotype has been described in people with cystic fibrosis (CF). Whether these findings are directly caused by loss of CF transmembrane conductance regulator (CFTR) function or secondary to chronic airway infection and/or inflammation has been difficult to determine. Airway contractility is primarily determined by airway smooth muscle. We tested the hypothesis that CFTR is expressed in airway smooth muscle and directly affects airway smooth muscle contractility. Newborn pigs, both wild type and with CF (before the onset of airway infection and inflammation), were used in this study. High-resolution immunofluorescence was used to identify the subcellular localization of CFTR in airway smooth muscle. Airway smooth muscle function was determined with tissue myography, intracellular calcium measurements, and regulatory myosin light chain phosphorylation status. Precision-cut lung slices were used to investigate the therapeutic potential of CFTR modulation on airway reactivity. We found that CFTR localizes to the sarcoplasmic reticulum compartment of airway smooth muscle and regulates airway smooth muscle tone. Loss of CFTR function led to delayed calcium reuptake following cholinergic stimulation and increased myosin light chain phosphorylation. CFTR potentiation with ivacaftor decreased airway reactivity in precision-cut lung slices following cholinergic stimulation. Loss of CFTR alters porcine airway smooth muscle function and may contribute to the airflow obstruction phenotype observed in human CF. Airway smooth muscle CFTR may represent a therapeutic target in CF and other diseases of airway narrowing.

Animals, Newborn

Animals

Swine

Muscle Contraction - physiology

Fluorescent Antibody Technique

Muscle, Smooth - physiopathology

Cystic Fibrosis Transmembrane Conductance Regulator - physiology

Sarcoplasmic Reticulum - physiology

Models, Animal

Lung - physiopathology

Blotting, Western

Details

Title: Subtitle: Cystic Fibrosis Transmembrane Conductance Regulator in Sarcoplasmic Reticulum of Airway Smooth Muscle. Implications for Airway Contractility
Creators: Daniel P Cook - 2 Department of Molecular Physiology and Biophysics
Michael V Rector - 1 Department of Internal Medicine
Drake C Bouzek - 1 Department of Internal Medicine
Andrew S Michalski - 1 Department of Internal Medicine
Nicholas D Gansemer - 1 Department of Internal Medicine
Leah R Reznikov - 1 Department of Internal Medicine
Xiaopeng Li - 1 Department of Internal Medicine
Mallory R Stroik - 1 Department of Internal Medicine
Lynda S Ostedgaard - 1 Department of Internal Medicine
Mahmoud H Abou Alaiwa - 1 Department of Internal Medicine
Michael A Thompson - 4 Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
Y S Prakash - 4 Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
Ramaswamy Krishnan - 5 Department of Emergency Medicine, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts; and
David K Meyerholz - 6 Department of Pathology
Chun Y Seow - 7 Department of Pathology and Laboratory Medicine, James Hogg Research Centre/St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
David A Stoltz - 9 Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa
Resource Type: Journal article
Publication Details: American journal of respiratory and critical care medicine, Vol.193(4), pp.417-426
DOI: 10.1164/rccm.201508-1562OC
PMID: 26488271
PMCID: PMC4803085
NLM abbreviation: Am J Respir Crit Care Med
ISSN: 1073-449X
eISSN: 1535-4970
Publisher: United States
Grant note: P30 ES005605 / NIEHS NIH HHS P01 HL091842 / NHLBI NIH HHS T32 HL007638 / NHLBI NIH HHS T32 GM007337 / NIGMS NIH HHS HL091842 / NHLBI NIH HHS HL117744 / NHLBI NIH HHS P01 HL051670 / NHLBI NIH HHS HL51670 / NHLBI NIH HHS T32 GM007737 / NIGMS NIH HHS P30 DK054759 / NIDDK NIH HHS DP2 HL117744 / NHLBI NIH HHS K99 HL119560 / NHLBI NIH HHS
Language: English
Date published: 02/15/2016
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Stead Family Department of Pediatrics; Pathology; Internal Medicine
Record Identifier: 9984025459902771

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