Protein Kinase Cζ Inhibitor Promotes Resolution of Bleomycin-Induced Acute Lung Injury

Luis G Vargas Buonfiglio; Mosaab Bagegni; Jennifer A Borcherding; Jessica C Sieren; Juan C Caraballo; Andrew Reger; Joseph Zabner; Xiaopeng Li; Alejandro P Comellas

doi:10.1165/rcmb.2015-0006OC

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Protein Kinase Cζ Inhibitor Promotes Resolution of Bleomycin-Induced Acute Lung Injury

Journal article

Open access

Peer reviewed

Protein Kinase Cζ Inhibitor Promotes Resolution of Bleomycin-Induced Acute Lung Injury

Luis G Vargas Buonfiglio, Mosaab Bagegni, Jennifer A Borcherding, Jessica C Sieren, Juan C Caraballo, Andrew Reger, Joseph Zabner, Xiaopeng Li and Alejandro P Comellas

American journal of respiratory cell and molecular biology, Vol.55(6), pp.869-877

12/2016

DOI: 10.1165/rcmb.2015-0006OC

PMCID: PMC5248948

PMID: 27486964

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Abstract

Protein kinase Cζ (PKCζ) is highly expressed in the lung, where it plays several regulating roles in the pathogenesis of acute lung injury (ALI). Proliferation and differentiation of integrin β4 distal lung epithelial progenitor cells seem to play a key role in proper lung regeneration. We investigated the effects of a myristoylated PKCζ inhibitor (PKCζi) in a murine model of bleomycin-induced ALI. After intratracheal injury, we treated mice three times a week with PKCζi or its vehicle, DMSO. We found that mice injured with bleomycin and then treated with PKCζi for one week showed decreased activation of PKCζ, improved lung compliance, and decreased lung protein permeability compared to injured mice treated with DMSO. Mice treated continuously with PKCζi for 6 weeks showed reduced evidence of lung fibrosis by computed tomographic images, decreased lung collagen deposition, and decreased active transforming growth factor-β in the bronchoalveolar lavage fluid. In addition, we found an increased number of lung β4 cells compared to DMSO at Week 6. Therefore, we grew isolated integrin β4 lung progenitor cells in the presence of PKCζi or DMSO and found that β4 cells treated with PKCζi proliferated more in vitro compared to DMSO. We conclude that the use of a PKCζi promotes resolution of lung fibrosis in a bleomycin ALI model and increases the number of β4 progenitor cells with regenerative potential in the lung.

Neutrophils - cytology

Epithelial Cells - metabolism

Reactive Oxygen Species - metabolism

Compliance

Epithelial Cells - drug effects

Stem Cells - metabolism

Acute Lung Injury - enzymology

Bleomycin

Protein Kinase C - metabolism

Acute Lung Injury - drug therapy

Bronchoalveolar Lavage Fluid - cytology

Cell Death - drug effects

Disease Models, Animal

Cell Separation

Pulmonary Fibrosis - complications

Mice, Inbred C57BL

Neutrophils - drug effects

Epithelial Cells - pathology

Protein Kinase C - antagonists & inhibitors

Pulmonary Fibrosis - pathology

Permeability

Enzyme Activation - drug effects

Acute Lung Injury - pathology

Cell Movement - drug effects

Animals

Models, Biological

Protein Kinase Inhibitors - therapeutic use

Pulmonary Fibrosis - enzymology

Stem Cells - drug effects

Cell Proliferation - drug effects

Protein Kinase Inhibitors - pharmacology

Transforming Growth Factor beta - metabolism

Details

Title: Subtitle: Protein Kinase Cζ Inhibitor Promotes Resolution of Bleomycin-Induced Acute Lung Injury
Creators: Luis G Vargas Buonfiglio - 1 Internal Medicine Department, Division of Pulmonary, Critical Care, and Occupational Medicine, and
Mosaab Bagegni - 1 Internal Medicine Department, Division of Pulmonary, Critical Care, and Occupational Medicine, and
Jennifer A Borcherding - 1 Internal Medicine Department, Division of Pulmonary, Critical Care, and Occupational Medicine, and
Jessica C Sieren - 2 Radiology Department, University of Iowa, Iowa City, Iowa
Juan C Caraballo - 1 Internal Medicine Department, Division of Pulmonary, Critical Care, and Occupational Medicine, and
Andrew Reger - 1 Internal Medicine Department, Division of Pulmonary, Critical Care, and Occupational Medicine, and
Joseph Zabner - 1 Internal Medicine Department, Division of Pulmonary, Critical Care, and Occupational Medicine, and
Xiaopeng Li - 1 Internal Medicine Department, Division of Pulmonary, Critical Care, and Occupational Medicine, and
Alejandro P Comellas - 1 Internal Medicine Department, Division of Pulmonary, Critical Care, and Occupational Medicine, and
Resource Type: Journal article
Publication Details: American journal of respiratory cell and molecular biology, Vol.55(6), pp.869-877
DOI: 10.1165/rcmb.2015-0006OC
PMID: 27486964
PMCID: PMC5248948
NLM abbreviation: Am J Respir Cell Mol Biol
ISSN: 1044-1549
eISSN: 1535-4989
Publisher: United States
Grant note: P30 ES005605 / NIEHS NIH HHS P01 HL091842 / NHLBI NIH HHS UL1 RR024979 / NCRR NIH HHS P30 DK054759 / NIDDK NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 12/2016
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Radiology; Pulmonary, Critical Care, and Occupational Medicine; ICTS; Internal Medicine
Record Identifier: 9984051727902771

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