title: Protein Kinase Cζ Inhibitor Promotes Resolution of Bleomycin-Induced Acute Lung Injury.
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.
authors.affiliation: 1 Internal Medicine Department, Division of Pulmonary, Critical Care, and Occupational Medicine, and.
authors.forename: Luis G Vargas
authors.initials: LG
authors.lastname: Buonfiglio
authors.affiliation: 1 Internal Medicine Department, Division of Pulmonary, Critical Care, and Occupational Medicine, and.
authors.forename: Mosaab
authors.initials: M
authors.lastname: Bagegni
authors.affiliation: 1 Internal Medicine Department, Division of Pulmonary, Critical Care, and Occupational Medicine, and.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Borcherding
authors.affiliation: 2 Radiology Department, University of Iowa, Iowa City, Iowa.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Sieren
authors.affiliation: 1 Internal Medicine Department, Division of Pulmonary, Critical Care, and Occupational Medicine, and.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Caraballo
authors.affiliation: 1 Internal Medicine Department, Division of Pulmonary, Critical Care, and Occupational Medicine, and.
authors.forename: Andrew
authors.initials: A
authors.lastname: Reger
authors.affiliation: 1 Internal Medicine Department, Division of Pulmonary, Critical Care, and Occupational Medicine, and.
authors.forename: Joseph
authors.initials: J
authors.lastname: Zabner
authors.affiliation: 1 Internal Medicine Department, Division of Pulmonary, Critical Care, and Occupational Medicine, and.
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Li
authors.affiliation: 1 Internal Medicine Department, Division of Pulmonary, Critical Care, and Occupational Medicine, and.
authors.forename: Alejandro P
authors.initials: AP
authors.lastname: Comellas
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D001761:Bleomycin; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016923:Cell Death / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D003187:Compliance; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D010539:Permeability; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011658:Pulmonary Fibrosis / Q000150:complications / Q000201:enzymology / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000099221:Protein Kinase C zeta
chemical_list: D001761:Bleomycin; D011493:Protein Kinase C; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; D000099221:Protein Kinase C zeta
keywords: adult stem cells; integrin-β4; lung compliance; lung fibrosis; respiratory distress syndrome