title: Protein kinase D is increased and activated in lung epithelial cells and macrophages in idiopathic pulmonary fibrosis.
abstract: Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive and usually fatal lung disease of unknown etiology for which no effective treatments currently exist. Hence, there is a profound need for the identification of novel drugable targets to develop more specific and efficacious therapeutic intervention in IPF. In this study, we performed immunohistochemical analyses to assess the cell type-specific expression and activation of protein kinase D (PKD) family kinases in normal and IPF lung tissue sections. We also analyzed PKD activation and function in human lung epithelial cells. We found that PKD family kinases (PKD1, PKD2 and PKD3) were increased and activated in the hyperplastic and regenerative alveolar epithelial cells lining remodeled fibrotic alveolar septa and/or fibroblast foci in IPF lungs compared with normal controls. We also found that PKD family kinases were increased and activated in alveolar macrophages, bronchiolar epithelium, and honeycomb cysts in IPF lungs. Interestingly, PKD1 was highly expressed and activated in the cilia of IPF bronchiolar epithelial cells, while PKD2 and PKD3 were expressed in the cell cytoplasm and nuclei. In contrast, PKD family kinases were not apparently increased and activated in IPF fibroblasts or myofibroblasts. We lastly found that PKD was predominantly activated by poly-L-arginine, lysophosphatidic acid and thrombin in human lung epithelial cells and that PKD promoted epithelial barrier dysfunction. These findings suggest that PKD may participate in the pathogenesis of IPF and may be a novel target for therapeutic intervention in this disease.
authors.affiliation: Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America.
authors.forename: Huachen
authors.initials: H
authors.lastname: Gan
authors.affiliation: Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America.
authors.forename: Raymond
authors.initials: R
authors.lastname: McKenzie
authors.affiliation: Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America.
authors.forename: Qin
authors.initials: Q
authors.lastname: Hao
authors.affiliation: Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America; Texas Lung Injury Institute, The University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America.
authors.forename: Steven
authors.initials: S
authors.lastname: Idell
authors.affiliation: Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America.
authors.forename: Hua
authors.initials: H
authors.lastname: Tang
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000201:enzymology* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D007124:Immunoenzyme Techniques; D008168:Lung / Q000201:enzymology* / Q000473:pathology; D016676:Macrophages, Alveolar / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058628:Myofibroblasts / Q000201:enzymology* / Q000473:pathology; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D012333:RNA, Messenger; C089212:protein kinase D; D011493:Protein Kinase C