title: Pim1 kinase protects airway epithelial cells from cigarette smoke-induced damage and airway inflammation.
abstract: Exposure to cigarette smoke (CS) is the main risk factor for developing chronic obstructive pulmonary disease and can induce airway epithelial cell damage, innate immune responses, and airway inflammation. We hypothesized that cell survival factors might decrease the sensitivity of airway epithelial cells to CS-induced damage, thereby protecting the airways against inflammation upon CS exposure. Here, we tested whether Pim survival kinases could protect from CS-induced inflammation. We determined expression of Pim kinases in lung tissue, airway inflammation, and levels of keratinocyte-derived cytokine (KC) and several damage-associated molecular patterns in bronchoalveolar lavage in mice exposed to CS or air. Human bronchial epithelial BEAS-2B cells were treated with CS extract (CSE) in the presence or absence of Pim1 inhibitor and assessed for loss of mitochondrial membrane potential, induction of cell death, and release of heat shock protein 70 (HSP70). We observed increased expression of Pim1, but not of Pim2 and Pim3, in lung tissue after exposure to CS. Pim1-deficient mice displayed a strongly enhanced neutrophilic airway inflammation upon CS exposure compared with wild-type controls. Inhibition of Pim1 activity in BEAS-2B cells increased the loss of mitochondrial membrane potential and reduced cell viability upon CSE treatment, whereas release of HSP70 was enhanced. Interestingly, we observed release of S100A8 but not of double-strand DNA or HSP70 in Pim1-deficient mice compared with wild-type controls upon CS exposure. In conclusion, we show that expression of Pim1 protects against CS-induced cell death in vitro and neutrophilic airway inflammation in vivo. Our data suggest that the underlying mechanism involves CS-induced release of S100A8 and KC.
authors.affiliation: University of Groningen, University Medical Center Groningen, Laboratory of Allergology and Pulmonary Diseases, Department of Pathology and Medical Biology, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: de Vries
authors.affiliation: University of Groningen, University Medical Center Groningen, Laboratory of Allergology and Pulmonary Diseases, Department of Pathology and Medical Biology, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: I H
authors.initials: IH
authors.lastname: Heijink
authors.affiliation: University of Groningen, University Medical Center Groningen, Laboratory of Allergology and Pulmonary Diseases, Department of Pathology and Medical Biology, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Gras
authors.affiliation: University of Groningen, University Medical Center Groningen, Laboratory of Allergology and Pulmonary Diseases, Department of Pathology and Medical Biology, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: L E
authors.initials: LE
authors.lastname: den Boef
authors.affiliation: University of Groningen, University Medical Center Groningen, Pathology Section, Department of Pathology and Medical Biology, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Reinders-Luinge
authors.affiliation: University of Groningen, University Medical Center Groningen, Laboratory of Allergology and Pulmonary Diseases, Department of Pathology and Medical Biology, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: S D
authors.initials: SD
authors.lastname: Pouwels
authors.affiliation: University of Groningen, University Medical Center Groningen, Pathology Section, Department of Pathology and Medical Biology, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: M N
authors.initials: MN
authors.lastname: Hylkema
authors.affiliation: University of Groningen, University Medical Center Groningen, Laboratory of Allergology and Pulmonary Diseases, Department of Pathology and Medical Biology, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: van der Toorn
authors.affiliation: University of Groningen, University Medical Center Groningen, Laboratory of Allergology and Pulmonary Diseases, Department of Pathology and Medical Biology, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: U
authors.initials: U
authors.lastname: Brouwer
authors.affiliation: University of Groningen, University Medical Center Groningen, Laboratory of Allergology and Pulmonary Diseases, Department of Pathology and Medical Biology, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: A J M
authors.initials: AJ
authors.lastname: van Oosterhout
authors.affiliation: University of Groningen, University Medical Center Groningen, Laboratory of Allergology and Pulmonary Diseases, Department of Pathology and Medical Biology, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands m.c.nawijn@umcg.nl.
authors.forename: M C
authors.initials: MC
authors.lastname: Nawijn
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism / Q000473:pathology; D012907:Smoking / Q000009:adverse effects* / Q000378:metabolism* / Q000473:pathology
chemical_list: D018925:Chemokines; D018840:HSP70 Heat-Shock Proteins; C074302:keratinocyte-derived chemokines; D051573:Proto-Oncogene Proteins c-pim-1
keywords: cell survival; chronic obstructive pulmonary disease; damage-associated molecular patterns; innate immune response; mice