title: Depletion of bone marrow CCSP-expressing cells delays airway regeneration.
abstract: The contribution of bone marrow cells (BMC) in lung repair is controversial. We previously reported a subpopulation of BMC that express Clara cell secretory protein (CCSP). To determine the contribution of endogenous CCSP(+) BMC to airway regeneration, we performed bone marrow transplantation studies using the CCtk mouse, which expresses a thymidine kinase suicide gene under regulation of the CCSP promoter. Mice were transplanted with wild-type or CCtk BMC and treated with ganciclovir to eliminate CCSP(+) cells. After airway injury using naphthalene, mice depleted of CCSP(+) BMC had more inflammatory cells in lung and decreased levels of oxygen in arterial blood. They also had reduced expression of airway epithelial genes and less Clara cells compared to control mice that had intact CCSP(+) BMC and bone marrow derived CCSP(+) cells in the airways. After naphthalene injury, administration of CCSP reproduced the beneficial effect of CCSP(+) BMC by improving recovery of airway epithelium, reducing lung inflammation and increasing oxygen in arterial blood from mice depleted of CCSP(+) BMC. Our data demonstrate that ablation of CCSP(+) BMC delays airway recovery and suggests the beneficial effect of CCSP(+) BMC in lung recovery is in part due to production of CCSP itself.
authors.affiliation: Latner Thoracic Surgery Research Laboratories and McEwen Centre for Regenerative Medicine, University of Toronto, Toronto General Hospital, Toronto Medical Discovery Tower, Toronto, Ontario, Canada.
authors.forename: Martha L
authors.initials: ML
authors.lastname: Bustos
authors.affiliation: Latner Thoracic Surgery Research Laboratories and McEwen Centre for Regenerative Medicine, University of Toronto, Toronto General Hospital, Toronto Medical Discovery Tower, Toronto, Ontario, Canada.
authors.forename: Marco
authors.initials: M
authors.lastname: Mura
authors.affiliation: Latner Thoracic Surgery Research Laboratories and McEwen Centre for Regenerative Medicine, University of Toronto, Toronto General Hospital, Toronto Medical Discovery Tower, Toronto, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Hwang
authors.affiliation: Department of Pathology, Princess Margaret Hospital, Toronto, Ontario, Canada.
authors.forename: Olga
authors.initials: O
authors.lastname: Ludkovski
authors.affiliation: Latner Thoracic Surgery Research Laboratories and McEwen Centre for Regenerative Medicine, University of Toronto, Toronto General Hospital, Toronto Medical Discovery Tower, Toronto, Ontario, Canada.
authors.forename: Amy P
authors.initials: AP
authors.lastname: Wong
authors.affiliation: Cell Therapy Program, University Health Network, Toronto, Ontario, Canada.
authors.forename: Armand
authors.initials: A
authors.lastname: Keating
authors.affiliation: Latner Thoracic Surgery Research Laboratories and McEwen Centre for Regenerative Medicine, University of Toronto, Toronto General Hospital, Toronto Medical Discovery Tower, Toronto, Ontario, Canada.
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Waddell
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D016026:Bone Marrow Transplantation; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D005804:Genes, Lethal; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008822:Mice, Transgenic; D009281:Naphthalenes; D010100:Oxygen / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012038:Regeneration / Q000235:genetics*; D015398:Signal Transduction; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D019076:Transgenes; D014598:Uteroglobin / Q000235:genetics* / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D009281:Naphthalenes; C556390:Scgb1a1 protein, mouse; D014764:Viral Proteins; C031721:naphthalene; D014598:Uteroglobin; C099241:thymidine kinase, Canid herpesvirus 1; D013937:Thymidine Kinase; D010100:Oxygen