Repopulation of the irradiation damaged lung with bone marrow-derived cells.

Department of Radiation Oncology, University of Pittsburgh Cancer Institute, 5150 Centre Avenue, Pittsburgh, PA 15232, USA.
In vivo (Athens, Greece) (Impact Factor: 1.15). 01/2012; 26(1):9-18.
Source: PubMed

ABSTRACT The effect of lung irradiation on reduction of lung stem cells and repopulation with bone marrow-derived cells was measured.
Expression of green fluorescent protein positive cells (GFP(+)) in the lungs of thoracic irradiated FVB/NHsd mice (Harlan Sprague Dawley, Indianapolis, IN, USA) was determined. This was compared to the repopulation of bone marrow-derived cells found in the lungs from naphthalene treated male FVB/NHsd mice and gangciclovir (GCV) treated FeVBN GFP(+) male marrow chimeric HSV-TK-CCSP. The level of mRNA for lung stem cell markers clara cell (CCSP), epithelium 1 (FOXJ1) and surfactant protein C (SP-C), and sorted single cells positive for marrow origin epithelial cells (GFP(+)CD45(-)) was measured.
The expression of pulmonary stem cells as determined by PCR was reduced most by GCV, then naphthalene, and least by thoracic irradiation. Irradiation, like GCV, reduced mRNA expression of CCSP, CYP2F2, and FOXJ1, while naphthalene reduced that of CCSP and CYP2F2. Ultrastructural analysis showed GFP(+) pulmonary cells of bone marrow origin, with the highest frequency being found in GCV-treated groups.
Bone marrow progenitor cells may not participate in the repopulation of the lung following irradiation.

Download full-text


Available from: Michael W Epperly, Jul 02, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondrial targeted radiation damage protectors (delivered prior to irradiation) and mitigators (delivered after irradiation, but before the appearance of symptoms associated with radiation syndrome) have been a recent focus in drug discovery for (1) normal tissue radiation protection during fractionated radiotherapy, and (2) radiation terrorism counter measures. Several categories of such molecules have been discovered: nitroxide-linked hybrid molecules, including GS-nitroxide, GS-nitric oxide synthase inhibitors, p53/mdm2/mdm4 inhibitors, and pharmaceutical agents including inhibitors of the phosphoinositide-3-kinase pathway and the anti-seizure medicine, carbamazepine. Evaluation of potential new radiation dose modifying molecules to protect normal tissue includes: clonogenic radiation survival curves, assays for apoptosis and DNA repair, and irradiation-induced depletion of antioxidant stores. Studies of organ specific radioprotection and in total body irradiation-induced hematopoietic syndrome in the mouse model for protection/mitigation facilitate rational means by which to move candidate small molecule drugs along the drug discovery pipeline into clinical development.
    Frontiers in Oncology 01/2011; 1:59. DOI:10.3389/fonc.2011.00059
  • [Show abstract] [Hide abstract]
    ABSTRACT: Viral infections have been associated with exacerbation of disease in human cases of idiopathic pulmonary fibrosis. Since pulmonary fibrosis is a common outcome after irradiation to the lung, we hypothesized that viral infection after radiation exposure would exacerbate radiation-induced lung injury. Epithelial injury, a frequent outcome after infection, has been hypothesized to contribute to the pathogenesis of pulmonary fibrosis and bronchiolar epithelial Clara cells participate in epithelial repair. Therefore, it was further hypothesized that altered responses after irradiation involve the bronchiolar epithelial Clara cells. C57BL/6J or CCSP(-/-) mice were irradiated with 0 (sham), 5, 10 or 15 Gy to the whole thorax. At ten weeks post-irradiation, animals were mock infected or infected with influenza A virus and body weight and survival were monitored. Pulmonary function was assessed by whole-body plethysmography. The Clara cell markers, CCSP and Cyp2f2, were measured in the lung by qRT-PCR, and protein expression was visualized in the lung by immunofluorescence. Following pulmonary function tests, mice were sacrificed and tissues were collected for pathological analysis. In 15 Gy irradiated animals infected with influenza A virus, accelerated respiratory rates, reduced pulmonary function, and exacerbated lung pathology occurred earlier post-irradiation than previously observed after irradiation alone, suggesting infection accelerates the development of radiation injury. After irradiation alone, CCSP and Cyp2f2 mRNA levels were reduced, correlating with reductions in the number of Clara cells lining the airways. When combined with infection, these markers further declined and an apparent delay in recovery of mRNA expression was observed, suggesting that radiation injury leads to a chronic reduction in the number of Clara cells that may potentiate the epithelial injury observed after influenza A virus infection. This novel finding may have considerable therapeutic implications with respect to both thoracic tumor patients and recipients of bone marrow transplants.
    Radiation Research 04/2013; 179(6). DOI:10.1667/RR3279.1 · 2.45 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Adipose-derived stem cells (ADSCs), a subset of mesenchymal stem cells, have promising potential for regenerative medicine applications. However, the efficient culture of mouse adipose-derived stem cells (mADSCs) is complicated or impracticable and many properties of mADSCs are still unknown. Here, we report that vitamin C (Vc) is available for the long-term culture of mADSCs in vitro. Compared with that cultured without Vc, mADSCs growing in Vc-added media proliferate faster. The occurrence of replicative senescence and transformation of Vc-treated mADSCs is also postponed. Vc also enhanced the secretory activity of collagen and adipogenic differentiation ability of mADSCs. Moreover, the expression of CD44, Sca-1, and CD105 is higher in Vc-treated mADSCs than nontreated ones. We also found that genes related to proliferation, secretion, and pluripotency are all promoted in Vc-treated mADSCs. However, the adipogenesis ability and expression of CD44, Sca-1, and CD105 decreased when passage increased from very low passages, in parallel to the downregulation of closed-related gene expression. Our results indicate that Vc is essential for the maintenance of original properties of mADSCs in vitro; additional insights into the function of Vc on mADSCs are provided. Furthermore, as the passage increased in six passages, the characteristics of mADSCs with Vc addition were also revealed.
    In Vitro Cellular & Developmental Biology - Animal 08/2013; DOI:10.1007/s11626-013-9673-6 · 1.00 Impact Factor