Repopulation of the irradiation damaged lung with 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: 0.97). 01/2012; 26(1):9-18.
Source: PubMed


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.


Available from: Michael W Epperly
  • Source
    • "It is agreed by many researchers that formation of interstitial and alveolar deformation is a consistent finding in lung tissue pathology of severe radiation exposure. This deformation could be formed as a direct toxic effect of radiation on some constituent of interstitial tissue, resulting in elevated osmotic pressure and increasing in the ground substances (Bernard et al., 2012; Davis et al., 1992; Guerry-Force, Perkett, Brigham, & Meyrick, 1988; Kononenko, 1985; Kurus et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The purpose of this study was to investigate the ultrastructural effects of ultraviolet C radiation on the lung cells of mole rats. Mole rats were divided into controlled and experiment groups. Controlled group did not receive any radiation. The other groups were irradiated with UV radiation for 14 and 28 days. The lung tissue samples were prepared and analyzed by light and transmission electron microscopy. A number of effects were observed in some groups which suggest some magnitude of UVC radiation affected in the lung tissue. The first changes detected in mole rats lung tissue after 14 days UVC radiation consisted of deformation in alveolar cells and in the interstitial space. There became a deformation in the alveolar epithelial cells, endothelial cells and interstitium space of the lung cells. After 28 days of UVC exposure, there happened a complete destruction of a large fraction in the capillaries. These cells showed signs of necrosis, irregularity, and their cytoplasm contained vacuoles with containing fluid-filled substantives. There happened an increase in capillary volume and a destruction in the collagen fibrins. Some destruction occurred concurrently in the alveolar epithelial cells. These findings clearly demonstrated the ultrastructural effects of UVC radiation on lung cells in an exposure-period dependent manner.
    09/2014; 7(4). DOI:10.1016/j.jrras.2014.09.003
  • Source
    • "Plasmid liposomes were considered to be the safest delivery system (Greenberger et al., 2003). Elimination of potential immunologic responses to viral sequences using virus vectors and careful optimization of liposome delivery vehicles with cationic properties lead to design of a MnSOD–PL construct suitable for delivery in animal model systems by either intra-oral/oropharyngeal administration (Epperly et al., 1999a; Guo et al., 2003a,b,c), intra-esophageal delivery (Stickle et al., 1999), or delivery into the lungs by either intra-tracheal injection or inhalation using a nebulizer system (Epperly et al., 1998; Carpenter et al., 2005; Bernard et al., in press). In all of these systems, a significant radiation protection of specific organs was documented by the physiological, pathophysiological, and histopathological evidence of decreasing both acute and chronic radiation side effects (Epperly et al., 1999b). "
    [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 · 2.91 Impact Factor
Show more