New insights into the molecular pathology of radiation-induced pneumopathy

Cappuccini, Federica; Eldh, Therese; Bruder, Dunja; Gereke, Marcus; Jastrow, Holger; Schulze‐Osthoff, Klaus; Fischer, Ute; Köhler, David; Stuschke, Martin; Jendrossek, Verena

doi:10.1016/j.radonc.2011.05.064

Cited by 61 publications

(81 citation statements)

References 27 publications

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“…It is generally accepted that blood vessels are critical components of the radiation response and that vascular damage upon irradiation is particularly prominent in the radiation response of normal tissues (9,25,31,44,84). We and others showed that thorax irradiation results in impairment of various pulmonary vascular parameters such as structural changes in pulmonary …”

Section: Discussionmentioning

confidence: 95%

“…We and others showed in preclinical studies that radiationinduced normal tissue toxicity in the lung is closely linked to vascular EC damage and dysfunction of the blood-air barrier (9,25,31,84). However, the underlying mechanisms of radiationinduced adverse late effects are still not well understood, and no causative radioprotective treatment is available to date.…”

Section: Introductionmentioning

confidence: 99%

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Mesenchymal Stem Cell Therapy Protects Lungs from Radiation-Induced Endothelial Cell Loss by Restoring Superoxide Dismutase 1 Expression

Klein

Steens

Wiesemann

et al. 2017

Antioxidants & Redox Signaling

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Aims: Radiation-induced normal tissue toxicity is closely linked to endothelial cell (EC) damage and dysfunction (acute effects). However, the underlying mechanisms of radiation-induced adverse late effects with respect to the vascular compartment remain elusive, and no causative radioprotective treatment is available to date. Results: The importance of injury to EC for radiation-induced late toxicity in lungs after whole thorax irradiation (WTI) was investigated using a mouse model of radiation-induced pneumopathy. We show that WTI induces EC loss as long-term complication, which is accompanied by the development of fibrosis. Adoptive transfer of mesenchymal stem cells (MSCs) either derived from bone marrow or aorta (vascular wall-resident MSCs) in the early phase after irradiation limited the radiation-induced EC loss and fibrosis progression. Furthermore, MSC-derived culture supernatants rescued the radiation-induced reduction in viability and longterm survival of cultured lung EC. We further identified the antioxidant enzyme superoxide dismutase 1 (SOD1) as a MSC-secreted factor. Importantly, MSC treatment restored the radiation-induced reduction of SOD1 levels after WTI. A similar protective effect was achieved by using the SOD-mimetic EUK134, suggesting that MSCderived SOD1 is involved in the protective action of MSC, presumably through paracrine signaling. Innovation: In this study, we explored the therapeutic potential of MSC therapy to prevent radiation-induced EC loss (late effect) and identified the protective mechanisms of MSC action. Conclusions: Adoptive transfer of MSCs early after irradiation counteracts radiation-induced vascular damage and EC loss as late adverse effects. The high activity of vascular wall-derived MSCs for radioprotection may be due to their tissue-specific action. Antioxid. Redox Signal. 26, 563-582.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Mesenchymal Stem Cell Therapy Protects Lungs from Radiation-Induced Endothelial Cell Loss by Restoring Superoxide Dismutase 1 Expression

Klein

Steens

Wiesemann

et al. 2017

Antioxidants & Redox Signaling

Self Cite

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“…Secondly, Rexo2 is an RNA exonuclease and recently another similar enzyme, Xrn2 has been associated with murine lung cancer [19] through its involvement in epithelial cell proliferation. Impaired restoration of the alveolar epithelium following the initial stimulus is a potential trigger for pulmonary fibrosis [40,41], therefore variation in a gene implicated in alveolar cell proliferation could contribute to radiation-induced lung damage.…”

Section: Discussionmentioning

confidence: 99%

“…Supporting this, Ddr1 -/-mice have been shown to develop a reduced amount of pulmonary fibrosis in response to a related challenge, that of bleomycin-induced lung injury [44], and in separate work [45], to be protected from renal fibrosis. An inflammatory contribution to the tissue response of fibrosis has also been suggested [46] and polymorphisms within particular candidate genes which function to alter the inflammatory response (Slamf6, Btnl1) could thus affect susceptibility to radiation-induced lung disease [41,47,48]. Further, increased levels of the cytokine transforming growth factor beta (Tgf-β) in lung tissue have been implicated in the development of fibrosis in animal models [49], including in response to irradiation [50] and specific candidate genes identified in our analysis (Cdkn1a or p21, Pin1) have been demonstrated to influence fibrosis development by altering Tgf-β levels [51,52].…”

Section: Discussionmentioning

confidence: 99%

Genomic and genome-wide association of susceptibility to radiation-induced fibrotic lung disease in mice

Paun¹,

Haston

2012

Radiotherapy and Oncology

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“…Radiation-induced lung injury (RILI) is a common complication of radiotherapy and a key dose-limiting factor, which may reduce the probability of tumor control and affect the patient's quality of life (1). The pathology of RILI is complex, and includes radiation-induced pneumonitis and fibrosis (2). Although intensive study in the previous decades has elucidated a number of the associated underlying mechanisms, involving, for example, cells and cytokines, the specific mechanism remains unclear (3).…”

Section: Introductionmentioning

confidence: 99%

Role of matrix metalloproteinases in radiation-induced lung injury in alveolar epithelial cells of Bama minipigs

Yue

Liu

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. Radiation-induced lung injury (RILI) is a common complication associated with thoracic radiotherapy. The aim of the present study was to investigate the effects of a single 15-Gy dose of right-thoracic lung irradiation on the expression levels of matrix metalloproteinases (MMPs) and other proteins in the alveolar epithelial type II (AE2) cells of Bama minipigs. All minipigs received either right-thoracic irradiation or sham irradiation under anesthesia, and were sacrificed at 4, 8, 12 or 24 weeks after irradiation. Collagen deposition was measured using Masson's trichrome staining. Surfactant protein A (SP-A), transforming growth factor β1 (TGFβ1), MMP2, MMP9, vimentin and E-cadherin protein expression levels were evaluated using western blot analysis, and the MMP2 and MMP9 gelatinase activities were tested using gelatin zymography. SP-A and α-smooth muscle actin (α-SMA) co-localization was visualized using double immunofluorescence staining. At each time-point following irradiation, a significant increase in TGFβ1, α-SMA, MMP2, MMP9 and vimentin protein expression levels and MMP2 and MMP9 gelatinase activity were observed in the irradiated lungs compared with the sham-irradiated controls. By contrast, SP-A and E-cadherin protein expression levels decreased in a time-dependent manner post-irradiation. SP-A and α-SMA co-localization was observed in irradiated alveolar epithelial cells. These data demonstrate that E-cadherin, SP-A, MMP2 and MMP9 may function as sensitive predictors of RILI. Epithelial-mesenchymal transition (EMT) occurs in the irradiated lungs of Bama minipigs, and MMP2 and MMP9 may contribute to EMT in AE2 cells by regulating TGFβ1. Therefore, EMT may serve a crucial function in the development of RILI.

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New insights into the molecular pathology of radiation-induced pneumopathy

Abstract: CitationNew insights into the molecular pathology of radiationinduced pneumopathy. Background and Purpose: Pneumonitis and fibrosis constitute dose-limiting side effects of thorax

Cited by 61 publications

References 27 publications

Mesenchymal Stem Cell Therapy Protects Lungs from Radiation-Induced Endothelial Cell Loss by Restoring Superoxide Dismutase 1 Expression

Mesenchymal Stem Cell Therapy Protects Lungs from Radiation-Induced Endothelial Cell Loss by Restoring Superoxide Dismutase 1 Expression

Genomic and genome-wide association of susceptibility to radiation-induced fibrotic lung disease in mice

Role of matrix metalloproteinases in radiation-induced lung injury in alveolar epithelial cells of Bama minipigs

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