Strain dependent differences in a quantitative histological study and expression analysis in irradiated murine lung

Although clinical observation can often reveal individual differences in the severity of lung fibrosis after radiation therapy, the actual influences of inherent individual factor is difficult to determine a clinical setting. In this paper, the usefulness of mouse model for research of heterogeneity in response of cancer treatment was investigated.C57BL/6J and C3H/HeMs mice were used for pathological and transcriotional experiments. The thorax of mice was locally irradiated at a dose of 10 or 20 Gy. Four-fold more CD44 positive cells had accumulated in the lungs of C3H/HeMs than of C57BL/6J mice. At sites of lung inflammation, HA accumulated at 12 hours after irradiation and the rapid resolution was achieved within 2 weeks in the lungs in both C57BL/6J mice and C3H/HheMs mice. An immunochemical investigation of C57BL/6J mice lungs revealed dense collagen accumulation at 8 weeks. The expression of Cap1, II18 and Rad51ap1 was constantly higher for 72 hours in C3H/HeMs mice than C57BL/6J mice. The expression of Mmp12 and Per3 was more induced in C3H/HeMs mice than C57BL/6J mice at 12 hours after irradiation. The expresion of Ltf was especially higher at 1 hour after iiradiation and that of Ifi202a was more induced at 72 hour in C57BL/6J mice than C3H/HeMs mice. Investigations into the mechanism of radiation-induced lung damage using animal models showed a powerful impact upon molecular studies of individual radiosensitivity.Mouse Models of Human Cancer (B7

Strain dependent differences in a quantitative histological study and expression analysis in irradiated murine lung

Although clinical observation can often reveal individual differences in the severity of lung fibrosis after radiation therapy, the actual influences of inherent individual factor is difficult to determine a clinical setting. In this paper, the usefulness of mouse model for research of heterogeneity in response of cancer treatment was investigated.C57BL/6J and C3H/HeMs mice were used for pathological and transcriotional experiments. The thorax of mice was locally irradiated at a dose of 10 or 20 Gy. Four-fold more CD44 positive cells had accumulated in the lungs of C3H/HeMs than of C57BL/6J mice. At sites of lung inflammation, HA accumulated at 12 hours after irradiation and the rapid resolution was achieved within 2 weeks in the lungs in both C57BL/6J mice and C3H/HheMs mice. An immunochemical investigation of C57BL/6J mice lungs revealed dense collagen accumulation at 8 weeks. The expression of Cap1, II18 and Rad51ap1 was constantly higher for 72 hours in C3H/HeMs mice than C57BL/6J mice. The expression of Mmp12 and Per3 was more induced in C3H/HeMs mice than C57BL/6J mice at 12 hours after irradiation. The expresion of Ltf was especially higher at 1 hour after iiradiation and that of Ifi202a was more induced at 72 hour in C57BL/6J mice than C3H/HeMs mice. Investigations into the mechanism of radiation-induced lung damage using animal models showed a powerful impact upon molecular studies of individual radiosensitivity.Mouse Models of Human Cancer (B7

CD44 and Bak expression in IL-6 or TNF-alpha gene knockout mice after whole lung irradiation

To understand the molecular mechanisms that underlie radiation pneumonitis, we examined whether knockout of the TNF or the IL-6 gene could give mice an inherent resistance to radiation in the acute phase of alveolar damage after thoracic irradiation. The temporal expression of inflammation (CD44) and apoptosis (Bak) markers in lung after thoracic irradiation was measured to determine the degree of alveolar damage. At 4 weeks post-irradiation (10 Gy), small inflammatory foci were observed in all mice, but there were no obvious histological differences between control (C57BL/6JSlc), TNF-alpha knockout (TNF KO), and IL-6 knockout (IL-6 KO) mice. However, immunohistochemical analysis of CD44 and Bak expression over a time course of 2 weeks highlighted significant differences between the three groups. C57BL/6JSlc and TNF KO mice had increased numbers of both CD44-positive and Bak-positive cells after irradiation, while the IL-6 KO mice showed stable levels of CD44 and Bak. In conclusion, the radioresistant status of IL-6 KO mice in the acute phase of alveolar damage after irradiation suggested an important role for IL-6 in radiation pneumonitis

Strain dependent differences in a histological study of CD44 and collagen fibers with an expression analysis of inflammatory response related genes in irradiated murine lung

Using a mouse model, we investigated the mechanisms of heterogeneity in response to ionizing radiation in this research. C57BL/6J and C3H/HeMs mice were irradiated with gamma rays at 10 and 20 Gy. The animals were sacrificed at times corresponding to the latent period, the pneumonic phase, and the start of the fibrotic phase for histological investigation. Small areas of fibrosis initially appeared in C57BL/6J mice at 4 weeks postirradiation with 20 Gy, whereas small inflammatory lesions appeared at 4 and 8 weeks after 20 and 10 Gy, respectively. The alveoli septa were thickened by an infiltration of inflammatory cells, and alveoli were obliterated in lungs from C57BL/6J mice after 20 Gy irradiation. At 24 hours and from 2 to 4 weeks postirradiation, fourfold more CD44 positive cells had accumulated in the lungs of C3H/HeMs than in C57BL/6J mice. Hyaluronan accumulated 12 hours after irradiation, and the rapid resolution was achieved within 2 weeks in the lungs in both strains of mice. C57BL/6J mice lungs accumulated dense collagen at 8 weeks. Quantitative RT-PCR assay was performed for several genes selected by cDNA microarray analysis. The expression of several genes, such as Cap1, Il18, Mmp12, Per3, Ltf, Ifi202a, and Rad51ap1 showed strain-dependent variances. In conclusion, a histological investigation suggested that C3H/HeMs mice were able to induce a more rapid clearance of matrix after irradiation than C57BL/6J mice. The expression analysis showed that the several genes are potentially involved in interstrain differences in inflammatory response causing radiation-induced lung fibrosis

Correlation between single nucleotide polymorphisms and jejunal crypt cell apoptosis after whole body irradiation

PURPOSE: To identify loci concerned with radiosensitivity in a mouse model using single nucleotide polymorphism (SNP) markers. MATERIALS AND METHODS: We subjected 276 second filial generation (F2) mice descended from two inbred mouse strains, radiation-induced apoptosis sensitive C57BL/6JNrs (B6) and radiation-induced apoptosis resistant C3H/HeNrs (C3H), to 2.5 Gy whole-body irradiation. We quantified jejunal crypt apoptosis, performed a genome-wide survey, and identified quantitative trait loci (QTL) associated with radiation sensitivity. We expressed apoptosis levels as an apoptotic score (AS), which was equal to the number of apoptotic bodies divided by the number of crypts. We genotyped the mice for 109 SNP markers. RESULTS: AS values were 97.7+/-32.9 in B6 mice and 49.0+/-24.9 in C3H mice (p < 0.01). Genome-wide analysis revealed 8 markers (2 on chromosome 9, 4 on 15, 1 on 17, and 1 on 18) affecting radiation-induced jejunal apoptosis with log odds (LOD) scores ranging from 2.11+/-3.91. We found a significant locus on chromosome 15, which was previously reported by Weil and colleagues. CONCLUSION: These findings support the view that the radiosensitivity of clinically normal tissue depends on variations in several genes

Inter-strain variation of apoptotic index of jejunal crypts between mouse systems after gamma ray whole body irradiation

In the clinic, interindividual differences in normal tissue response to radiotherapy have been observed and genetic factors are suggested to be responsible for this variation. Murine models have proven to be useful for the study of cytotoxic agents including radiation on the jejunum. We here report three murine strain differences in the levels of radiation-induced apoptosis in jejunal crypt cells. The apotosis positivity cell in jejunum carried out apoptosis index comparatively, and radiation susceptibility of strains was evaluated. Apoptosis index in C3 H/Hem was consistently lower than in A/J, or C57BL/6J at various times up to 24 hr after irradiation with 0.5 Gy. (P< 0.05). There was no difference among three strains after irradiation with 5 Gy. In the frequency of appearance of an apoptosis cell, C57BL/6J and A/J were radiation quantity susceptibility as compared with C3 H/Hem.日本放射線影響学会第４６回大

Inter-strain variance in late phase of erythematous reaction or leg contracture after local irradiation among three strains of mice.

Aim Radiotherapy for the treatment of cancer is limited by the tolerance of normal tissues within the treatment area. In this study, late phase of erythema, as a sequential endpoint of radiation effects on ski, and leg contracture as an endpoint for slowly responses of normal tissues was investigated among three strains of mice. We also examined the expression profiles of several genes to gain insights into inter-strain differences in radiosensitivity. \nMethods Mice of the inbred strains A/J, C57BL/6J, and C3H/HeMs, were irradiated using gamma rays at graded doses ranging from 10 to 60 Gy. The late skin reaction was scored for 300 days. Leg contracture assay was performed by measurement of extensibility of the hind legs of each mouse. Gene expression in the skin irradiated was quantified by quantitative RT-PCR assay.\nResults The three different strains showed various degrees of susceptibility to irradiation. Large inter-strain differences were also detected in the lengths of contracture. The expression of Alad, Cap1, Il18 and Rad51ap1 increased in A/J, and C3H/HeMs, and that of Mmp12 increased 12 hours after irradiation in A/J mice. The expression of Ang and that of Rad51ap1 increased 72 and 1 hours after irradiation in C3H/HeMs mice respectively. \nConclusions The continuum model of tissue injury supports the investigation of mechanism of radiosusceptibility. Our data suggest that genetic factors cause obvious variations in severity of damage after irradiation.The 7th International Symposium on Predictive Oncolog