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Chronic lung injury by constitutive expression of activation-induced cytidine deaminase leads to focal mucous cell metaplasia and cancer.

Kitamura J, Uemura M, Kurozumi M, Sonobe M, Manabe T, Hiai H, Date H, Kinoshita K - PLoS ONE (2015)

Bottom Line: Activation-induced cytidine deaminase (AID) is an enzyme required for antibody diversification, and it causes DNA mutations and strand breaks.Increased cell death was observed in the lungs of AID transgenic mice compared with wild-type mice.AID expression in such regenerating tissue should predispose cells to malignant transformation via its mutagenic activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Kyoto, Japan; Department of Thoracic Surgery, Nagahama City Hospital, Nagahama, Japan.

ABSTRACT
Activation-induced cytidine deaminase (AID) is an enzyme required for antibody diversification, and it causes DNA mutations and strand breaks. Constitutive AID expression in mice invariably caused lung lesions morphologically similar to human atypical adenomatous hyperplasia (AAH), which can be a precursor of bronchioloalveolar carcinoma. Similar to AAH, mouse AAH-like lesion (MALL) exhibited signs of alveolar differentiation, judging from the expression of alveolar type II (AT2) cell marker surfactant protein C (SP-C). However, electron microscopy indicated that MALL, which possessed certain features of a mucous cell, is distinct from an AAH or AT2 cell. Although MALL developed in all individuals within 30 weeks after birth, lung tumors occurred in only 10%; this suggests that the vast majority of MALLs fail to grow into visible tumors. MALL expressed several recently described markers of lung alveolar regeneration such as p63, keratin 5, keratin 14, leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5), and Lgr6. Increased cell death was observed in the lungs of AID transgenic mice compared with wild-type mice. Based on these observations, we speculate that MALL is a regenerating tissue compensating for cellular loss caused by AID cytotoxicity. AID expression in such regenerating tissue should predispose cells to malignant transformation via its mutagenic activity.

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Cell deaths and cell proliferation in AID transgenic mice.TUNEL staining of A, MALL; B, Lung of AID Tg mouse; and C, Liver of AID Tg mouse. Arrowheads indicate TUNEL positive cells. Cell proliferation assay by EdU labeling in the lung of AID Tg mice and WT mice: D, Representative figure of EdU-positive MALL on day 1. An arrowhead indicates EdU-positive MALL (the region is surrounded by a dashed line). E, Representative figure of the lung of AID Tg mice on day 20. An arrowhead indicates EdU-positive MALL and an arrow indicates EdU-negative MALL. The region of each MALL is surrounded by a dashed line. TUNEL, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick endlabeling; EdU, 5-ethynyl-2’-deoxyuridine.
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pone.0117986.g005: Cell deaths and cell proliferation in AID transgenic mice.TUNEL staining of A, MALL; B, Lung of AID Tg mouse; and C, Liver of AID Tg mouse. Arrowheads indicate TUNEL positive cells. Cell proliferation assay by EdU labeling in the lung of AID Tg mice and WT mice: D, Representative figure of EdU-positive MALL on day 1. An arrowhead indicates EdU-positive MALL (the region is surrounded by a dashed line). E, Representative figure of the lung of AID Tg mice on day 20. An arrowhead indicates EdU-positive MALL and an arrow indicates EdU-negative MALL. The region of each MALL is surrounded by a dashed line. TUNEL, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick endlabeling; EdU, 5-ethynyl-2’-deoxyuridine.

Mentions: The presence of phagocytic epithelial cells in MALLs prompted us to speculate that lung cell death occurs more frequently in AIDon mice than WT mice. In the TUNEL assay, we occasionally found dead cells within MALLs (Fig. 5A). However, dead cells were recognized even in the area outside MALL. The occurrence of dead cells outside MALL in AIDon mice lungs (0.43%) was significantly higher than in WT mice (0.09%, P = 0.013; Fig. 5B, Table 2). To examine whether AID cytotoxicity is specific to the lung, we performed TUNEL staining of liver tissue. The number of TUNEL-positive hepatocytes increased in AIDon mice compared with WT mice (6.0% vs. 4.8%, P = 0.036; Fig. 5C, Table 2). This finding clearly indicates that AID-induced cell death is not specific to the lung.


Chronic lung injury by constitutive expression of activation-induced cytidine deaminase leads to focal mucous cell metaplasia and cancer.

Kitamura J, Uemura M, Kurozumi M, Sonobe M, Manabe T, Hiai H, Date H, Kinoshita K - PLoS ONE (2015)

Cell deaths and cell proliferation in AID transgenic mice.TUNEL staining of A, MALL; B, Lung of AID Tg mouse; and C, Liver of AID Tg mouse. Arrowheads indicate TUNEL positive cells. Cell proliferation assay by EdU labeling in the lung of AID Tg mice and WT mice: D, Representative figure of EdU-positive MALL on day 1. An arrowhead indicates EdU-positive MALL (the region is surrounded by a dashed line). E, Representative figure of the lung of AID Tg mice on day 20. An arrowhead indicates EdU-positive MALL and an arrow indicates EdU-negative MALL. The region of each MALL is surrounded by a dashed line. TUNEL, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick endlabeling; EdU, 5-ethynyl-2’-deoxyuridine.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4320068&req=5

pone.0117986.g005: Cell deaths and cell proliferation in AID transgenic mice.TUNEL staining of A, MALL; B, Lung of AID Tg mouse; and C, Liver of AID Tg mouse. Arrowheads indicate TUNEL positive cells. Cell proliferation assay by EdU labeling in the lung of AID Tg mice and WT mice: D, Representative figure of EdU-positive MALL on day 1. An arrowhead indicates EdU-positive MALL (the region is surrounded by a dashed line). E, Representative figure of the lung of AID Tg mice on day 20. An arrowhead indicates EdU-positive MALL and an arrow indicates EdU-negative MALL. The region of each MALL is surrounded by a dashed line. TUNEL, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick endlabeling; EdU, 5-ethynyl-2’-deoxyuridine.
Mentions: The presence of phagocytic epithelial cells in MALLs prompted us to speculate that lung cell death occurs more frequently in AIDon mice than WT mice. In the TUNEL assay, we occasionally found dead cells within MALLs (Fig. 5A). However, dead cells were recognized even in the area outside MALL. The occurrence of dead cells outside MALL in AIDon mice lungs (0.43%) was significantly higher than in WT mice (0.09%, P = 0.013; Fig. 5B, Table 2). To examine whether AID cytotoxicity is specific to the lung, we performed TUNEL staining of liver tissue. The number of TUNEL-positive hepatocytes increased in AIDon mice compared with WT mice (6.0% vs. 4.8%, P = 0.036; Fig. 5C, Table 2). This finding clearly indicates that AID-induced cell death is not specific to the lung.

Bottom Line: Activation-induced cytidine deaminase (AID) is an enzyme required for antibody diversification, and it causes DNA mutations and strand breaks.Increased cell death was observed in the lungs of AID transgenic mice compared with wild-type mice.AID expression in such regenerating tissue should predispose cells to malignant transformation via its mutagenic activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Kyoto, Japan; Department of Thoracic Surgery, Nagahama City Hospital, Nagahama, Japan.

ABSTRACT
Activation-induced cytidine deaminase (AID) is an enzyme required for antibody diversification, and it causes DNA mutations and strand breaks. Constitutive AID expression in mice invariably caused lung lesions morphologically similar to human atypical adenomatous hyperplasia (AAH), which can be a precursor of bronchioloalveolar carcinoma. Similar to AAH, mouse AAH-like lesion (MALL) exhibited signs of alveolar differentiation, judging from the expression of alveolar type II (AT2) cell marker surfactant protein C (SP-C). However, electron microscopy indicated that MALL, which possessed certain features of a mucous cell, is distinct from an AAH or AT2 cell. Although MALL developed in all individuals within 30 weeks after birth, lung tumors occurred in only 10%; this suggests that the vast majority of MALLs fail to grow into visible tumors. MALL expressed several recently described markers of lung alveolar regeneration such as p63, keratin 5, keratin 14, leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5), and Lgr6. Increased cell death was observed in the lungs of AID transgenic mice compared with wild-type mice. Based on these observations, we speculate that MALL is a regenerating tissue compensating for cellular loss caused by AID cytotoxicity. AID expression in such regenerating tissue should predispose cells to malignant transformation via its mutagenic activity.

Show MeSH
Related in: MedlinePlus