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Mouse model of paraquat-poisoned lungs and its gene expression profile.
Toxicology. 2007 Mar 07; 231(2-3):200-9.T

Abstract

Paraquat (PQ)-induced pulmonary toxicity is characterized by initial development of pulmonary edema, infiltration of inflammatory cells, and damage to the alveolar epithelium, which may progress to severe fibrosis. However, the exact role of PQ in the progression of the pathogenesis has not been clearly established. To understand the mechanism of PQ in pulmonary toxicity, we developed an animal model of PQ-induced lung injury by intranasal instillation of PQ solution using C57Black/6J mice. Twenty microliters of PQ solution (0.01, 0.01, and 0.04 mg/mouse) was applied through the nares, and the same amount of vehicle was applied in control mice. The pathological progression of lung pathology in our mouse model was very similar to that of patients suffering from PQ poisoning. The lungs of some animals exposed to PQ showed acute fulmination, resulting in death from 5 days post-exposure, but others showed a more protracted injury, resulting in typical pulmonary fibrosis at 3 weeks. Using this PQ-poisoned mouse model, we examined the gene expression at the initial destructive phase (within 5 days) that fibrosis has not completely developed. We prepared RNAs after 6h, 24h, and 5 days and examined the changes of the expression levels for 45 selected genes. The genes showing >2-fold increase at 6h or a time-dependent decrease during this experimental period may be the early markers for the destructive phase. These genes are Mt1, Mt2, Hmox1, Gcl, GR, IL-6, IL-13, Txn1, Fas, FasL, Lpin2, Mmp1a, Mmp12, Sfp-B, Sfp-D, CAT, EC-SOD, GST, and Pltp. On the other hand, the genes involved in the development of fibrosis, such as procollagen, Fn1, Eln, SMA, and Mmp9, Timp1 were significantly increased on day 5, not at 6h nor at 24h, after PQ treatment (the late marker). The genes showing a significant increase (Mmp3 and Mmp8) or decrease (VEGFA) at 24h and 5 days and not at 6h may be also the late markers. These changes in gene expression, which are equalled to functional activities of proteins, will be the targets for future studies focused on the development on PQ-induced pulmonary damage.

Authors+Show Affiliations

Department of Medical Toxicology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Japan. toxicology@med.kawasaki-m.ac.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17215068

Citation

Tomita, Masafumi, et al. "Mouse Model of Paraquat-poisoned Lungs and Its Gene Expression Profile." Toxicology, vol. 231, no. 2-3, 2007, pp. 200-9.
Tomita M, Okuyama T, Katsuyama H, et al. Mouse model of paraquat-poisoned lungs and its gene expression profile. Toxicology. 2007;231(2-3):200-9.
Tomita, M., Okuyama, T., Katsuyama, H., Miura, Y., Nishimura, Y., Hidaka, K., Otsuki, T., & Ishikawa, T. (2007). Mouse model of paraquat-poisoned lungs and its gene expression profile. Toxicology, 231(2-3), 200-9.
Tomita M, et al. Mouse Model of Paraquat-poisoned Lungs and Its Gene Expression Profile. Toxicology. 2007 Mar 7;231(2-3):200-9. PubMed PMID: 17215068.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mouse model of paraquat-poisoned lungs and its gene expression profile. AU - Tomita,Masafumi, AU - Okuyama,Toshiko, AU - Katsuyama,Hironobu, AU - Miura,Yoshie, AU - Nishimura,Yasumitsu, AU - Hidaka,Kazuo, AU - Otsuki,Takemi, AU - Ishikawa,Takaki, Y1 - 2006/12/15/ PY - 2006/10/11/received PY - 2006/11/20/revised PY - 2006/12/04/accepted PY - 2007/1/12/pubmed PY - 2007/4/18/medline PY - 2007/1/12/entrez SP - 200 EP - 9 JF - Toxicology JO - Toxicology VL - 231 IS - 2-3 N2 - Paraquat (PQ)-induced pulmonary toxicity is characterized by initial development of pulmonary edema, infiltration of inflammatory cells, and damage to the alveolar epithelium, which may progress to severe fibrosis. However, the exact role of PQ in the progression of the pathogenesis has not been clearly established. To understand the mechanism of PQ in pulmonary toxicity, we developed an animal model of PQ-induced lung injury by intranasal instillation of PQ solution using C57Black/6J mice. Twenty microliters of PQ solution (0.01, 0.01, and 0.04 mg/mouse) was applied through the nares, and the same amount of vehicle was applied in control mice. The pathological progression of lung pathology in our mouse model was very similar to that of patients suffering from PQ poisoning. The lungs of some animals exposed to PQ showed acute fulmination, resulting in death from 5 days post-exposure, but others showed a more protracted injury, resulting in typical pulmonary fibrosis at 3 weeks. Using this PQ-poisoned mouse model, we examined the gene expression at the initial destructive phase (within 5 days) that fibrosis has not completely developed. We prepared RNAs after 6h, 24h, and 5 days and examined the changes of the expression levels for 45 selected genes. The genes showing >2-fold increase at 6h or a time-dependent decrease during this experimental period may be the early markers for the destructive phase. These genes are Mt1, Mt2, Hmox1, Gcl, GR, IL-6, IL-13, Txn1, Fas, FasL, Lpin2, Mmp1a, Mmp12, Sfp-B, Sfp-D, CAT, EC-SOD, GST, and Pltp. On the other hand, the genes involved in the development of fibrosis, such as procollagen, Fn1, Eln, SMA, and Mmp9, Timp1 were significantly increased on day 5, not at 6h nor at 24h, after PQ treatment (the late marker). The genes showing a significant increase (Mmp3 and Mmp8) or decrease (VEGFA) at 24h and 5 days and not at 6h may be also the late markers. These changes in gene expression, which are equalled to functional activities of proteins, will be the targets for future studies focused on the development on PQ-induced pulmonary damage. SN - 0300-483X UR - https://www.unboundmedicine.com/medline/citation/17215068/Mouse_model_of_paraquat_poisoned_lungs_and_its_gene_expression_profile_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0300-483X(06)00731-1 DB - PRIME DP - Unbound Medicine ER -