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Overexpression of nitric oxide synthase by the endothelium attenuates bleomycin-induced lung fibrosis and impairs MMP-9/TIMP-1 balance.
Respirology. 2006 Sep; 11(5):546-56.R

Abstract

BACKGROUND

Nitric oxide (NO) produced by endothelial NO synthase (eNOS) is thought to effect an anti-inflammatory response, but its mechanism is still unknown.

METHODS

eNOS transgenic (eNOS-TG) mice and their littermate controls (C57/BL6) were used to clarify the role of NO derived from eNOS. Bleomycin hydrochloride (1 U/body/day) or PBS was injected intraperitoneally.

RESULTS

Subpleural fibrotic changes and hydroxyproline content in the eNOS-TG mice were significantly reduced compared with those of the wild-type (WT) mice by day 56. Administration of N(omega)-nitro-L-arginine methyl ester, a potent inhibitor of NO synthase, worsened the fibrotic response in bleomycin-treated eNOS-TG mice. Gelatinolytic activity in lung homogenates, corresponding to metalloproteinase-9 (MMP-9), was significantly increased in bleomycin-injured WT mice on day 14. In contrast, the level of tissue inhibitor of metalloproteinases-1 (TIMP-1), an endogenous MMP-9 inhibitor, was increased in the bleomycin-treated eNOS-TG mice compared with WT. Immunohistochemical analysis demonstrated that MMP-9 and TIMP-1 were strongly expressed in inflammatory cells, including subpleural fibrotic lesions.

CONCLUSION

These data suggested that eNOS overexpression attenuates bleomycin-induced lung injury by ameliorating the MMP-9/TIMP-1 balance.

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Authors+Show Affiliations

Yoshimura S
Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Nishimura Y
No affiliation info available
Nishiuma T
No affiliation info available
Yamashita T
No affiliation info available
Kobayashi K
No affiliation info available
Yokoyama M
No affiliation info available

MeSH

AnimalsBleomycinBlotting, WesternBronchoalveolar Lavage FluidEndothelium, VascularFibrosisHydroxyprolineImmunohistochemistryLungLung DiseasesMatrix Metalloproteinase 9MiceMice, TransgenicNitric Oxide Synthase Type IINitric Oxide Synthase Type IIITissue Inhibitor of Metalloproteinase-1Up-RegulationVascular Endothelial Growth Factor A

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16916326

Citation

Yoshimura, Sho, et al. "Overexpression of Nitric Oxide Synthase By the Endothelium Attenuates Bleomycin-induced Lung Fibrosis and Impairs MMP-9/TIMP-1 Balance." Respirology (Carlton, Vic.), vol. 11, no. 5, 2006, pp. 546-56.
Yoshimura S, Nishimura Y, Nishiuma T, et al. Overexpression of nitric oxide synthase by the endothelium attenuates bleomycin-induced lung fibrosis and impairs MMP-9/TIMP-1 balance. Respirology. 2006;11(5):546-56.
Yoshimura, S., Nishimura, Y., Nishiuma, T., Yamashita, T., Kobayashi, K., & Yokoyama, M. (2006). Overexpression of nitric oxide synthase by the endothelium attenuates bleomycin-induced lung fibrosis and impairs MMP-9/TIMP-1 balance. Respirology (Carlton, Vic.), 11(5), 546-56.
Yoshimura S, et al. Overexpression of Nitric Oxide Synthase By the Endothelium Attenuates Bleomycin-induced Lung Fibrosis and Impairs MMP-9/TIMP-1 Balance. Respirology. 2006;11(5):546-56. PubMed PMID: 16916326.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Overexpression of nitric oxide synthase by the endothelium attenuates bleomycin-induced lung fibrosis and impairs MMP-9/TIMP-1 balance. AU - Yoshimura,Sho, AU - Nishimura,Yoshihiro, AU - Nishiuma,Teruaki, AU - Yamashita,Tomoya, AU - Kobayashi,Kazuyuki, AU - Yokoyama,Mitsuhiro, PY - 2006/8/19/pubmed PY - 2007/1/11/medline PY - 2006/8/19/entrez SP - 546 EP - 56 JF - Respirology (Carlton, Vic.) JO - Respirology VL - 11 IS - 5 N2 - BACKGROUND: Nitric oxide (NO) produced by endothelial NO synthase (eNOS) is thought to effect an anti-inflammatory response, but its mechanism is still unknown. METHODS: eNOS transgenic (eNOS-TG) mice and their littermate controls (C57/BL6) were used to clarify the role of NO derived from eNOS. Bleomycin hydrochloride (1 U/body/day) or PBS was injected intraperitoneally. RESULTS: Subpleural fibrotic changes and hydroxyproline content in the eNOS-TG mice were significantly reduced compared with those of the wild-type (WT) mice by day 56. Administration of N(omega)-nitro-L-arginine methyl ester, a potent inhibitor of NO synthase, worsened the fibrotic response in bleomycin-treated eNOS-TG mice. Gelatinolytic activity in lung homogenates, corresponding to metalloproteinase-9 (MMP-9), was significantly increased in bleomycin-injured WT mice on day 14. In contrast, the level of tissue inhibitor of metalloproteinases-1 (TIMP-1), an endogenous MMP-9 inhibitor, was increased in the bleomycin-treated eNOS-TG mice compared with WT. Immunohistochemical analysis demonstrated that MMP-9 and TIMP-1 were strongly expressed in inflammatory cells, including subpleural fibrotic lesions. CONCLUSION: These data suggested that eNOS overexpression attenuates bleomycin-induced lung injury by ameliorating the MMP-9/TIMP-1 balance. SN - 1323-7799 UR - https://www.unboundmedicine.com/medline/citation/16916326/Overexpression_of_nitric_oxide_synthase_by_the_endothelium_attenuates_bleomycin_induced_lung_fibrosis_and_impairs_MMP_9/TIMP_1_balance_ L2 - https://doi.org/10.1111/j.1440-1843.2006.00894.x DB - PRIME DP - Unbound Medicine ER -