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Impaired liver regeneration in inducible nitric oxide synthasedeficient mice.

Publication ,  Journal Article
Rai, RM; Lee, FY; Rosen, A; Yang, SQ; Lin, HZ; Koteish, A; Liew, FY; Zaragoza, C; Lowenstein, C; Diehl, AM
Published in: Proc Natl Acad Sci U S A
November 10, 1998

The mechanisms that permit adult tissues to regenerate when injured are not well understood. Initiation of liver regeneration requires the injury-related cytokines, tumor necrosis factor (TNF) alpha and interleukin (IL) 6, and involves the activation of cytokine-regulated transcription factors such as NF-kappabeta and STAT3. During regeneration, TNFalpha and IL-6 promote hepatocyte viability, as well as proliferation, because interventions that inhibit either cytokine not only block hepatocyte DNA synthesis, but also increase liver cell death. These observations suggest that the cytokines induce hepatoprotective factors in the regenerating liver. Given evidence that nitric oxide can prevent TNF-mediated activation of the pro-apoptotic protease caspase 3 and protect hepatocytes from cytokine-mediated death, cytokine-inducible nitric oxide synthase (iNOS) may be an important hepatoprotective factor in the regenerating liver. In support of this hypothesis we report that the hepatocyte proliferative response to partial liver resection is severely inhibited in transgenic mice with targeted disruption of the iNOS gene. Instead, partial hepatectomy is followed by increased caspase 3 activity, hepatocyte death, and liver failure, despite preserved induction of TNFalpha, IL-6, NF-kappabeta, and STAT3. These results suggest that during successful tissue regeneration, injury-related cytokines induce factors, such as iNOS and its product, NO, that protect surviving cells from cytokine-mediated death.

Duke Scholars

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

November 10, 1998

Volume

95

Issue

23

Start / End Page

13829 / 13834

Location

United States

Related Subject Headings

  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase
  • Mice, Knockout
  • Mice
  • Liver Regeneration
  • Cytokines
  • Animals
 

Citation

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Rai, R. M., Lee, F. Y., Rosen, A., Yang, S. Q., Lin, H. Z., Koteish, A., … Diehl, A. M. (1998). Impaired liver regeneration in inducible nitric oxide synthasedeficient mice. Proc Natl Acad Sci U S A, 95(23), 13829–13834. https://doi.org/10.1073/pnas.95.23.13829
Rai, R. M., F. Y. Lee, A. Rosen, S. Q. Yang, H. Z. Lin, A. Koteish, F. Y. Liew, C. Zaragoza, C. Lowenstein, and A. M. Diehl. “Impaired liver regeneration in inducible nitric oxide synthasedeficient mice.Proc Natl Acad Sci U S A 95, no. 23 (November 10, 1998): 13829–34. https://doi.org/10.1073/pnas.95.23.13829.
Rai RM, Lee FY, Rosen A, Yang SQ, Lin HZ, Koteish A, et al. Impaired liver regeneration in inducible nitric oxide synthasedeficient mice. Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13829–34.
Rai, R. M., et al. “Impaired liver regeneration in inducible nitric oxide synthasedeficient mice.Proc Natl Acad Sci U S A, vol. 95, no. 23, Nov. 1998, pp. 13829–34. Pubmed, doi:10.1073/pnas.95.23.13829.
Rai RM, Lee FY, Rosen A, Yang SQ, Lin HZ, Koteish A, Liew FY, Zaragoza C, Lowenstein C, Diehl AM. Impaired liver regeneration in inducible nitric oxide synthasedeficient mice. Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13829–13834.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

November 10, 1998

Volume

95

Issue

23

Start / End Page

13829 / 13834

Location

United States

Related Subject Headings

  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase
  • Mice, Knockout
  • Mice
  • Liver Regeneration
  • Cytokines
  • Animals