Arrest of endotoxin-induced hypotension by transforming growth factor β1

Mark A. Perrella, Chung Ming Hsieh, Wen Sen Lee, Sherry Shieh, Jer Chia Tsai, Cam Patterson, Charles J. Lowenstein, Nancy C. Long, Edgar Haber, Stephanie Shore, Mu En Lee

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Abstract

Septic shock is a cytokine-mediated process typically caused by a severe underlying infection. Toxins generated by the infecting organism t rigger a cascade of events leading to hypotension, to multiple organ system failure, and frequently to death. Beyond supportive care, no effective therapy is available for the treatment of septic shock. Nitric oxide (NO) is a potent vasodilator generated late in the sepsis pathway leading to hypotension; therefore, NO represents a potential target for therapy. We have previously demonstrated that transforming growth factor (TGF) β1 inhibits inducible NO synthase (iNOS) mRNA and NO production in vascular smooth muscle cells after its induction by cytokines critical in the sepsis cascade. Thus, we hypothesized that TGF-β1 may inhibit iNOS gene expression in vivo and be beneficial in the treatment of septic shock. In a conscious rat model of septic shock produced by Salmonella typhosa lipopolysaccharide (LPS), TGF- β1 markedly reduced iNOS mRNA and protein levels in several organs. In contrast, TGF-β1 did not decrease endothelium-derived constitutive NOS mRNA in organs of rats receiving LPS. We also performed studies in anesthetized rats to evaluate the effect of TGF-β1 on the hemodynamic compromise of septic shock; after an initial 25% decrease in mean arterial pressure, TGF- β1 arrested LPS-induced hypotension and decreased mortality. A decrease in iNOS mRNA and protein levels in vascular smooth muscle cells was demonstrated by in situ hybridization and NADPH diaphorase staining in rats treated with TGF-β1. Thus these studies suggest that TGF-β1 inhibits iNOS in vivo and that TGF-β1 may be of future benefit in the therapy of septic shock.

Original languageEnglish
Pages (from-to)2054-2059
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume93
Issue number5
DOIs
Publication statusPublished - Mar 5 1996
Externally publishedYes

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Keywords

  • inducible nitric oxide synthase
  • selective inhibition
  • septic shock
  • vascular smooth muscle cells

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Perrella, M. A., Hsieh, C. M., Lee, W. S., Shieh, S., Tsai, J. C., Patterson, C., Lowenstein, C. J., Long, N. C., Haber, E., Shore, S., & Lee, M. E. (1996). Arrest of endotoxin-induced hypotension by transforming growth factor β1. Proceedings of the National Academy of Sciences of the United States of America, 93(5), 2054-2059. https://doi.org/10.1073/pnas.93.5.2054