Pyrrolidine Dithiocarbamate Attenuates Endotoxin-induced Acute Lung Injury

Avery B. Nathens, Richard Bitar, Christopher Davreux, Michael Bujard, John C. Marshall, Alan P B Dackiw, Ronald W G Watson, Ori D. Rotstein

Research output: Contribution to journalArticle

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Abstract

Lung injury in the acute respiratory distress syndrome (ARDS) is in part due to polymorphonuclear leukocyte (PMN)-mediated oxidative tissue damage. By means of nuclear factor-κB (NF-κB) activation, oxidants may also induce several genes implicated in the inflammatory response. The dithiocarbamates are antioxidants with potent inhibitory effects on NF-κB. We postulated that the pyrrolidine derivative pyrrolidine dithiocarbamate (PDTC) would attenuate lung injury following intratracheal challenge with endotoxin (lipopolysaccharide; LPS) through its effect as an antioxidant and inhibitor of gene activation. Rats were given PDTC (1 mmole/kg) by intraperitoneal injection, followed by intratracheal administration of LPS. The transpulmonary flux of [125I] albumin (permeability index; PI) was used as a measure of lung injury. Northern blot analysis of total lung RNA was performed to assess induction of tumor necrosis factor-α (TNF-α) and intercellular adhesion molecule-1 (ICAM-1) messenger RNA (mRNA) as markers of NF-κB activation. The effect of in vivo treatment with PDTC on LPS-induced NF-κB DNA binding activity in macrophage nuclear extracts was evaluated with the electrophoretic mobility shift assay (EMSA). PDTC administration attenuated LPS-induced increases in lung permeability (PI = 0.16 ± 0.02 for LPS versus 0.06 ± 0.01 for LPS + PDTC; P < 0.05). TNF-α levels and PMN counts in bronchoalveolar lavage fluid (BALF) were unaffected, as were whole-lung TNF-α and ICAM-1 mRNA expression. PDTC had no effect on NF-κB activation as evaluated with EMSA. PDTC reduced lung lipid peroxidation as assessed by levels of malondialdehyde, without reducing neutrophil oxidant production. We conclude that PDTC attenuates LPS-induced acute lung injury. This effect occurs independently of any effect on NF-κB. PDTC reduces oxidant-mediated cellular injury, as demonstrated by a reduction in the accumulation of malondialdehyde. Administration of PDTC may represent a novel approach to limiting neutrophil-mediated oxidant injury.

Original languageEnglish (US)
Pages (from-to)608-616
Number of pages9
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume17
Issue number5
StatePublished - 1997

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Acute Lung Injury
Endotoxins
Oxidants
Lung Injury
Neutrophils
Chemical activation
Lung
Electrophoretic mobility
Tumor Necrosis Factor-alpha
Electrophoretic Mobility Shift Assay
Intercellular Adhesion Molecule-1
Malondialdehyde
Permeability
Assays
Antioxidants
Genes
pyrrolidine dithiocarbamic acid
Messenger RNA
Macrophages
Adult Respiratory Distress Syndrome

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Pulmonary and Respiratory Medicine

Cite this

Nathens, A. B., Bitar, R., Davreux, C., Bujard, M., Marshall, J. C., Dackiw, A. P. B., ... Rotstein, O. D. (1997). Pyrrolidine Dithiocarbamate Attenuates Endotoxin-induced Acute Lung Injury. American Journal of Respiratory Cell and Molecular Biology, 17(5), 608-616.

Pyrrolidine Dithiocarbamate Attenuates Endotoxin-induced Acute Lung Injury. / Nathens, Avery B.; Bitar, Richard; Davreux, Christopher; Bujard, Michael; Marshall, John C.; Dackiw, Alan P B; Watson, Ronald W G; Rotstein, Ori D.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 17, No. 5, 1997, p. 608-616.

Research output: Contribution to journalArticle

Nathens, AB, Bitar, R, Davreux, C, Bujard, M, Marshall, JC, Dackiw, APB, Watson, RWG & Rotstein, OD 1997, 'Pyrrolidine Dithiocarbamate Attenuates Endotoxin-induced Acute Lung Injury', American Journal of Respiratory Cell and Molecular Biology, vol. 17, no. 5, pp. 608-616.
Nathens, Avery B. ; Bitar, Richard ; Davreux, Christopher ; Bujard, Michael ; Marshall, John C. ; Dackiw, Alan P B ; Watson, Ronald W G ; Rotstein, Ori D. / Pyrrolidine Dithiocarbamate Attenuates Endotoxin-induced Acute Lung Injury. In: American Journal of Respiratory Cell and Molecular Biology. 1997 ; Vol. 17, No. 5. pp. 608-616.
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AU - Dackiw, Alan P B

AU - Watson, Ronald W G

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