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

85 Scopus citations

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
DOIs
StatePublished - Jan 1 1997

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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    Nathens, A. B., Bitar, R., Davreux, C., Bujard, M., Marshall, J. C., Dackiw, A. P. B., Watson, R. W. G., & Rotstein, O. D. (1997). Pyrrolidine Dithiocarbamate Attenuates Endotoxin-induced Acute Lung Injury. American journal of respiratory cell and molecular biology, 17(5), 608-616. https://doi.org/10.1165/ajrcmb.17.5.2661