Pyrrolidine dithiocarbamate attenuates endotoxin-induced acute lung injury.
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-kappaB (NF-kappaB) activation, oxidants may also induce several genes implicated in the inflammatory response. The dithiocarbamates are antioxidants with potent inhibitory effects on NF-kappaB. 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-alpha (TNF-alpha) and intercellular adhesion molecule-1 (ICAM-1) messenger RNA (mRNA) as markers of NF-kappaB activation. The effect of in vivo treatment with PDTC on LPS-induced NF-kappaB 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-alpha levels and PMN counts in bronchoalveolar lavage fluid (BALF) were unaffected, as were whole-lung TNF-alpha and ICAM-1 mRNA expression. PDTC had no effect on NF-kappaB 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-kappaB. 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.
Nathens
A B
AB
Department of Surgery, University of Toronto, and the Toronto Hospital Research Institute, Ontario, Canada.
Bitar
R
R
Davreux
C
C
Bujard
M
M
Marshall
J C
JC
Dackiw
A P
AP
Watson
R W
RW
Rotstein
O D
OD
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D004731:Endotoxins / Q000633:toxicity*; D006801:Humans; D007231:Infant, Newborn; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D012127:Respiratory Distress Syndrome, Newborn / Q000188:drug therapy* / Q000473:pathology; D013859:Thiocarbamates / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000975:Antioxidants; D004731:Endotoxins; D016328:NF-kappa B; D011759:Pyrrolidines; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; C020972:pyrrolidine dithiocarbamic acid