Pyrrolidine dithiocarbamate attenuates the development of organ failure induced by zymosan in mice.
OBJECTIVE
Nuclear factor (NF) kappaB is a transcription factor which plays a pivotal role in the induction of genes involved in physiological processes as well as in the response to injury and inflammation. Dithiocarbamates are anti-oxidants which are potent inhibitors of NF-kappaB. We postulated that pyrrolidine dithiocarbamate (PDTC) would attenuate multiple-organ failure (MOF).


METHODS
Rats in a university research laboratory.


METHODS
We investigated the effects of PDTC (10 mg/kg) on the MOF caused by zymosan (500 mg/kg, administered i.p. as a suspension in saline) in mice. MOF in mice was assessed 18 h after administration of zymosan and/or PDTC and monitored for 7 days (for loss of body weight and mortality).


RESULTS
Treatment of mice with PDTC (10 mg/kg i.p., 1 and 6 h after zymosan) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by zymosan. PDTC also attenuated the lung, liver and pancreatic injury and renal dysfunction caused by zymosan as well as the increase in myeloperoxidase activity and malondialdehyde levels caused by zymosan in the lung, liver and intestine. Immunohistochemical analysis for inducible nitric oxide synthase, nitrotyrosine and poly(ADP-ribose) revealed positive staining in lung, liver and intestine tissues obtained from zymosan-treated mice. The degree of staining for nitrotyrosine and poly(ADP-ribose) were markedly reduced in tissue sections obtained from zymosan-treated mice which received PDTC. Furthermore, treatment of mice with PDTC significantly reduced the expression of nitric oxide synthase in lung, liver and intestine.


CONCLUSIONS
This study provides the first evidence that PDTC attenuates the degree of zymosan-induced MOF in mice.
Cuzzocrea
Salvatore
S
Institute of Pharmacology, School of Medicine, Torre Biologicala, Policlinico Universitario, University of Messina, Via C. Valeria Gazzi, 98100, Messina, Italy. salvator@www.unime.it
Rossi
Antonietta
A
Pisano
Barbara
B
Di Paola
Rosanna
R
Genovese
Tiziana
T
Patel
Nimesh S A
NS
Cuzzocrea
Elisabetta
E
Ianaro
Angela
A
Sautebin
Lidia
L
Fulia
Francesco
F
Chatterjee
Prabal K
PK
Caputi
Achille P
AP
Thiemermann
Christoph
C
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D015153:Blotting, Western; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D007150:Immunohistochemistry; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D051379:Mice; D008815:Mice, Inbred Strains; D009102:Multiple Organ Failure / Q000139:chemically induced* / Q000175:diagnosis / Q000276:immunology / Q000517:prevention & control*; D016328:NF-kappa B / Q000032:analysis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II; D009195:Peroxidase / Q000032:analysis / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D013859:Thiocarbamates / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000032:analysis / Q000187:drug effects; D015054:Zymosan
D000975:Antioxidants; D016328:NF-kappa B; D011759:Pyrrolidines; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D008315:Malondialdehyde; D015054:Zymosan; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D011065:Poly(ADP-ribose) Polymerases