Paraquat Poisonings: Mechanisms of Lung Toxicity, Clinical Features, and Treatment

Abstract

Paraquat dichloride (methyl viologen; PQ) is an effective and widely used herbicide that has a proven safety record when appropriately applied to eliminate weeds. However, over the last decades, there have been numerous fatalities, mainly caused by accidental or voluntary ingestion. PQ poisoning is an extremely frustrating condition to manage clinically, due to the elevated morbidity and mortality observed so far and due to the lack of effective treatments to be used in humans. PQ mainly accumulates in the lung (pulmonary concentrations can be 6 to 10 times higher than those in the plasma), where it is retained even when blood levels start to decrease. The pulmonary effects can be explained by the participation of the polyamine transport system abundantly expressed in the membrane of alveolar cells type I, II, and Clara cells. Further downstream at the toxicodynamic level, the main molecular mechanism of PQ toxicity is based on redox cycling and intracellular oxidative stress generation. With this review we aimed to collect and describe the most pertinent and significant findings published in established scientific publications since the discovery of PQ, focusing on the most recent developments related to PQ lung toxicity and their relevance to the treatment of human poisonings. Considerable space is also dedicated to techniques for prognosis prediction, since these could allow development of rigorous clinical protocols that may produce comparable data for the evaluation of proposed therapies.

Key words :

• Chemistry
• Clinical Features
• History
• Human Intoxication
• Paraquat
• Toxicokinetics
• Treatment

ABBREVIATIONS
Ab,	=	antibody.
ACE,	=	angiotensin-converting enzyme.
AP-1,	=	activator protein-1.
ARDS,	=	acute respiratory distress syndrome.
ATP,	=	adenosine triphosphate.
BALF,	=	bronchoalveolar lavage fluid.
BHs,	=	bipyridylium herbicides.
b.w.,	=	body weight.
CHP,	=	charcoal hemoperfusion.
CLCr,	=	creatinine clearance.
CLPQ,	=	paraquat clearance.
Cmax,	=	concentration.
CNS,	=	central nervous system.
CP,	=	cyclophosphamide.
CP51,	=	1-(2′-methoxyethyl)-2-methyl-3-hydroxypyridin-4-one.
Cyt c,	=	cytochrome c.
DEX,	=	dexamethasone.
DFO,	=	desferoxamine.
DLCO,	=	lung carbon monoxide diffusing capacity.
DNA,	=	deoxyribonucleic acid.
ERG,	=	electroretinogram.
exEth,	=	ethane in the expired breath
Fe2+,	=	ferrous ion.
Fe3+,	=	ferric ion.
FiO2,	=	fraction of inspired oxygen.
FR,	=	Fenton reaction.
FRD,	=	ferrodoxin.
G6PD,	=	glucose-6-phosphate dehydrogenase.
GFR,	=	glomerular filtration rate.
GGO,	=	ground-glass opacification.
GIT,	=	gastrointestinal tract.
GPx,	=	glutathione peroxidase.
Gred,	=	glutathione reductase.
GSH,	=	reduced glutathione.
GSSG,	=	oxidized glutathione.
H2O2,	=	hydrogen peroxide.
HMP,	=	hexose monophosphate pathway.
HO−,	=	hydroxyl radical.
HRCT,	=	high-resolution computed tomography.
HWR,	=	Haber–Weiss reaction.
i.p.,	=	intraperitoneal.
i.v.,	=	intravenous.
ICI,	=	Imperial Chemical Industries (now Syngenta).
Km,	=	Michaelis–Menten constant.
LPO,	=	lipid peroxidation.
MDA,	=	malondialdehyde.
MINA,	=	4-methylisonicotinic acid.
MGBG,	=	methylglyoxal bis-(guanylhydrazone).
MP,	=	methylprednisolone.
Na+,	=	sodium.
NAC,	=	N-acetylcysteine.
NADP+,	=	oxidized nicotinamide adenine dinucleotide phosphate.
NADPH,	=	reduced nicotinamide adenine dinucleotide phosphate.
NaSAL,	=	sodium salicylate.
NF-κB,	=	nuclear factor kappa-B.
NMN,	=	N-methylnicotinamide.
NO,	=	nitric oxide.
NOS,	=	nitric oxide synthase.
O2,	=	oxygen.
O2· −,	=	superoxide radical.
PaCO2,	=	partial pressure of carbon dioxide in arterial blood.
PAH,	=	p-aminohippurate.
PaO2,	=	partial pressure of oxygen in arterial blood.
PAO2,	=	partial pressure of oxygen in the alveolus.
PEEP,	=	positive end-expiratory pressure.
PFTs	=	pulmonary function tests.
P-gp,	=	P-glycoprotein.
PQ or PQ2+,	=	paraquat.
PQ·+,	=	paraquat monocation free radical.
PUFAs,	=	polyunsaturated fatty acids
PUS,	=	polyamine uptake system.
RNA,	=	ribonucleic acid.
ROS,	=	reactive oxygen species.
s.c.,	=	subcutaneous.
SH,	=	thiol.
SOD,	=	superoxide dismutase.
t1/2,	=	half-life.
Tmax,	=	time to maximum plasma concentration.
TPC,	=	TUNEL-positive cells.
TUNEL,	=	terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling.
VER,	=	verapamil.
Vmax,	=	maximal rate.
WBC,	=	white blood cell.
XD,	=	xanthine dehydrogenase.
XO,	=	xanthine oxidase.

ABBREVIATIONS
Ab,	=	antibody.
ACE,	=	angiotensin-converting enzyme.
AP-1,	=	activator protein-1.
ARDS,	=	acute respiratory distress syndrome.
ATP,	=	adenosine triphosphate.
BALF,	=	bronchoalveolar lavage fluid.
BHs,	=	bipyridylium herbicides.
b.w.,	=	body weight.
CHP,	=	charcoal hemoperfusion.
CLCr,	=	creatinine clearance.
CLPQ,	=	paraquat clearance.
Cmax,	=	concentration.
CNS,	=	central nervous system.
CP,	=	cyclophosphamide.
CP51,	=	1-(2′-methoxyethyl)-2-methyl-3-hydroxypyridin-4-one.
Cyt c,	=	cytochrome c.
DEX,	=	dexamethasone.
DFO,	=	desferoxamine.
DLCO,	=	lung carbon monoxide diffusing capacity.
DNA,	=	deoxyribonucleic acid.
ERG,	=	electroretinogram.
exEth,	=	ethane in the expired breath
Fe2+,	=	ferrous ion.
Fe3+,	=	ferric ion.
FiO2,	=	fraction of inspired oxygen.
FR,	=	Fenton reaction.
FRD,	=	ferrodoxin.
G6PD,	=	glucose-6-phosphate dehydrogenase.
GFR,	=	glomerular filtration rate.
GGO,	=	ground-glass opacification.
GIT,	=	gastrointestinal tract.
GPx,	=	glutathione peroxidase.
Gred,	=	glutathione reductase.
GSH,	=	reduced glutathione.
GSSG,	=	oxidized glutathione.
H2O2,	=	hydrogen peroxide.
HMP,	=	hexose monophosphate pathway.
HO−,	=	hydroxyl radical.
HRCT,	=	high-resolution computed tomography.
HWR,	=	Haber–Weiss reaction.
i.p.,	=	intraperitoneal.
i.v.,	=	intravenous.
ICI,	=	Imperial Chemical Industries (now Syngenta).
Km,	=	Michaelis–Menten constant.
LPO,	=	lipid peroxidation.
MDA,	=	malondialdehyde.
MINA,	=	4-methylisonicotinic acid.
MGBG,	=	methylglyoxal bis-(guanylhydrazone).
MP,	=	methylprednisolone.
Na+,	=	sodium.
NAC,	=	N-acetylcysteine.
NADP+,	=	oxidized nicotinamide adenine dinucleotide phosphate.
NADPH,	=	reduced nicotinamide adenine dinucleotide phosphate.
NaSAL,	=	sodium salicylate.
NF-κB,	=	nuclear factor kappa-B.
NMN,	=	N-methylnicotinamide.
NO,	=	nitric oxide.
NOS,	=	nitric oxide synthase.
O2,	=	oxygen.
O2· −,	=	superoxide radical.
PaCO2,	=	partial pressure of carbon dioxide in arterial blood.
PAH,	=	p-aminohippurate.
PaO2,	=	partial pressure of oxygen in arterial blood.
PAO2,	=	partial pressure of oxygen in the alveolus.
PEEP,	=	positive end-expiratory pressure.
PFTs	=	pulmonary function tests.
P-gp,	=	P-glycoprotein.
PQ or PQ2+,	=	paraquat.
PQ·+,	=	paraquat monocation free radical.
PUFAs,	=	polyunsaturated fatty acids
PUS,	=	polyamine uptake system.
RNA,	=	ribonucleic acid.
ROS,	=	reactive oxygen species.
s.c.,	=	subcutaneous.
SH,	=	thiol.
SOD,	=	superoxide dismutase.
t1/2,	=	half-life.
Tmax,	=	time to maximum plasma concentration.
TPC,	=	TUNEL-positive cells.
TUNEL,	=	terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling.
VER,	=	verapamil.
Vmax,	=	maximal rate.
WBC,	=	white blood cell.
XD,	=	xanthine dehydrogenase.
XO,	=	xanthine oxidase.