Assessment of early acute lung injury in rodents exposed to phosgene

Abstract

Phosgene is a highly reactive oxidant gas used in the chemical industry. Phosgene can cause life-threatening pulmonary edema by reacting with peripheral lung compartment tissue components. Clinical evidence of edema is not usually apparent until well after the initial exposure. This study was designed to investigate early signs of acute lung injury in rodents within 45-60 min after the start of exposure. Male mice, rats, or guinea pigs were exposed to 87 mg/m3 (22 ppm) phosgene or filtered room air for 20 min followed by room air washout for 5 min. This concentration-time exposure causes a doubling of lung wet weight within 5 h. After exposure, animals were immediately anesthetized i.p., with pentobarbital. Bronchoalveolar lavage (BAL) was performed and fluid analyzed for total glutathione (GSH), lipid peroxidation thiobarbituric acid reactive substances (TBARS), and protein concentration. Lungs were perfused with saline to remove blood, freeze-snapped in liquid N2, analyzed for tissue GSH, and TBARS. Lung edema was assessed gravimetrically by measuring tissue wet/dry (W/D) weight ratios and tissue wet weights (TWW). W/D and TWW were significantly higher in mice for phosgene vs air (P=0.001, P < 0.0001, respectively), but not in rats or guinea pigs. Tissue TBARS was significantly higher in phosgene-exposed guinea pigs, P=0.027; however, BAL TBARS was higher in both rats and guinea pigs, P=0.013 and P=0.006, respectively. Tissue GSH was significantly lower in phosgene-exposed rats and guinea pigs but not mice, whereas BAL GSH was higher in rats, P < 0.0001. There were significantly higher BAL protein levels in all phosgene-exposed species: mice, P < 0.0001; rats, P < 0.0001; and guinea pigs, P=0.002. Although there appears to be a species-specific biochemical effect of phosgene exposure for some biochemical indices, measurement of BAL protein in all three species is a better indicator of ensuing edema formation.

Relationship between neutrophil influx and oxidative stress in alveolar space in lipopolysaccharide-induced lung injury

“…This is probably due to the rapid extracellular oxidation of GSH (Winterbourn et al, 2000). The increase of total GSH in BAL fluid, despite being reduced in lung tissues in a mouse model of lung damage caused by oxidative stress, is probably associated with alveolar cell rupture (Sciuto, 1998).…”

Surfactant lipid peroxidation damages surfactant protein A and inhibits interactions with phospholipid vesicles

“…Oxidized proteins accumulate with aging (33-35), after lung injury or toxic inhalation (36), and in various pathological states, including diabetes (37) and Alzheimer's disease (38). Oxidative modification and functional inactivation of proteins may occur by direct interaction with the oxidizing substance or indirectly through interaction with free radicals or reactive oxidation products, such as the aldehydic intermediates MDA (39) and 4-hydroxynonenal (40).…”

Oxidative Stress in Early Stage of Acute Lung Injury Induced with Oleic Acid in Guinea Pigs.

“…[2][3][4][5][6] ROS production systems from activated polymorphonuclear leukocytes (PMNs) and endothelial cells are considered to be two major pathways in acute lung injuries. 7) Extensive studies have demonstrated that sources for ROS in the lungs are reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (including the phagocytic cell oxidase and nonphagocyte oxidase in the vascular endothelial cells), xanthine dehydrogenase/xanthine oxidase (XDH/XO), and mitochondrial respiration.…”

“…There is some evidence demonstrating that lipid peroxidation may contribute to oleic acidinduced lung injury. 21,22) The contributions of NADPH oxidase, XDH/XO, and effects of the antioxidant defense system have been reported in animal models of acute lung injuries, 2,6,9,11,23,24) but only a few papers demonstrated an involvement of the system in oleic acid-induced lung injury. 24) In addition, the characteristics of the ROS-generating pathway with oleic acid-induced lung injury are unclear.…”