Lazaroid U-74389F attenuates phorbol ester-induced lung injury in rabbits

Abstract

We examined the effect of the antioxidant lazaroid U-74389F on acute lung injury induced in rabbits by phorbol myristate acetate (PMA).Thirty minutes after receiving either U-74389F (15 mg·kg -1 i.v.) or U-74389F vehicle, rabbits (n=60) were given PMA (60 µg·kg -1 i.v.). PMA vehicle injected rabbits (n=20) served as controls. Over a 5 h period after PMA or PMA vehicle injection, we measured arterial pH, arterial oxygen tension (Pa,O 2 ), arterial carbon dioxide tension (Pa,CO 2 ), and the plasma concentration of the neutrophil chemoattractant interleukin-8 (IL-8). At postmortem, lungs were inspected for macroscopic injury and examined histologically. Malondialdehyde levels were assayed in lung tissue as an index of lipid peroxidation. In bronchoalveolar lavage (BAL), total and differential cell counts, protein and IL-8 concentrations were measured.Compared to normal controls, rabbits challenged with PMA alone developed arterial acidosis, hypercapnia and hypoxaemia, accompanied by significant rise in plasma IL-8 concentration. U-74389F pretreated animals did not develop significant arterial blood gas abnormalities and had significantly lower IL-8 concentration in plasma. U-74389F did not prevent PMA-induced lipid peroxidation. However, macroscopic signs of lung injury and the degree of alveolar haemorrhage and protein extravasation were significantly less severe in pretreated rabbits than in those given PMA alone. In addition, U-74389F significantly reduced IL-8 concentration and neutrophil number in BAL. By histological assessment, 80% of lung neutrophils were localized in alveolar spaces of animals receiving PMA alone. Conversely, in U-74389F pretreated animals, 75% of neutrophils were distributed within extraalveolar blood vessels and alveolar septa.We conclude that lazaroid U-74389F attenuates lung injury in rabbits given PMA by preventing neutrophil migration into pulmonary alveoli. This effect may, in part, be related to downregulation of IL-8 production. Eur Respir J., 1996, 9, 758-764

A lazaroid mitigates postresuscitation myocardial dysfunction

“…Tonoue et al (46) demonstrated that the PaO 2 and PaCO 2 from the lazaroid-treated group were significantly better than control in lung preservation. Miniati et al (49) also documented the same results in rabbit lungs injured by phorbol myristate acetate.…”

Antioxidant pharmacological therapies for COPD

“…The protective effects of lazaroids have been reported in many animal models of lung injury [63-64], including the effects of cigarette smoke [65]. Their protective effect is mainly by inhibition of lipid peroxidation.…”

Pharmacological antioxidant strategies as therapeutic interventions for COPD

“…Lazaroids (21-aminsteroids, U75412E or trilizad mesylate) are a group of nonglucocorticoid analogues of methyl-prednisolone which are able to penetrate hydrophobic regions of the cell membrane, specifically to prevent peroxidation of membrane lipids [180–181]. The protective efficacy of lazaroids has been reported in many animal models of lung injury, such as injury by endotoxin [181], ischemic/reperfusion [182] and tobacco smoke [183].…”

“…The protective efficacy of lazaroids has been reported in many animal models of lung injury, such as injury by endotoxin [181], ischemic/reperfusion [182] and tobacco smoke [183]. The findings from the above studies have revealed that lazaroids may exert their protective effect by various mechanisms, inhibition of lipid peroxidation being the main.…”