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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 micrograms.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,O2), arterial carbon dioxide tension (Pa,CO2), 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 extra-alveolar 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.
Insights
The antioxidant lazaroid U-74389F reduced acute lung injury in rabbits by preventing neutrophil migration into alveoli. This protective effect involved downregulating interleukin-8 (IL-8) production.
Area of Science:
- Pharmacology
- Pulmonary Medicine
- Inflammation Research
Background:
- Acute lung injury (ALI) is a critical condition characterized by inflammation and impaired gas exchange.
- Phorbol myristate acetate (PMA) is a potent inducer of acute lung injury in experimental models.
- Interleukin-8 (IL-8) is a key neutrophil chemoattractant implicated in inflammatory lung diseases.
Purpose of the Study:
- To investigate the protective effects of the antioxidant lazaroid U-74389F against PMA-induced acute lung injury in rabbits.
- To assess the impact of U-74389F on physiological parameters, inflammatory markers, and neutrophil infiltration in the lungs.
Main Methods:
- Rabbits were pretreated with U-74389F or vehicle before intravenous administration of PMA.
- Arterial blood gases (pH, PaO2, PaCO2), plasma and bronchoalveolar lavage (BAL) IL-8 levels were measured.
- Lung injury was evaluated macroscopically, histologically, and by measuring lipid peroxidation and BAL cell counts.
Main Results:
- PMA induced significant arterial acidosis, hypercapnia, hypoxemia, and elevated plasma IL-8.
- U-74389F pretreatment attenuated blood gas derangements and reduced plasma and BAL IL-8 concentrations.
- U-74389F significantly reduced macroscopic lung injury, alveolar hemorrhage, and protein extravasation, with fewer neutrophils in alveoli.
Conclusions:
- Lazaroid U-74389F effectively attenuates acute lung injury induced by PMA in rabbits.
- The protective mechanism involves inhibiting neutrophil migration into pulmonary alveoli, potentially via IL-8 downregulation.
- U-74389F demonstrates potential as a therapeutic agent for inflammatory lung conditions.