Inhibitory effects of cyclic AMP elevating agents on lipopolysaccharide (LPS)-induced microvascular permeability change in mouse skin

Abstract

1. Anti-inflammatory effects of cyclic AMP elevating agents were examined in a mouse model of lipopolysaccharide (LPS)-induced microvascular permeability change. 2. Vascular permeability on the back skin was measured by the local accumulation of Pontamine sky blue (PSB) after subcutaneous injection of LPS (400 μg site-1) from Salmonella typhimurium. 3. Dye leakage in the skin was significantly increased 2 h after injection of LPS. This LPS-induced dye leakage was suppressed by phosphodiesterase inhibitors, including pentoxifylline (160 mg kg-1), milrinone (5-10 mg kg-1), rolipram (0.5-10 mg kg-1) and zaprinast (5-10 mg kg-1). The dye leakage was also inhibited by β-adrenoceptor agonists, including isoproterenol (0.5-5 mg kg-1) and salbutamol (0.05-5 mg kg-1), an adenylate cyclase activator, forskolin (5 mg kg-1), and a cell permeable cyclic AMP analogue, 8-bromo-cyclic AMP (8-Br-cAMP, 10 mg kg-1). 4. LPS caused a transient increase in serum TNF-α level peaking at 1 h after the injection. This increase in serum TNF-α was completely blocked by a pretreatment with pentoxifylline (160 mg kg-1), milrinone (5 mg kg-1), rolipram (1 mg kg-1), zaprinast (10 mg kg-1), salbutamol (0.5 mg kg-1), forskolin (1 mg kg-1) and 8-Br-cAMP (10 mg kg-1). 5. LPS caused an increase in serum IL-1α level peaking at 3 h after injection. This increase in serum IL-1α was not significantly suppressed by the cyclic AMP elevating agents. 6. Our study suggests that cyclic AMP elevating agents attenuate LPS-induced microvascular permeability change by suppressing TNF-α up regulation.