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

摘要

class="enumerated" style="list-style-type:decimal">Anti-inflammatory effects of cyclic AMP elevating agents were examined in a mouse model of lipopolysaccharide (LPS)-induced microvascular permeability change.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.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).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).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.Our study suggests that cyclic AMP elevating agents attenuate LPS-induced microvascular permeability change by suppressing TNF-α up regulation.