Upregulation of Phosphodiesterase-4 in the Lung of Allergic Rats

Abstract

Inhibitors of phosphodiesterase-4 (PDE4) are efficacious for allergic asthma in animal models and have shown some efficacy in human asthma. Regulation of PDE4 in allergy and asthma has been widely investigated in blood leukocytes, with discrepant results. This study investigated PDE4 regulation in the lung in a rat model of allergic asthma. Ovalbumin sensitization and challenge significantly increased pulmonary resistance and lung interleukin (IL)-4 production. The increases in pulmonary resistance and IL-4 production were both suppressed by the PDE4-selective inhibitor rolipram or the corticosteroid drug dexamethasone. Furthermore, cAMP-PDE enzyme activity in the lung was also significantly increased by the sensitization and challenge. mRNA analysis confirmed that PDE4 gene expression was increased in the lung of the allergic rats. A highly significant correlation was observed between the increases in PDE activity and IL-4 production. Our data suggest, for the first time, that PDE4 may be upregulated in the lung and play a role in the pathogenesis of allergic asthma.

Mechanism regulating proasthmatic effects of prolonged homologous β2-adrenergic receptor desensitization in airway smooth muscle

“…The latter finding concurs with those in previous studies on different cell types wherein the attenuated physiological responses to cAMP-elevating agents detected under conditions associated with either heterologous or homologous ␤2AR desensitization were found to be critically regulated by PDE activity (3,6,15,34). Furthermore, it is well documented that PDE4 activity plays a crucial role in regulating ASM contractility (27) and in mediating the constrictor hyperresponsiveness of the airways accompanying allergen challenge in asthmatic subjects (35) and in animal models of allergic asthma (4,14,18,32,33). Little is known, however, regarding the mechanism regulating PDE4 expression and its role in contributing to the impaired cAMP signaling and altered responsiveness of ASM under conditions of prolonged homologous ␤2AR desensitization.…”

Monoammonium glycyrrhizinate inhibited the inflammation of LPS-induced acute lung injury in mice

“…This experiment was conducted according to procedures described previously [16]. Briefly, frozen lungs were thawed and cut into small cubes, and 25 mg of lung tissues was homogenized in 100 μl of icecold 30 mM HEPES (pH 7.4) containing 0.1% Trion X-100.…”

Action of a Novel PDE4 inhibitor ZL-n-91 on lipopolysaccharide-induced acute lung injury

“…This experiment was conducted according to procedures described previously [12]. Briefly, frozen lungs were thawed and cut into small cubes, twenty-five mg of lung tissues was homogenized in 100 μl of ice-cold 30 mM HEPES (pH 7.4) containing 0.1% Trion X-100.…”