Molecular and cellular actions of Pentoxifylline
Pentoxifylline is a xanthine derivative drug with a wide range of actions at the cellular and molecular level. pentoxifylline has rheological actions increasing erythrocyte deformability and was originally licensed for the treatment of peripheral vascular disease on the basis of suggested improvement of microvascular and capillary blood flow [7]. More recently pentoxifylline has been determined to have extensive anti-inflammatory properties [8]. pentoxifylline inhibits 5’-nucleotidase and phosphodiesterases (PDE). PDE inhibition results in increased cAMP levels, increased protein kinase A (PKA) activity and altered transcriptional regulation of pro-inflammatory genes through modulation of the NFκB/IκB pathway [8]. Pentoxifylline downregulates transcription and expression levels of TNFα, IL1b, IL6, IFNγ, ICAM1 and VCAM1. pentoxifylline 5’-nucleotidase inhibition reduces the production of adenosine and inosine from adenosine monophosphate (AMP) and inosine monophosphate (IMP) respectively. Pentofxyfilline appears able to downregulate the pathologically important pro-inflammatory adenosine receptor A2A pathway [9]. These effects contribute to the extensive actions of pentoxifylline in reducing pro-inflammatory signals. For example, pentoxifylline reduces cytokine release from pulmonary macrophages derived from patients with sarcoidosis [10]. Lungs have the highest proportion of total resident macrophages in the human body, around 1 trillion.