During systemic inflammatory response syndromes (SIRS), amplifying endogenous adenosine action by inhibiting adenosine deaminase (ADA) with 2-deoxycoformycin (pentostatin) reduces proinflammatory cytokine responses, limits tissue peroxidation, and has the potential to improve regional perfusion. Our long-term goal is to use pentostatin in the treatment of SIRS. For this to be a viable agent, we need todetermine the half-life of its activity and effects on the balance of pro- and anti-inflammatory mediators in macrophages, target cells in this response. From a vascular perspective, we must also demonstrate that inhibition of ADA will not exacerbate the low systemic vascular resistance associated with sepsis. Thus, for phase one we will: 1) Measure the time-course of restoration of ADA activity in peritoneal and alveolar macrophages after in vitro or vivo administration of pentostatin. ADA activity will be measured at various times after in vitro exposure, or in macrophages collected at various times after in vivo administration. 2) Determine how treatment of septic rats with pentostatin affects the responsiveness of their peritoneal and alveolar macrophages to in vitro LPS. The end-points to be examined will be the relative changes in selected pro- and anti-inflammatory cytokines in of macrophage culture media and macrophage membrane homogenates from septic and non- 3) Verify that inhibition of ADA will not exacerbate the low systemic vascular resistance associated with SIRS caused by sepsis. This will be done by measuring blood pressure, cardiac output, and systemic vascuolar resistance after pentostatin administration to septic rats during their hyperdynamic phase of the pathology. These studies have the potential to vastly improve clinical outcome in SIRS patients with a compound previously approved for use only as an anti-neoplastic agent. PROPOSED COMMERCIAL APPLICATION: Pentostatin is currently in use to treat hairy cell leukemia. If successful, the proposed research will extent the application of pentostatin to treat systemic inflammatory response syndromes through transfer if the technology developed at the University of Illinois to the product, pentostatin.
Thesaurus Terms: adenosine deaminase, antiinflammatory agent, blood toxicology, deoxycoformycin, drug screening /evaluation, inflammation, pharmacokinetics adenosine, adult respiratory distress syndrome, cytokine, lipopolysaccharide, macrophage laboratory rat
