Melanie L. Hart

Role of extracellular nucleotide phosphohydrolysis in intestinal ischemia-reperfusion injury

Extracellular adenosine has been implicated as an innate antiinflammatory metabolite, particularly during conditions of limited oxygen availability such as ischemia. Because extracellular adenosine generation is primarily produced via phosphohydrolysis from its precursor molecule adenosine‐monophosphate (AMP) through the enzyme ecto‐5′‐nucleotidase (CD73), we examined the contribution of CD73‐dependent adenosine production in modulation of intestinal ischemia‐reperfusion (IR) injury. Following transcriptional and translational profiling of intestinal tissue that revealed a prominent induction of murine CD73, we next determined the role of CD73 in protection against intestinal IR injury. Interestingly, pharmacological inhibition or targeted gene deletion of CD73 significantly enhanced not only local intestinal injury, but also secondary organ injury, following IR as measured by intestinal and lung myeloperoxidase, aspartate and alanine aminotransferase, interleukin (IL) ‐1, IL‐6, and histological injury. To confirm the role of CD73 in intestinal adenosine production, we measured adenosine tissue levels and found that they were increased with IR injury. In contrast, CD73‐deficient (cd73−/−) mice had lower adenosine levels at baseline and no increase with IR injury. Finally, reconstitution of cd73−/− mice or treatment of wild‐type mice with soluble 5′‐nucleotidase was associated with significantly lower levels of injury. These data reveal a previously unrecognized role of CD73 in attenuating intestinal IR‐mediated injury.—Hart, M. L., Henn, M., Köhler, D., Kloor, D., Mittelbronn, M., Gorzolla, I. C., Stahl, G. L., Eltzschig, H. K. Role of extracellular nucleotide phosphohydrolysis in intestinal ischemia‐reperfusion injury. FASEB J. 22, 2784–2797 (2008)

Role of Complement in Myocardial Ischemia and Infarction

The complement system is involved in several aspects of the pathophysiology of myocardial ischemia and infarction. Initially a role for complement in ischemic heart disease was inferred from the deposition of complement components within the myocardium of experimental models of myocardial infarction. Further animal models demonstrated that depletion or inhibition of complement prior to myocardial ischemia/reperfusion (MI/R) can reduce complement-mediated tissue injury. Recently, in vivo examination of naturally occurring complement inhibitors and monoclonal antibodies directed at specific complement components has confirmed complement dependent injury following MI/R. Current research provides intriguing evidence on the initiating pathways and the possible methods of complement regulation in the management of MI/R injury. This chapter focuses on many of the studies demonstrating complement activation and deposition in MI/R, the functional consequences of complement activation following MI/R, the initial and recent anti-complement therapies used in vivo and the current insight of the mechanisms of complement activation following MI/R.