This may result from the observations that PGI2 and PGE2 are more closely linked to COX-2 metabolism while COX-1 is aligned with TXA2 synthesis. Thus, the selectivity of the NSAIDs used may determine whether KRX-0401 parasite or host production of PGs is the VE-821 primary target of the treatment regimen used. Our data with COX-1 null mice and pharmacological antagonism strongly indicate that host-derived PGH2 is involved in PG synthesis throughout infection. A key question is whether the host or parasite is the primary source of the lipid mediators regulating the pathogenesis of disease. Pharmacological inhibition does not distinguish between these two sources of eicosanoids. The reduction in PGF2a release in COX-1 null, but not TXA2 synthase null, mice indicates that COX activity in the host provides precursor molecules required for the biosynthetic pathways of this parasite. This ����scavenging���� hypothesis is confirmed by the inability of the parasite to sustain TXA2 release in the COX-1 null mice. If the parasite is scavenging precursors from the host then they would only need the terminal synthases to produce bioactive lipids. Fatty acid biosynthetic pathways in trypanosomes are poorly defined and little homology is reported between the mammalian enzymes and their trypanosomal homologues. Some putative candidates, such as the PGF2a synthase ����old yellow enzyme����, have been identified. However, reports have indicated that parasitic biosynthetic pathways are resistant to mammalian antagonists, such as ASA, which have little effect on parasite biology. Conversely, the recent report of anti-parasitic activity of indomethacin derivatives indicates that the active sites of parasite enzymes, if not their primary sequences, are sufficiently homologous to their mammalian counterparts. Recent structural characterization of the target enzyme, which participates in sterol biosynthesis of T. cruzi, has facilitated understanding of the integral nature of this enzyme to T. cruzi and has revealed much of the kinetics of the mechanism of action of indomethacin amides. Interestingly, no enzyme other than COX isoforms has been identified as sensitive to indomethacin. However, it remains to be determined whether TcCYP51 is an integral component of the eicosanoid biosynthetic pathway in T. cruzi.. The identification of the PGH2 derivatives that are most important for disease remains unsolved. Several species of eicosanoids have been implicated in both acute and chronic Chagas disease. Plasma from infected mice displayed increased levels of PGF2a, PGI2, TXA2 and PGE2 compared to uninfected mice from 10 dpi onwards. Previously, we determined that the main prostaglandins derived from T. cruzi are TXA2 and PGF2a, indicating that host is the likely source of the elevated PGI2 and PGE2. No specific role has been delineated for the elevated PGI2 and PGF2a observed in plasma from experimental T. cruzi infection.