Chagas disease is caused by Trypanosoma cruzi, a protozoan parasite.
Chagas disease remains a serious health problem in large parts of Mexico and Central and South America, where it is a major cause of morbidity and mortality. This disease is being increasingly recognized in non-endemic regions due to immigration.
Heart disease develops in 10-30% of infected individuals. It is increasingly clear that parasite- and host-derived bioactive
lipids potently modulate
disease progression. Many of the changes that occur during acute and chronic
Chagas disease can be accounted for by the effects of
arachidonic acid (AA)-derived
lipids such as
leukotrienes,
lipoxins, H(P)ETEs,
prostaglandins (PGs) and
thromboxane. During the course of
infection with T. cruzi, changes in circulating levels of AA metabolites are observed. Antagonism of PG synthesis with
cyclooxygenase (COX) inhibitors has both beneficial and adverse effects. Treatment with COX inhibitors during acute
infection may result in increased parasite load and mortality. However, treatment instituted during
chronic infection may be beneficial with no increase in mortality and substantial improvement with cardiac function. Recently, T. cruzi
infection of mice deficient in AA biosynthetic
enzymes for various pathways has yielded more insightful data than pharmacological inhibition and has highlighted the potential deleterious effects of inhibitors due to "off-target" actions. Using COX-1 null mice, it was observed that parasite biosynthesis is dependent upon host metabolism, that the majority of TXA(2) liberated during T. cruzi
infection is derived from the parasite and that this molecule may act as a quorum sensor to control parasite growth/differentiation. Thus,
eicosanoids present during acute
infection may act as
immunomodulators aiding the transition to, and maintenance of, the chronic stage of the disease. It is also likely that the same mediators that initially function to ensure host survival may later contribute to cardiovascular damage. Collectively, the
eicosanoids represent a new series of targets for
therapy in
Chagas disease with defined potential therapeutic windows in which to apply these agents for greatest effect. A deeper understanding of the mechanism of action of non-steroidal anti-inflammatory drugs may provide clues to the differences between host responses in acute and chronic T. cruzi
infection.