| Cardiovascular disease is a major cause of morbidity and mortality in industrialized nations. Neutrophils are key contributors not only in killing invading pathogens, but also in the pathophysiology of myocardial infarction. Neutrophil-derived myeloperoxidase (MPO) produces reactive chlorinating species (RCS) which mediate host cell injury, such as that occurring in ischemic injury. These studies tested the hypothesis that the accumulation of chlorinated metabolites derived from RCS attack of plasmalogens will impact intracellular lipid accumulation and contribute to the pathophysiology of myocardial infarction. These studies show that both 2-chlorohexadecanoic acid (2-ClHA) and 2-chlorohexadecanol (2-ClHOH) are produced in activated neutrophils in an MPO- and time-dependent manner, and are released by neutrophils into media and prevent the chemoattraction of neutrophils. Furthermore, mice exposed to intranasal Sendai virus displayed lung neutrophil recruitment, as well as elevated 2-ClHA levels in plasma and bronchoalveolar lavage compared to control-treated mice. Taken together, these data demonstrate, for the first time, that metabolites of 2-ClHDA are produced both in vivo as well as in isolated human neutrophils. The present study demonstrates that chlorinated triglycerides are produced endogenously in an in vivo model of rat myocardial infarction. Comparisons of neutropenic and normopenic animals suggest that chlorinated triglyceride production is dependent on the activity of neutrophil derived myeloperoxidase. This study also demonstrates that the activity of myocardial lipases can be attenuated by increasing concentrations of chlorinated triglyceride. This suggests that tissues prevent the accumulation of detrimental free fatty acids by esterifying them in the form of triglycerides. However, the increased accumulation of the chlorinated triglycerides may prevent the lipolysis of other triglycerides, leaving accumulated lipid droplets to disrupt normal function of cardiomyocytes. |
