Macrophage Targeted PET/MRI (p 755)
Majmudar et al devise a macrophage imaging technique that could help identify unstable atherosclerotic plaques.
Macrophage abundance in atherosclerotic plaques is strongly associated with the risk of plaque rupture, which can cause thrombus formation and even myocardial infarction or stroke. Therefore, it is important to image and quantify macrophages in human plaques to identify high-risk patients and to inform therapeutic interventions. However, existing imaging techniques lack sufficient sensitivity. Therefore, Majmudar and colleagues set out to develop a viable alternative. They generated radioactive dextran nanoparticles that could be efficiently taken up by macrophages. They injected these nanoparticles into the tail veins of mice and, after allowing time for phagocytosis, they tracked their vascular distribution using a combination of positron emission tomography (PET)—to detect the radioactive signal—and MRI—to determine anatomical location. They found that compared with wild-type mice, mice that were prone to atherosclerosis exhibited considerably higher nanoparticle PET signals from their aortas. The team also found that preventing the recruitment of macrophages to inflammation sites lowered these aortic PET signals. Because nanoparticles used in the study were biodegradable, this technique could perhaps be used to monitor atherosclerotic plaques in humans, say the authors.
Cathelicidins and Monocyte Adhesion (p 792)
Wantha et al show how neutrophils recruit monocytes to sites of inflammation.
It is currently believed that during early stages of acute inflammation, soluble granule proteins released from neutrophils are required for subsequent recruitment of monocytes to the inflammation site. However, the underlying mechanisms remain unclear. Wantha and colleagues investigated the monocyte-attracting ability of cathelicidin and cathepsin - two neutrophil granule proteins conserved between mice and humans. They found that deletion of cathelicidin in mice reduced the recruitment of classical monocytes to inflammation sites. Mice lacking cathepsin, on the other hand, showed no such defect. In vitro experiments using cathelicidin treated human vascular endothelial cells confirmed that the protein is indeed able to recruit classical monocytes. By blocking different receptor proteins on the surface of monocytes, the team discovered that one specific receptor was responsible for mediating cathelicidin-dependent recruitment. Interaction between cathelicidin and this receptor, FRP2, induced the activation of integrins that enable monocytes to adhere to sites of inflammation. This interaction could thus be targeted to treat for a variety of inflammatory disorders, say the authors.
SDF-1 in Heart Failure (p 816)
Penn et al report the outcome of a Phase I gene therapy trial for the treatment of ischemic heart failure.
The tissue damage that occurs after a myocardial infarction can lead to progressive heart failure and, if left untreated, to death. Mending damaged cardiac tissue with the help of stem cells is the goal of several current therapeutic investigations. One such approach, adopted by Penn and colleagues, is to recruit the body’s own stem cells to the heart. Stromal cell-derived factor 1 (SDF-1) is a naturally occurring cytokine that attracts stem cells and is upregulated in injured tissues. In the infarcted heart tissue, however, SDF-1 action lasts less than a week, after which stem cell recruitment diminishes. Artificially maintaining SDF-1 expression in damaged myocardium has been shown to improve cardiac function in a number of pre-clinical studies. Penn et al now provide preliminary evidence that the same approach works in patients too. They injected a non-viral DNA vector encoding the SDF-1 gene into the peri-infarcted myocardia of 17 heart failure patients. Four months later, these patients exhibited improvements in quality of life, 6 minute walking distance, and in the overall clinical classification of their condition. And 12 months later, these improvements persisted. Although this was a relatively small Phase I trial, the results indicate that a larger, randomized trial is warranted.
- © 2013 American Heart Association, Inc.