Macrophage antioxidant protection within atherosclerotic plaques

Abstract

Macrophage cells within inflammatory lesions are exposed to a wide range of degrading and cytotoxic molecules including reactive oxygen species. Unlike neutrophils, macrophages do not normally die in this environment but continue to generate oxidants, phagocytose cellular remains, and release a range of cyto-active agents which modulate the immune response. It is this potential of the macrophage cell to survive in an oxidative environment that allows the growth and complexity of advanced atherosclerotic plaques. This review will examine the oxidants encountered by macrophages within an atherosclerotic plaque and describe some of the potential antioxidant mechanisms which enable macrophages to function within inflammatory lesions. Ascorbate, a-tocopherol, and glutathione appear to be central to the protection of macrophages yet additional antioxidant mechanisms appear to be involved. Gamma-Interferon causes macrophages to generate 7,8-dihydroneopterin, neopterin and 3-hydroxyanthranilic acid both of which have antioxidant properties. Manganese superoxide dismutase is also upregulated in macrophages. The evidence that these antioxidants provide further protection, so allowing the macrophage cells to survive within sites of chronic inflammation such as atherosclerotic plaques, will be described.

Cerebral inflammatory response and predictors of admission clinical grade after aneurysmal subarachnoid hemorrhage

“…A correlate to support this idea is seen in studies of the inflammatory and oxidative cascades produced by coronary plaques causing myocardial infarction, with extent of oxidative stress shown to correlate with severity of atherosclerosis in the coronary arteries. [26, 27] Additionally, evidence exists that tumor necrosis factor-α, a known key inflammatory mediator, significantly modulates the risk for aneurysm formation and aSAH[28]…”

Intracellular glutathione protects human monocyte-derived macrophages from hypochlorite damage

“…For clarity, not all the cell preparations' HOCl viability curves have been shown in (A). 7,8-dihydroneopterin to protect cells has not been demonstrated (Gieseg et al, , 2009). …”

“…Here we have shown that when 7,8-dihydroneopterin is added extracellularly, it can also outcompete the intracellular GSH even at high HOCl concentrations. 7,8-Dihydroneopterin is generated at micromolar concentrations in sites of inflammation by interferon stimulated macrophages (Firth et al, 2008;Gieseg et al, 2009). Unfortunately attempts to reproduce these 7,8-dihydroneopterin concentrations in tissue culture with stimulated cells have to date been unsuccessful, so the potential of de novo synthesized Fig.…”

“…This suggests a role for HOCl in killing macrophages, leading to the formation of advanced complex atherosclerotic plaques. Since macrophage death is a relatively late phase of the disease progression it is apparent that macrophages are able to neutralise the toxic effects of inflammatory oxidants through a number of antioxidant defense mechanisms (Gieseg et al, 2009).…”

Neopterin and 7,8-dihydroneopterin are generated within atherosclerotic plaques

“…HOCl reacts extremely rapidly with 7,8-dihydroneopterin to generate neopterin [20,21], suggesting that a significant amount of the neopterin measured in serum and urine may be from the scavenging of HOCl released by neutrophils and macrophages during inflammation. These in vitro studies have led to the proposal that 7,8-dihydroneopterin is generated by macrophages to protect these cells from oxidants generated during inflammation [6,13,22,23].…”