|
|
||
| Lesion progression and establishment of chronic inflammation The establishment of chronic inflammation involves, among other factors, the continued presence of oxLDL leading to an inability of the MØ inflammatory response to remove the stimulating agent. The response itself causes lesion progression from fatty streak to a more complex lesion, a process characterized by the migration of SMCs from the medial layer to the subendothelial intima and subsequent proliferation; see Figure 4. This is mediated by a number of cytokines; e.g. IL-1, TNF-alpha and IL-6, released from MØ foam cells and activated endothelium. Following activation, SMCs may themselves become foam cells, but more importantly they accumulate in the plaque and lay down an abundant extracellular matrix composed of proteins, e.g. collagen and elastin, and proteoglycans, contributing to the fibrous cap formation (Figure 2). Eventually, the foam cells, whether MØ or SMC-derived, may die by either apoptosis or necrosis, releasing their contained lipid, thus producing an extracellular necrotic core. Lesion progression is further influenced by the interactions between MØs and T cells (Figure 4). As in the case of monocytes, T cells enter the intima facilitated by binding to adhesion molecules. Once in the arterial intima, the T cells may encounter numerous stimulators, such as oxLDL, bacterial and viral antigens, as well as antigens presented by MØ foam cells, SMC-derived foam cells and ECs (the two latter can be induced to express class I and II MHC molecules). Upon antigen-T cell receptor interaction, T cells are activated to produce cytokines that influence the behaviour of other cells in the growing atheroma. Expression of CD40 on T cells enables an interaction with CD40 ligand (CD40L) on MØs, inducing these to express proinflammatory cytokines, matrix metalloproteinases (MMPs) and tissue factor (TF), all of which providing an amplification loop between the prototypical cells of the innate (MØ) and adaptive (T cells) immune system. Furthermore, differentiation of T cells can be polarized into those secreting proinflammatory cytokines and those secreting predominantly anti-inflammatory cytokines. In general, proinflammatory T cells predominate in the atheroma. |
||
 |
||
| Figure 4 1) Excess LDL particles accumulate in the artery wall and undergo chemical alterations, e.g. oxidative modification. 2) The modified LDL then stimulates endothelial cells to express adhesion molecules, e.g. VCAM-I, and CC chemokines, e.g. MCP-1. 3) Monocytes enter the intima by binding to adhesion molecules and migrate to relevant sites by binding to chemokines. 4) In the intima, monocytes mature into active macrophages (MØ) and start secreting enzymes for oxidative modification, cytokines, and display scavenger receptors, which help them ingest modified LDL, e.g. lipoxygenase, TNF-alpha and SR-A respectively. 5) By ingesting lipids, MØ turn into foam cells, contributing to fatty streak formation. Smooth muscle cells are stimulated to emigrate from the media to the intima. Here, they proliferate and secrete extracellular matrix, contributing to the fibrous cap formation. Like MØ, they can ingest lipid as well and become foam cells. Eventually, the foam cells may die by apoptosis or necrosis, releasing their contained lipid and producing a necrotic core. |
||
 |
||