**6. Apoptosis**

TNF family of cytokines from platelets has a pronounced effect on the apoptosis of VSMCs. In addition, chemokines such as IL-1beta, TNF-alpha, and IFN-gamma by activated macrophages and T cells in the immediate environment, induce apoptosis in VSMC and block collagen production [26]. Myeloperoxidase produces hypochlorous acid in the event of increased oxidative stress, which induces apoptosis in EC. Increased caspase-3 and DNA ladders in ECs support the theory that oxidative stress inherent in inflammation-induced plaque formation leads to a cyclic deterioration of plaque stability [19].

Loss of collagen through apoptosis of VSMCs, increased MMPs, and the accumulation of necrotic debris by apoptotic macrophages, all cumulatively result in an unstable plaque, increasing the chance for rupture. Risk of plaque rupture also increases with superficial erosion of endothelial monolayer, the risk of which is increased with apoptosis of endothelial cells due to inflammation [19]. Apoptosis is beneficial in clearing the cells that help eliminate oxidized elements in the initial lesion, but the same processes, if left unchecked, are detrimental during the later stages. Removing the injurious agen<sup>t</sup> or resolving the inflammation could reverse the progression of the lesion from a fatty streak to an unstable plaque.

### **7. Resolution of Inflammation**

Resolution of inflammation has been established as an active process that begins with and is characterized by a reduction in neutrophil recruitment and an increase in efferocytosis, a non-phlogistic clearance of cellular debris by macrophages [8].

As with the active inflammation process, its resolution involves a myriad of chemical modulators from a variety of cell populations through complex chemical pathways that are interconnected. Resolution of an ongoing inflammation is kicked off by the "class switching" of prostaglandins and leukotrienes to lipoxins, which are also derived from arachidonic acid [27].

The resolution of acute inflammation was studied by analyzing the exudate from inflamed tissues and was found to be mediated by molecules derived from essential fatty acids, Eicosapentaenoic acid, and Docosahexaenoic acid (DHA). These molecules are termed SPMs and are classified into further subdivisions—resolvins (E and D series), protectins, lipoxins, and maresins. E-series resolvins are generated from EPA, lipoxins from arachidonic acid, while the rest, D-series resolvins, protectins, and Maresins, are derived from DHA [21,28]. These SPMs assist in reducing inflammation via several mechanisms, including increasing efferocytosis, as shown in (Figure 2) [29].

**Figure 2.** SPMs including maresins, lipoxins, resolvins, and protectins, assist in plaque resolution through various pathways: converting pro-inflammatory M1 to anti-inflammatory M2 macrophages, increasing effective efferocytosis, downregulating pro-inflammatory LTB4, VCAM-1, and MCP-1.

Resolution of an ongoing inflammation stimulates the increased formation of lipoxins, which facilitate resolution by stopping further recruitment of neutrophils, inducing nonphlogistic migration, and induction of macrophages to clear apoptotic neutrophils [27].
