Involvement of Inflammation and Its Resolution in Disease and Therapeutics

Abstract

Inflammation plays a critical role in the response to and survival from injuries and/or infections. It occurs in two phases: initiation and resolution; however, when these events do not resolve and persist over time, the inflammatory response becomes chronic, prompting diseases that affect several systems and organs, such as the vasculature and the skin. Here, we reviewed inflammation that occurs in selected infectious and sterile pathologies. Thus, the immune processes induced by bacterial sepsis as well as T. cruzi and SARS-CoV-2 infections are shown. In addition, vaccine adjuvants as well as atherosclerosis are revised as examples of sterile-mediated inflammation. An example of the consequences of a lack of inflammation resolution is given through the revision of wound healing and chronic wounds. Then, we revised the resolution of the latter through advanced therapies represented by cell therapy and tissue engineering approaches, showing how they contribute to control chronic inflammation and therefore wound healing. Finally, new pharmacological insights into the management of chronic inflammation addressing the resolution of inflammation based on pro-resolving mediators, such as lipoxin, maresin, and resolvins, examining their biosynthesis, biological properties, and pharmacokinetic and pharmaceuticals limitations, are given. We conclude that resolution pharmacology and advanced therapies are promising tools to restore the inflammation homeostasis.

Keywords: chronic wounds; inflammation; maresin; resolvins; stem cells; tissue engineering.

Figure 1

Cellular and molecular events of inflammation. (A) Pro-inflammatory cytokines activate nuclear factor kappa B (NF-κB), which in turn increases the expression of endothelin-1 (ET-1), thromboxane A2 (TXA2), reactive oxygen species (ROS), cell adhesion molecules (CAMs), and von Willebrand factor (vWF). (B,C) Hemodynamic changes and extracellular matrix adhesion molecules (E-CAMs) expression mediate leukocyte recruitment to the extravascular tissues. (D) Monocytes differentiate into M1 macrophages type that release pro-inflammatory cytokines. (E) Increased expression of TXA2 and vWF favors platelet aggregation (created with BioRender.com, accessed on 30 July 2022).

Figure 2

Regulation of the inflammatory response by tissue engineering devices. (A) Represents the capacity of biomaterials to scavenge oxidative species. (B) The inhibition by MSCs of the pro-inflammatory cytokines. (C) The polarization of macrophages towards the M2 phenotype. (D) The blockade of immune cell migration (created with BioRender.com, accessed on 30 August 2022).

Figure 3

Early and sequential release of specialized pro-resolving mediators in acute inflammation and its resolution. SPMs play an important role in the initiation and resolution of inflammation. Resolvin D2 (RvD2) increases temporally during the transition from initiation to resolution phase with a great effect on neutrophils. Maresin 1 (MaR1) promotes macrophage switch from M1 to M2 after their marked increase. Resolvin E1 (RvE1), the most effective of the RvE-series, inhibits neutrophil migration in vitro and promotes resolution phenotype in macrophages (created with BioRender.com, accessed on 30 July 2022).

Figure 4

Biosynthesis of SPMs. (a) Lipoxin biosynthesis. The precursor of lipoxins is arachidonic acid (AA), which gives rise to lipoxin A4 (LXA4) and lipoxin B4 (LXB4), which are positional isomers, and epi-lipoxin A4 and epi-lipoxin B4, which are more stable than the former. (b) Biosynthesis of E-series resolvins (RvE). The precursor of RvE is acid eicosapentaenoic acid (EPA) of 20 carbons. Resolvin E1 (RvE1), resolvin E2 (RvE2), and resolvin E3 (RvE3) are similar in the presence of a hydroxyl group (OH) at carbon 18 (C18) (red circle). RvE1 and RvE2, unlike RvE3, present an OH group at C5 position (green circle). In addition, RvE1 has a third OH group at the C12 position (blue circle). Finally, RvE3 has an OH group in position C17 (brown circle). (c) Biosynthesis of D-series resolvins (RvD) RvD originates from the 22-carbon docosahexaenoic acid (DHA). All D-series resolvins have a hydroxyl group (OH) at the C17 position (blue circle). RvD1, RvD2, and RvD5 are generated from the oxygenation of 17S-hydroperoxy-docosahexaenoic acid (17S-HpDHA) in position C7; therefore, these resolvins have in common OH group in the said position (green circle). RvD1 and RvD2, unlike RvD5, are characterized by having a third OH group; RvD1 contains the OH group at the C8 position, while RvD2 has it at the C16 position. On the other hand, RvD3, RvD4, and RvD6 originate from the oxygenation of 17S-HpDHA at the C4 position, therefore these resolvins have a common OH group at that position (yellow circle). RvD3 has a third OH group in the C11 position, while RvD4 has the third OH group in the C5 position. (d) Biosynthesis of maresins. The precursor of maresins is DHA originating from two exponents, MaR1 and MaR2. (e) Protectin biosynthesis. The precursor of protectins is DHA and originates through enzymatic epoxidation and subsequent hydrolysis of PD1 (created with BioRender.com, accessed on 9 September 2022).