Pro-Resolving Molecules-New Approaches to Treat Sepsis?

Abstract

Inflammation is a complex response of the body to exogenous and endogenous insults. Chronic and systemic diseases are attributed to uncontrolled inflammation. Molecules involved in the initiation of inflammation are very well studied while pathways regulating its resolution are insufficiently investigated. Approaches to down-modulate mediators relevant for the onset and duration of inflammation are successful in some chronic diseases, while all of them have failed in sepsis patients. Inflammation and immune suppression characterize sepsis, indicating that anti-inflammatory strategies alone are inappropriate for its therapy. Heme oxygenase 1 is a sensitive marker for oxidative stress and is upregulated in inflammation. Carbon monoxide, which is produced by this enzyme, initiates multiple anti-inflammatory and pro-resolving activities with higher production of omega-3 fatty acid-derived lipid metabolites being one of its protective actions. Pro-resolving lipids named maresins, resolvins and protectins originate from the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid while lipoxins are derived from arachidonic acid. These endogenously produced lipids do not simply limit inflammation but actively contribute to its resolution, and thus provide an opportunity to combat chronic inflammatory diseases and eventually sepsis.

Keywords: carbon monoxide; cyclooxygenase; lipoxygenase; resolvin.

Figure 1

Role of carbon monoxide in the resolution of inflammation. Heme oxygenase 1 in macrophages is induced in inflammation and carbon monoxide is produced. Carbon monoxide increases phagocytosis, efferocytosis and synthesis of anti-inflammatory cytokines and pro-resolving lipids. It suppresses the production of inflammatory lipids and cytokines. IL-10: interleukin-10; LPS: lipopolysaccharide. ↑, induced; ↓, reduced.

Figure 2

Crosstalk and positive feedback loop of pro-resolving pathways in macrophages. Carbon monoxide upregulates heme oxygenase 1 and the production of pro-resolving lipids, which by themselves induce heme oxygenase 1. Synthesis of prostaglandins and thromboxanes is reduced by carbon monoxide. +, upregulation; −, downregulation.

Figure 3

Lipids derived from arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid. Arachidonic acid is metabolized by cyclooxygenases (COX) 1/2 to prostaglandins and thromboxanes and by 5-lipoxygenase (5-LOX) to leukotrienes which are involved in the initiation of the inflammatory response (red boxes). Hydroxyeicosatetraenoic acids (HETEs) and lipoxins are also synthesized from arachidonic acid and here 5-, 12- and 15-LOX and cytochrome (Cyt) P450 are involved. Eicosapentaenoic acid is metabolized to E-series resolvins by Cyt P450 and 5-LOX. Resolvins of the D-series, protectins and maresins are derived from docosahexaenoic acid. Lipoxins, resolvins, protectins and maresins (faint green boxes) contribute to the resolution of inflammation.

Figure 4

Aspirin-triggered pro-resolving lipids. Aspirin-acetylated cyclooxygenase 2 synthesizes 15(R)-hydroxyeicosatetraenoic acid from arachidonic acid and 18(S)- and 18(R)-hydroxyeicosapentaenoic acid from eicosapentaneoic acid (EPA). These lipids are released from endothelial and epithelial cells and are taken up by polymorphonuclear leukocytes. Here, they are converted to 15-epi-lipoxin, resolvin E1 and resolvin E2 by 5-lipoxygenase. For resolvin E1 synthesis, leukotriene A4 (LTA4) hydrolase is also needed.

Figure 5

Biologic effects of pro-resolving lipid mediators in inflamed tissues. These lipid species reduce neutrophil immigration, degranulation and survival. They enhance the recruitment of monocytes. These cells differentiate to macrophages, and pro-resolving lipid mediators enhance phagocytosis, efferocytosis and survival. These lipids also promote the polarization of macrophages to M2 cells and induce heme oxygenase 1 (HO-1) and synthesis of protectins. Release of inflammatory cytokines is reduced; +, increase; −, reduction.