Oxidative stress in acute pulmonary embolism: emerging roles and therapeutic implications

Abstract

Oxidative stress is an imbalance between the body's reactive oxygen species and antioxidant defense mechanisms. Oxidative stress is involved in the development of several cardiovascular diseases, such as pulmonary hypertension, atherosclerosis, and diabetes mellitus. A growing number of studies have suggested the potential role of oxidative stress in the pathogenesis of pulmonary embolism. Biomarkers of oxidative stress in pulmonary embolism have also been explored, such as matrix metalloproteinases, asymmetric dimethylarginine, and neutrophil/lymphocyte ratio. Here, we comprehensively summarize some oxidative stress mechanisms and biomarkers in the development of acute pulmonary embolism and summarize related treatments based on antioxidant stress to explore effective treatment strategies for acute pulmonary embolism.

Keywords: Acute Pulmonary Embolism; Antioxidants; Endothelial cells; Oxidative stress; Reactive oxygen species.

Fig. 1

Metabolic pathways of ROS and how NO affects smooth muscle cells. Oxidative stress is the imbalance of the oxidative system and antioxidant system. Several enzymes and pathways form the antioxidant system. The ROS-producting system contains enzymes such as enzyme in mitochondria, XO, eNOS, and NOX. Under the catalysis of enzymes, O₂⁻ and H₂O₂ are produced. ROS can either be transformed into water or strong oxidizing substances. NO relaxes smooth muscle by signal transduction. By inhibiting the cGMP pathway specifically, sildenafil promotes the relaxation of smooth muscle cells (ADP: adenosine diphosphate; ATP: adenosine triphosphate; CAT: catalase; cGMP: cyclic guanosine monophosphate; Cl⁻: chloride ion; eNOS: endothelial nitric oxide synthase; Fe2⁺: ferrous iron; GC: guanylate cyclase; GTP: guanosine triphosphate; H₂O₂: hydrogen peroxide; L-Arg: L-arginine; MPO: myeloperoxidase; NO: nitric oxide;NOX: nicotinamide adenine dinucleotide phosphate oxidase; NADPH: nicotinamide adenine dinucleotide phosphate-reduced; NADP⁺: nicotinamide adenine dinucleotide phosphate; NO: nitric oxide; O₂: oxygen; ·O₂⁻: superoxide;·ONOO⁻: peroxynitrite anion;·OH: hydroxyl radical; OCl⁻: hypochlorite ion; PDE-5: 5-phosphodiesterase; PKG: protein kinase G SOD: superoxide dismutase; XO: xanthine oxidase)

Fig. 2

Partial mechanisms of APE (red font). Under conditions of oxidative stress, endothelial cells become injured, and tissue factors and endothelial microparticles are released to activate leukocytes and platelets. sICAM and E-selectin were abnormally elevated. Meanwhile, leukocytes are overactivated by CINC-1, CINC-2, MCP-1, and MIP-1. Lysophosphatidic acid released by activated platelets stimulates neutrophils to release neutrophil extracellular traps, which promote thrombotic stability. High mobility group box 1 and platelet-derived microparticles also activate neutrophils to trigger venous thrombosis. Besides, the absence of blood flow in shear stress and reperfusion causes damage to endothelial cells via a mechanical signal cascade “sense”. These mechanisms interact to aggravate oxidative stress in APE (APE: acute pulmonary embolism; CINC: cytokine-induced neutrophil chemoattractant; EMP: endothelial microparticle; HMGB: high mobility group box 1; sICAM: soluble intercellular cell adhesion molecule; MCP: monocyte chemotactic protein; MIP: macrophage inflammatory protein; MMP-9: matrix metalloprotein-9; NETs: neutrophil extracellular traps; PDMP: platelet-derived microparticles; TF: tissue factor)