Research Progress of Macromolecules in the Prevention and Treatment of Sepsis

Abstract

Sepsis is associated with high rates of mortality in the intensive care unit and accompanied by systemic inflammatory reactions, secondary infections, and multiple organ failure. Biological macromolecules are drugs produced using modern biotechnology to prevent or treat diseases. Indeed, antithrombin, antimicrobial peptides, interleukins, antibodies, nucleic acids, and lentinan have been used to prevent and treat sepsis. In vitro, biological macromolecules can significantly ameliorate the inflammatory response, apoptosis, and multiple organ failure caused by sepsis. Several biological macromolecules have entered clinical trials. This review summarizes the sources, efficacy, mechanism of action, and research progress of macromolecular drugs used in the prevention and treatment of sepsis.

Keywords: RNA; antibody; biomolecule; polypeptide; polysaccharide; protein; sepsis.

Figure 1

Anticoagulation mechanism of rhTM, ART-123, Annexin, and FGF-2. AKT: protein kinase B; APC: activated protein C; ART-123: Recombinant hu-man soluble thrombomodulin; FGF-2: fibroblast growth factor 2; HMGB1: high-mobility group box protein 1; IL-6: interleukin-6; LPS: lipopolysaccharide; mTOR: mammalian target of rapamycin; PAI-1: plasminogen activator inhibitor-1; rhTM: Recombinant human soluble thrombomodulin; S6K1: p70 ribosomal protein subunit 6 kinase 1; TF: tissue factor; TLR4: Toll-like receptor 4; TNF-α: tumor necrosis factor; VIIIa: activated factor seven; Va: activated factor five.

Figure 2

Antibacterial mechanism of WIKE-14, PS1-2, and Pep19-2.5. LPS: lipopolysaccharide; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; Pep19-2.5: aspidasept; TLR2: Toll-like receptor 2; TLR4: Toll-like receptor 4; TNF-α: tumor necrosis factor.

Figure 3

Antioxidant mechanism of α-ch, FGF-19, MFG-E8, MG53, and GDF7. AMPK: adenosine 5′-monophosphate (AMP)-activated protein kinase; Bax: BCL2-associated X; FGF-19: fibroblast growth factor 19; GDF7: growth differentiation factor 7; GLA: gamma linolenic acid; GPX4: glutathione peroxidase 4; GSH: glutathione; HO-1: heme oxygenase-1; iNOS: inducible nitric oxide synthase; Keap1: Kelch-like ECH-associated protein 1; LA: linoleic acid; MDA: malondialdehyde; MFG-E8: milk fat globule epidermal growth factor 8; MG53: mitsugumin-53; MPO: myeloperoxidase; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; NOx: nitrite/nitrate; NRF2: nuclear factor erythroid 2-related factor 2; PPARα: peroxisome proliferator-activated receptor-alpha; ROS: reactive oxygen species; SOD: superoxide dismutase; STING: stimulator of interferon genes; TLR4: Toll-like receptor 4; α-ch: alpha-chymotrypsin.

Figure 4

Anti-apoptotic mechanism of HGF, IL-7, IL-15, IL-22, Ac2-26, Vaspin, Hsp22, and APN. AKT: protein kinase B; AMPK: adenosine 5′-monophosphate (AMP)-activated protein kinase; APN: adiponectin; ATF4: activating transcription factor 4; ATG7: autophagy related protein 7; Bax: BCL2-associated X; bcl-2: B-cell lymphoma-2; Bim: Bcl-2-like protein 11; c-Met: cellular mesenchymal–epithelial transition factor; HGF: hepatocyte growth factor; Hsp22: heat shock protein 22; IFN-γ: interferon-γ; IL-15: interleukin-15; IL-22: interleukin-22; IL-7: interleukin-7; JAK: Janus Kinase; KLK7: kallikrein 7; mTOR: mammalian target of rapamycin; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K: phosphoinositide 3-Kinase; PUMA: p53 upregulated modulator of apoptosis; ROS: Reactive oxygen species; S100A9: S100 calcium-binding protein A9; STAT3/5: signal transducer and activator of transcription 3/5; Vaspin: Serpin A12.

Figure 5

Anti-inflammatory mechanism of S100A8, CXT, Apelin-13, and SLPI. APJR: apelin receptor; CTX: crotoxin; IKK-α/β: inhibitor of kappa B kinase-α/β; IL-10: interleukin-10; IL-6: interleukin-6; Iκb-α: inhibitor kappa B alpha; LPS: lipopolysaccharide; LXA4: lipoxin A4; MAPK: mitogen-activated protein kinase; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; NOX4: NADPH oxidase 4; p38 MAPK: P38 mitogen-activated protein kinases; PFKFB3: 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase; PGE2: prostaglandin E2; ROS: reactive oxygen species; S1000A8: S100 calcium-binding protein A8; SLPI: secretory leukocyte protease inhibitor; SMAD2/3: drosophila mothers against decapentaplegic protein 2/3; TGF-β: transforming growth factor beta; TLR4: Toll-like receptor 4; TNF-α: tumor necrosis factor.

Figure 6

Therapeutic mechanism of anti-HMGB1pAb, atezolizumab, secukinumab, adrecizumab, and tocilizumab. HMGB1: high-mobility group box chromosomal protein 1; IL-10: interleukin-10; IL-1β: interleukin-1β; IL-4: interleukin-4; IL-6: interleukin-6; IRF3: interferon regulatory factor 3; IκBα: inhibitor kappa B alpha; JNK: Jun N-terminal Kinase; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3: NOD-like receptor thermal-protein-domain-associated protein 3; PD-L1: programmed cell death-ligand 1; S100A12: S100 calcium-binding protein A12; TLR4: Toll-like receptor 4; TNF-α: tumor necrosis factor.

Figure 7

Therapeutic mechanism of miR-25-5p, miR-214-3p, miR-142-5p, miR-340-5p, miR-26a-5p, and miR-490-3p. Bax: BCL2-associated X; bcl-2: B-cell lymphoma-2; CTGF: connective tissue growth factor; CTSB: cathepsin B; GSH: glutathione; IL-6: interleukin-6; IRAK1: interleukin 1 receptor-associated kinase 1; MAPK: mitogen-activated protein kinase; MDA: malondialdehyde; miR: microRNA; MyD88: myeloid differentiation factor 88; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3: NOD-like receptor thermal-protein-domain-associated protein 3; ROS: reactive oxygen species; SOD: superoxide dismutase; TNF-α: tumor necrosis factor; TRAF6: TNF receptor-associated factor 6; TXNIP: thioredoxin-interacting protein.

Figure 8

Treatment mechanism of UFH, NAH, lentinan, LBP, and PCP. Bax: BCL2-associated X; Gnb2: G protein subunit β2; GSDMD: Gasdermin D; GSH: glutathione; HMGB1: high-mobility group box protein 1; HPA: heparinase; IL-1β: interleukin-1β; IL-6: interleukin-6; LBP: Lycium barbarum polysaccharide; LPS: lipopolysaccharide; MDA: malondialdehyde; MPO: myeloperoxidase; NAH: N-acetyl heparin; Nedd4: neural precursor cell expressed developmentally downregulated protein 4; Nedd4L: NEDD4-like E3 ubiquitin protein ligase; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; PCPs:Poria cocos polysaccharides; PKM2: Pyruvate kinase muscle isoform 2; SOD: superoxide dismutase; TLR4: Toll-like receptor 4; TNF-α: tumor necrosis factor; UFH: unfractionated heparin; Xa: factor Xa.