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Table 2 Summary studies and therapeutics used to target NETs in intestinal inflammation

From: The emerging role of neutrophilic extracellular traps in intestinal disease

Model/Disease The change of NETs Therapeutic Agents The role of NETs and its effect to issues changes or cell Mechanisms of pro-inflammatory or Anti-inflammatory of NETs Author, References
Lethal endotoxemia, vivo, vitro NETs are formed in lungs during the lethal endotoxemia and that inhibition of PAD4 can abolish NET formation YW3–56(PAD2/PAD4 inhibitor) NETs can cause leakage of endothelial cells and that different NETs induce permeability to different extents and YW3–56 alleviates LPS-induced ALI, educing organ damage and raised survival rates PAD-NET-CitH3 pathway Liang et al. [77]
Endotoxaemia, vivo Avast distribution of NETs was observed in the liver vasculature of endotoxemic mice. Visualization of the terminal product of coagulation, fibrin, demonstrated colocalization with NETs DNase I NETs promote intravascular coagulation during sepsis. NET-induced intravascular coagulation is a fundamental contributor to microvascular hypoperfusion in sepsis. NETs are key pathological mediators in systemic intravascular coagulation and subsequent end-organ damage in bacterial sepsis A dynamic NET–platelet–thrombin axis that promotes intravascular coagulation and microvascular dysfunction in sepsis Mcdonald et al. [75]
CLP, vivo, vitro Induction of sepsis caused significant formation of NETs rhDNAse NET formation exerts proin-flammatory effects in septic lung injury NET activity regulates CXC, TNF-α, and HMGB1 chemokine formation Luo et al. [76]
Lethal septic shock, vivo, vitro NETs were significantly elevated in abdominal sepsis patients and there were significant correlations between NETs markers and intestinal damage markers in serum ODN2088(TLR9 antagonist) NETs participate in sepsis-induced intestinal apoptosis. NETs impair the integrity of intestinal epithelial cell monolayer barriers in vitro TLR9–ER stress signaling pathway possible participate in NETs-induced intestinal epithelial cell death Sun et al. [78]
trauma hemorrhagic shock, vivo Trauma-hemorrhagic shock induced the formation of intestinal NETs and disrupted the intestinal tight junction proteins DNase I NETs contribute to the dysfunction of the intestinal barrier in T/HS and aggregated intestinal injury Tranexamic acid appears to suppress NETs formation via the classic ROS/MAPK pathway Chu et al. [79]
ICU patients, Ex vivo NETs can be directly induced by incubating neutrophils with plasma or sera from patients with sepsis Inhibition of IL-8 or MAPK Sepsis is the predominant ICU condition associated with NET formation and degrees of NET formation predict DIC development and are associated with multisystem organ failure and mortality MAPK activation as the major pathway of IL-8–induced NET formation in patients Abrams et al. [87]
Midgut volvulus, vivo A significant increase in ceDNA within 4 h post midgut volvulus DNase1 and tPA / LMWH Formation NETs disrupts intestinal tissue integrity after torsion Diminished the inflammatory response Boettcher et al. [91]
Intestinal I/R, vivo NETs are present in the intestine and that cfDNA is released into the blood during intestinal I/R injury DNase-1 NETs contribute to the early inflammatory response after intestinal I/R injury Dnase could reduce NET density, downregulate the proinflammatory response, changes and maintain the functional integrity of tight junctions and the cytoskeleton Wang et al. [92]
Intestinal I/R, vivo, vitro Pre-ischemia, the number of NETing leukocytes was modest and postischemia NETosis was vastly enhanced in vivo. Isolated bone marrow-derived neutrophils from germ-free mice and broad-spectrum antibiotic-treated mice show hyperreactive LPS-induced NETosis Broad-spectrum antibiotics NETs mediated mesenteric I/R injury Tonic stimulation of the cell-intrinsic TLR4/TRIF (TIR-domain–containing adapter-inducing interferon-β) signaling pathway by gut commensals attenuates LPS-induced NETosis Ascher et al. [93]
NEC, vivo, Ex vivo NETs presented in human NEC ileum.NET formation was abundant in the small intestine of pups in the NEC group Cl-amidine NETs are critical in the innate immune defence during NEC in preventing systemic bacteraemia. NETs inhibition increases inflammation, bacteraemia and mortality in murine necrotizing enterocolitis NET formation may be disease- and model-specific, and in NEC, they depend largely upon the level of intestinal bacterial translocation Chaaban et al. [11]
NEC, vivo NEC significantly induced elevated cfDNA DNase1 NETs induced tissue damage, oxidative stress, and inflammation DNase1 treatment significantly reduced TLR4 and C5a receptor expression and thus interfered with the typical inflammatory cascade Klinke et al. [99]