Table 2.

Summary studies and therapeutics used to target NETs in intestinal inflammation

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]