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

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]