SiO2 oral exposure promotes the crosstalk between NETs and PANoptosis of lung epithelial cells by driving NOX1/ROS, triggering pneumonia in mice.

Modulation of the gut-lung axis by probiotic VSL#3 alleviates acute lung injury via restricting NETosis in sepsis.

Deciphering the role of damage-associated molecular patterns and inflammatory responses in acute lung injury

Protectin D1 (PD1), a DHA-derived lipid mediator, has recently been shown to possess anti-inflammatory and pro-resolving properties. To date, little is known about the effect of PD1 on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. The aim of the present study was to investigate the therapeutic effects of PD1 on LPS-induced ALI and its potential mechanisms of action. ALI was induced via an intraperitoneal injection of LPS, where PD1 (2 ng/mouse) was administered intravenously 30 min after LPS challenge. Mice were sacrificed 24 h after modeling. Lung histopathological changes were assessed using hematoxylin and eosin staining and myeloperoxidase (MPO) activity was tested using immunohistochemistry. Tumor necrosis-α and interleukin-6 levels in the bronchoalveolar lavage fluid (BALF) and serum were measured using ELISA. To detect neutrophil extracellular traps produced by infiltrated neutrophils in the lung tissue, immunofluorescence staining was performed using anti-MPO and anti-histone H3 antibodies. The results indicated that PD1 significantly attenuated histological damage and neutrophil infiltration in lung tissue, reduced the lung wet/dry weight ratio, protein concentration and proinflammatory cytokine levels in BALF and decreased proinflammatory cytokine levels in serum. Moreover, neutrophil citrullinated histone H3 (CitH3) expression was also reduced after PD1 administration. In conclusion, PD1 attenuated LPS-induced ALI in mice via inhibition of neutrophil extracellular trap formation in lung tissue. Therefore, PD1 administration may serve to be a new strategy for treating ALI.

SiO₂ exposure triggers NOX1/ROS-dependent epithelial necroptosis and drives Th17 cell activation to initiate pneumonia in mice.

Trypanosoma evansi triggered neutrophil extracellular traps formation dependent on myeloperoxidase, neutrophil elastase, and extracellular signal-regulated kinase 1/2 signaling pathways

Neutrophil infiltration is frequently observed in lung cancer tissues. Extracellular RNAs (exRNAs) may facilitate tumor progression. The present study investigated the cross-talk of tumor exRNAs and neutrophil extracellular traps (NETs) in lung cancer. Lewis lung carcinoma (LLC) cells were cultured with the deprived sera. And the cell culture supernatants (CCS) were analyzed in vitro and in vivo. The results revealed that exRNAs from lung cancer CCS promoted the inflammatory cytokine interleukin-1β and reduced the vascular cell adhesion molecule-1 expression in lung epithelial cells. Lung cancer CCS-treated epithelial cells induced the production of NETs. By contrast, NETs reduced the tight junction protein claudin-5 in epithelial cells. Furthermore, NETs caused the necrosis of epithelial cells, which resulted in the release of exRNAs. In mice, lung cancer cells instilled in the lung recruited neutrophils and initiated NETs. In patients with lung cancer, NETs were also observed. These results suggested that exRNAs in the cell culture supernatant may indirectly induce NETs and contribute to lung cancer oncogenesis.

NET formation in noninfectious conditionsFormation of neutrophil extracellular traps (NETs), a new effector function of neutrophils, was first described in 2004 [1].Since then, the formation of NETs has widely been studied.NETs have a web-like structure mainly made of decondensed chromatin fibers, whose expulsion from the cell is aided by enzymatic citrullination of histones and which are decorated with granule proteins, such as elastase, myeloperoxidase (MPO) and histones [2,3].There is ample evidence supporting the idea that formation of NETs plays an important role in immune responses, allowing neutrophils to capture, neutralize, and degrade a variety of invading microorganisms.NETosis, the type of programmed cell death resulting in NET formation, also occurs during sterile inflammation resulting in thrombosis [4,5], autoimmunity [6], and NET-mediated cytotoxicity [7,8], and therefore can be harmful.DNA and damage-associated molecular patterns (DAMPs) embedded within NETs act as alarmins, augmenting inflammation, and exerting cytotoxic effects.The prothrombotic role of NETs has been well documented [9][10][11].This feature of NETs may become problematic, especially in cases of sterile insults.Thus, while NETs may provide evolutionary advantages of trapping and killing bacteria in infectious diseases, they appear to do more harm in sterile inflammation and thrombosis, as dysregulated NET formation leads to vascular inflammation, thrombosis, and atherogenesis, Let us provide some examples of sterile insults causing NET formation.As shown by many of the studies we discuss below, ischemia/reperfusion (IR) injury is a clinically relevant cause for NET formation.IR injury is a major sterile insult resulting from hemoragic, traumatic or septic shock, burns, and surgical procedures, including organ transplantation.The response to IR injury is comprised of a diverse network ranging from, innate to adaptive immune responses.[12].Restoration of the blood supply, paradoxically, causes cell damage and exacerbation of inflammatory responses through reactive oxygen species (ROS) and other reactive molecules, worsening organ injury [13].However, the specific pathways that link IR to NETs are only partially understood.Besides IR injury, several milder insults are known to induce NET formation.Beiter et al. showed that NET formation increases in response to exhaustive treadmill or cycling exercise in healthy individuals [14].This study proved that NETosis is the main cause for increased cell-free DNA in the circulation, as reported in an earlier study [e.g., 15].Jain and coworkers analyzed NETosis associated with dry eye disease, in which hyperosmolar stress is considered the main factor [16].They further showed that hyperosmotic stress promotes NET formation by neutrophils [17].NETs have been found in venous and arterial thrombosis, trauma-induced coagulopathy, and disseminated intravascular coagulation [18][19][20].NETs promote clot formation; in addition to the interaction of NET components with the coagulation pathway, NETs provide scaffolds for clot growth by catching platelets, fibrin, von Willebrand factor (vWF), and other cells/molecules [21].It is notable that fluid shear stress is a critical factor for rapid and intense NETosis [22].Intriguingly, in sterile occlusive clots, fibrin suppresses NET generation, and the absence of fibrin promotes NETs.Shear-induced NETosis is strongly inversely correlated with fibrin in sterile occlusive clots.

Downregulation of p22phox in Retinal Pigment Epithelial Cells Inhibits Choroidal Neovascularization in Mice

This article is about Alexander Bogdanov's point of view at the reasons of global changes in bourgeois world shown in domination of the financial capital. By a consequence of unsufficient attention of labour movement ideologists to characteristics of new capitalist system was that superficial radicalism of the programs and slogans of proletarian parties did not correspond to those processes of transformation of a society, which on a boundary XIX and XX centuries obviously were not entered in the forecasts of K. Marx. A.A. Bogdanov by first has caught symptoms of these discrepancies which have been poured out in a triumph of a principle of capital globalization in a counterbalance to a principle of socialized manufacture internationalization and the slogan «Proletarians of all countries, incorporate!» The misunderstanding of this process has resulted in regeneration of the Marxist leaders to «social-bureaucracy» which wasn't capable to overcome cultural and world-viewing dependence of proletariat. Changed socio economic and political conditions could not be explained within the framework of the classical economic theory of Marx any more their analysis required the «all-scientific» method, which was possible on the basis of system thinking offered by Bogdanov's general organizational science.

Actinobacillus pleuropneumoniae (A.pp, Gram negative) and Streptococcus (S.) suis (Gram positive) can cause severe diseases in pigs. During infection, neutrophils infiltrate to counteract these pathogens with phagocytosis and/or neutrophil extracellular traps (NETs). NETs consist of a DNA-backbone spiked with antimicrobial components. The NET formation mechanisms in porcine neutrophils as a response to both of the pathogens are not entirely clear. The aim of this study was to investigate whether A.pp (serotype 2, C3656/0271/11) and S. suis (serotype 2, strain 10) induce NETs by NADPH oxidase- or CD18-dependent mechanisms and to characterize phenotypes of NETs in porcine neutrophils. Therefore, we investigated NET induction in porcine neutrophils in the presence and absence of NET inhibitors and quantified NETs after 3 h. Furthermore, NETosis and phagocytosis were investigated by transmission electron microscopy after 30 min to characterize different phenotypes. A.pp and S. suis induce NETs that are mainly ROS-dependent. A.pp induces NETs that are partially CD18-dependent. Thirty minutes after infection, both of the pathogens induced a vesicular NET formation with only slight differences. Interestingly, some neutrophils showed only NET-marker positive phagolysosomes, but no NET-marker positive vesicles. Other neutrophils showed vesicular NETs and only NET-marker negative phagolysosomes. In conclusion, both of the pathogens induce ROS-dependent NETs. Vesicular NETosis and phagocytosis occur in parallel in porcine neutrophils in response to S. suis serotype 2 and A.pp serotype 2.

Live-cell imaging captures the heterogenity of bacterial growth within intracellular bacterial communities and demonstrates that the constituent bacteria are protected from clearance by antibiotics delivered with a physiologically relevant pharmacodynamic profile.

Uric Acid Induces NADPH Oxidase–Independent Neutrophil Extracellular Trap Formation

Abdominal paracentesis drainage protects rats against severe acute pancreatitis-associated lung injury by reducing the mobilization of intestinal XDH/XOD

Oxidative stress and oxidized high-density lipoprotein (HDL) are implicated as risk factors for cardiovascular disease (CVD) in systemic lupus erythematosus (SLE). Yet, how HDL is oxidized and rendered dysfunctional in SLE remains unclear. Neutrophil extracellular traps (NETs), the levels of which are elevated in lupus, possess oxidant-generating enzymes, including myeloperoxidase (MPO), NADPH oxidase (NOX), and nitric oxide synthase (NOS). We hypothesized that NETs mediate HDL oxidation, impairing cholesterol efflux capacity (CEC). Plasma MPO levels and CEC activity were examined in controls and lupus patients, and 3-chlorotyrosine (MPO specific) and 3-nitrotyrosine (derived from reactive nitrogen species) were quantified in human HDL. Multivariable linear models were used to estimate and test differences between groups. HDL was exposed to NETs from control and lupus neutrophils in the presence or absence of MPO, NOX, NOS inhibitors, and chloroquine (CQ). Murine HDL oxidation was quantified after NET inhibition in vivo. SLE patients displayed higher MPO levels and diminished CEC compared to controls. SLE HDL had higher 3-nitrotyrosine and 3-chlorotyrosine content than control HDL, with site-specific oxidation signatures on apolipoprotein A-I. Experiments with human and murine NETs confirmed that chlorination was mediated by MPO and NOX, and nitration by NOS and NOX. Mice with lupus treated with the NET inhibitor Cl-amidine displayed significantly decreased HDL oxidation. CQ inhibited NET formation in vitro. Active NOS, NOX, and MPO within NETs significantly modify HDL, rendering the lipoprotein proatherogenic. Since NET formation is enhanced in SLE, these findings support a novel role for NET-derived lipoprotein oxidation in SLE-associated CVD and identify additional proatherogenic roles of neutrophils and putative protective roles of antimalarials in autoimmunity.

Neutrophils are armed with both oxidant-dependent and -independent pathways for killing pathogens. Activation of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase constitutes an emergency response to infectious threat and results in the generation of antimicrobial reactive oxidants. In addition, NADPH oxidase activation in neutrophils is linked to activation of granular proteases and generation of neutrophil extracellular traps (NETs). NETosis involves the release of nuclear and granular components that can target extracellular pathogens. NETosis is activated during microbial threat and in certain conditions mimicking sepsis, and can result in both augmented host defense and inflammatory injury. In contrast, apoptosis, the physiological form of neutrophil death, not only leads to non-inflammatory cell death but also contributes to alleviate inflammation. Although there are significant gaps in knowledge regarding the specific contribution of NETs to host defense, we speculate that the coordinated activation of NADPH oxidase and NETosis maximizes microbial killing. Work in engineered mice and limited patient experience point to varying susceptibility of bacterial and fungal pathogens to NADPH oxidase versus NET constituents. Since reactive oxidants and NET constituents can injure host tissue, it is important that these pathways be tightly regulated. Recent work supports a role for NETosis in both acute lung injury and in autoimmunity. Knowledge gained about mechanisms that modulate NETosis may lead to novel therapeutic approaches to limit inflammation-associated injury.