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Another study has found that NETs play a major role in the pathogenesis of sepsis.62 GPR77 expression and protein are upregulated in endothelial cells, and exposure to NETs results in increased GPR77 protein in endothelial cells.61,62 In the human lung, NETs are found in various lung diseases, as well as in the blood of patients with pneumonia.61 Chest pain is a symptom associated with NETosis and can be evaluated by taking a detailed history. In one study, a positive correlation between the number of NETs and the severity of chest pain was found in pneumonia.61 A recent study has found that NETosis is the mechanism of clot formation in lung hemorrhage.63 Thus, NETosis contributes to the formation of platelet clots and contributes to coagulopathy and thrombosis, which are features of ALI.63 In the context of ARDS, endothelial cells undergoing NETosis have also been shown to become apoptotic, providing another potential mechanism by which they could induce ARDS.61
A recent study has found that NETs, when released from neutrophils, play a significant role in the pathogenesis of acute lung injury.61 The NETosis of endothelium which provides a scaffold for NETs, is a form of host defense that may be beneficial to the host; however, NETosis of pulmonary endothelial cells has been shown to be deleterious and associated with systemic inflammation and organ failure.61
There are two ways that NETosis can promote inflammation. First, NETs can be internalized by macrophages, which actively promote NETosis in inflammation through the release of inflammatory mediators, that can damage the surrounding tissue.61,64,65,66 Second, NETs promote the recruitment of inflammatory cells to the inflamed tissue.64 NETs can promote the recruitment of inflammatory cells by binding to CXCL16 via its heparin-binding motif.64 NETs can also enhance the adhesion of inflammatory cells via integrins,66 and promote the recruitment of neutrophils to the lung by tethering neutrophils to the endothelium via interaction between the endothelial cell-expressed nucleosome-releasing factor (NEF) and the high mobility group box 1 (HMGB1) protein.67,68
In the event of a significant GSH deficit, the balance between host defense and resolution of inflammation is imbalanced, and NETosis can occur in neutrophils and other immune cells, leading to inflammatory injury of the lung. This hypothesis is supported by studies showing that GSH treatment of endothelial cells can inhibit MPO-derived ROS generation in endothelial cells,36,37 thus providing a plausible explanation of the beneficial role of GSH in the context of cardiovascular disease, lung injury, and inflammation.37
The importance of GSH is underscored by the high rates of neutrophilia and cytokine production in diseases such as cystic fibrosis (CF), smoking-associated lung injury, asthma and pulmonary fibrosis. 827ec27edc