Bay-117082 treats sepsis by inhibiting neutrophil extracellular traps (NETs) formation through down-regulating NLRP3/N-GSDMD.

During the inflammatory storm of sepsis, a significant quantity of neutrophil extracellular traps (NETs) are generated, which act as a double-edged sword and not only impede the invasion of foreign microorganisms but also exacerbate organ damage. This study provides evidence that NETs can cause damage to alveolar epithelial cells in vitro. The sepsis model developed in this study showed a significant increase in NETs in the bronchoalveolar lavage fluid (BALF). The development of NETs has been shown to increase the lung inflammatory response and aggravate injury to alveolar epithelial cells. Bay-117082, a well-known NF-κB suppressor, is used to modulate inflammation. This analysis revealed that Bay-117082 efficiently reduced total protein concentration, myeloperoxidase activity, and inflammatory cytokines in BALF. Moreover, Bay-117082 inhibited the formation of NETs, which in turn prevented the activation of the pore-forming protein gasdermin D (GSDMD). In summary, these results indicated that excessive NET production during sepsis exacerbated the onset and progression of acute lung injury (ALI). Therefore, Bay-117082 could serve as a novel therapeutic approach for ameliorating sepsis-associated ALI.

The role of neutrophil extracellular traps in sepsis and sepsis-related acute lung injury.

Neutrophils release neutrophil extracellular traps (NETs) to trap pathogenic microorganisms. NETs are involved in the inflammatory response and bacterial killing and clearance. However, their excessive activation can lead to an inflammatory storm in the body, which may damage tissues and cause organ dysfunction. Organ dysfunction is the main pathophysiological cause of sepsis and also a cause of the high mortality rate in sepsis. Acute lung injury caused by sepsis accounts for the highest proportion of organ damage in sepsis. NET formation can lead to the development of sepsis because by promoting the release of interleukin-1 beta, interleukin-8, and tumor necrosis factor-alpha, thereby accelerating acute lung injury. In this review, we describe the critical role of NETs in sepsis-associated acute lung injury and review the current knowledge and novel therapeutic approaches.

Necrostatin-1 Alleviates Diffuse Pulmonary Haemorrhage by Preventing the Release of NETs via Inhibiting NE/GSDMD Activation in Murine Lupus.

Diffuse alveolar haemorrhage (DAH) is a rapidly developing condition owing to a lack of effective treatment and resulting in a high mortality rate in systemic lupus erythematosus (SLE). Neutrophil extracellular traps (NETs) contain numerous antigens and proinflammatory substances that directly damage the vascular endothelium and aggravate vascular inflammation, which is considered an important pathogenic factor of DAH in SLE. Therefore, blocking the release of NETs from neutrophils is an important target for the treatment of DAH in SLE. In this study, we investigated whether the inhibition of neutrophils releasing NETs could relieve DAH in SLE. Necrostatin-1 (Nec-1), a small molecule, has been reported to inhibit the release of NETs by neutrophils. In vitro experiments revealed that Nec-1 inhibited alveolar epithelial cell damage by preventing the release of NETs. Furthermore, vivo studies showed that Nec-1 alleviated lupus pulmonary haemorrhage in mice by reducing lung pathology severity, body weight, and serum inflammatory cytokine levels. Mechanistically, Nec-1 prevented NET release by inhibiting neutrophil elastase (NE) activation and N-Gasdermin D (N-GSDMD) expression. Additionally, immunohistochemistry and immunofluorescence findings showed that Nec-1 decreased NE expression in the lung tissues of mice with lupus pulmonary haemorrhage. Thus, NETs released by neutrophils contributed to the pathogenesis of DAH in SLE, and Nec-1 showed protective effects by the inhibition of NET production via the reduction of NE activation and N-GSDMD expression.

Association of Obstructive Sleep Apnea Syndrome (OSA/OSAHS) with Coronary Atherosclerosis Risk: Systematic Review and Meta-Analysis.

Objective: Obstructive sleep apnea syndrome (OSA) is the most common type of sleep disorders. This study aimed to systematically review the correlation between OSA and the risk of coronary atherosclerosis. Methods: Literature on case-control studies on the relationship between coronary heart disease (CHD) and sleep apnea syndrome was collected and collated, and the incidence of SAS in CHD and non-CHD patients was observed and compared. RevMan 5.2 analysis software and Stata12SE analysis software were used for heterogeneity test and combination analysis of the included studies. The results were expressed with odds ratio (OR), 95% confidence intervals (CI) were calculated, and publication bias and sensitivity tests were evaluated. Results: There was a statistical difference in OSA associated with the risk of coronary atherosclerosis between the experimental group and the control group [OR = 1.38, 95% CI (1.18, 1.62), P < 0.0001, I 2 = 0%, Z = 3.93]. OSA associated with vascular endothelial injury [OR = 3.59, 95% CI (3.00, 4.29), P < 0.00001, I 2 = 90%, Z = 14.09]. OSA is associated with vascular oxidation emergency [OR = 2.19, 95% CI (2.05, 2.33), P < 0.00001, I 2 = 94%, Z = 23.40]; OSA is associated with chronic vascular inflammation [OR = 1.70, 95% CI (1.39, 2.07), P < 0.00001, I 2 = 16%, Z = 5.18]. Conclusion: The incidence of obstructive sleep apnea in patients with CHD was higher than that in non-CHD patients, and obstructive sleep apnea was a risk factor for CHD.

Neutrophil side fluorescence: a new indicator for predicting the severity of patients with bronchiectasis.

BACKGROUND: Neutrophilic inflammation in the airway is a hallmark of bronchiectasis. Neutrophil extracellular traps (NETs) have been reported to play an important role in the occurrence and development of bronchiectasis. Neutrophil side fluorescence is one of the characteristics of neutrophils that can reflect the activation of neutrophils and the formation of NETs. OBJECTIVE: To explore the relationship between the values of neutrophil side fluorescence (NEUT-SFL) in the peripheral blood of bronchiectasis patients, and the severity of the disease. METHODS: 82 patients with bronchiectasis from the Department of Respiratory and Critical Medicine, at the Third Affiliated Hospital of Southern Medical University and were scored with Bronchiectasis Severity Index (BSI) (2019-2021). The clinical data such as the value of NEUT-SFL, neutrophil count, C-reactive protein, and procalcitonin levels were collected and retrospectively analyzed. NEUT-SFL values neutrophil count from 28 healthy subjects were also used to ascertain cut-off values. RESULTS: Based on the BSI scores, patients were divided into three categories as mild (32%), moderate (29%), and severe (39%). Our results showed that the values of NEUT-SFL were higher in bronchiectasis patients compared to healthy controls. The levels of NEUT-SFL positively correlated with the high BSI scores in patients (P = 0.037, r = 0.23) and negatively correlated with the lung function in these patients (r = - 0.35, P = 0.001). The area under the ROC curve was 0.813, the best cut-off was 42.145, indicating that NEUT-SFL values > 42.145 can potentially predict the severity of bronchiectasis. CONCLUSIONS: The values of NEUT-SFL in the peripheral blood can be used for predicting the severity of bronchiectasis.