Neutrophil Elastase Inhibitors Suppress Oxidative Stress in Lung during Liver Transplantation

Abstract

Background Neutrophil infiltration plays a critical role in the pathogenesis of acute lung injury following liver transplantation (LT). Neutrophil elastase is released from neutrophils during pulmonary polymorphonuclear neutrophil activation and sequestration. The aim of the study was to investigate whether the inhibition of neutrophil elastase could lead to the restoration of pulmonary function following LT. Methods In in vivo experiments, lung tissue and bronchoalveolar lavage fluid (BALF) were collected at 2, 4, 8, and 24 h after rats were subjected to orthotopic autologous LT (OALT), and neutrophil infiltration was detected. Next, neutrophil elastase inhibitors, sivelestat sodium hydrate (exogenous) and serpin family B member 1 (SERPINB1) (endogenous), were administered to rats before OALT, and neutrophil infiltration, pulmonary oxidative stress, and barrier function were measured at 8 h after OALT. Results Obvious neutrophil infiltration occurred from 2 h and peaked at 8 h in the lungs of rats after they were subjected to OALT, as evidenced by an increase in naphthol-positive cells, BALF neutrophil elastase activity, and lung myeloperoxidase activity. Treatment with neutrophil elastase inhibitors, either sivelestat sodium hydrate or SERPINB1, effectively reduced lung naphthol-positive cells and BALF inflammatory cell content, increased expression of lung HO-1 and tight junction proteins ZO-1 and occludin, and increased the activity of superoxide dismutase. Conclusion Neutrophil elastase inhibitors, sivelestat sodium hydrate and SERPINB1, both reduced lung neutrophil infiltration and pulmonary oxidative stress and finally restored pulmonary barrier function.

The Regulation of Neutrophil Extracellular Trap–induced Tissue Damage by Human CD177

“…In contrast, under stable conditions, ROS induce neutrophil apoptosis primarily through the action of cathepsin D, which promotes the activation of caspase 8. 35 – 37 The end of inflammation is due to the efficient removal of neutrophils from the inflamed tissues by apoptosis of the neutrophils themselves. 38 The apoptosis of neutrophils itself not only ends effector activity but also induces the generation of anti-inflammatory signals that are transmitted to other immune cells.…”

TNF‐α Induces Neutrophil Apoptosis Delay and Promotes Intestinal Ischemia‐Reperfusion‐Induced Lung Injury through Activating JNK/FoxO3a Pathway

“…Histopathological changes of the lung were observed with optical microscopy and were scored in terms of the degree of (1) alveolar congestion, hemorrhage, and edema; (2) PMN infiltration and aggregation in the airways or (and) vascular walls; and (3) alveolar septa thickening and hyaline membrane formation [ 17 , 18 ]. Each lung section was microscopically observed in three fields of view, and the observation in each field was scored 0–3 according to Koksel's method [ 19 ], with score 0 indicating a normal state; score 1 indicating a mild interstitial congestion and PMN infiltration; score 2 indicating a perivascular edema, partial destruction of alveolar structures, and moderate PMN infiltration; and score 3 indicating a structural destruction of lung tissue and massive PMN infiltration.…”

Inflammation in Duchenne Muscular Dystrophy–Exploring the Role of Neutrophils in Muscle Damage and Regeneration

“…However, NE can also cause detrimental effects, including extracellular matrix destruction, tissue fibrosis and mucus production [52]. Neutrophil accumulation and elevated levels of NE are characteristic features of acute lung injury, which is associated with increased inflammation and oxidative stress [53,54]. Treatment with NE inhibitors significantly reduced neutrophil accumulation and oxidative stress in vivo, suggesting a role for NE in promoting tissue damage via increased oxidative stress [54].…”