Modulation of murine macrophage function by N‐acetylcysteine in a model of endotoxic shock

Abstract

In previous studies we have observed changes in several functions of peritoneal macrophages from BALB/c mice with irreversible endotoxic shock caused by intraperitoneal injection of E. coli lipopolysaccharide (LPS) (100 mg/kg), which were associated with a high production of superoxide anion. Since antioxidants, such as N-acetylcysteine (NAC), are free radical scavengers that improve the immune response, in the present work we have studied different functions of peritoneal macrophages from BALB/c mice suffering the endotoxic shock above indicated and administered N-acetylcysteine (150 mg/kg i.p.) at 30 minutes after LPS injection. In the peritoneal macrophages obtained at 2, 4, 12 and 24 h after LPS injection, the following functions were studied: adherence to substrate, mobility, ingestion of particles, and production of superoxide anion and tumour necrosis factor (TNF alpha). The increase in adherence, ingestion and superoxide anion and TNF alpha production shown by macrophages from animals with endotoxic shock was counteracted by NAC injection. Moreover, the survival time of mice with endotoxic shock was increased in the presence of NAC. These data suggest that NAC, administered intraperitoneally, may be useful for the treatment of irreversible endotoxic shock by modulation of the function of macrophages with decreased superoxide anion and TNF alpha production and concomitant increase of survival time.

Involvement of Reactive Oxygen Species in Toll-Like Receptor 4-Dependent Activation of NF-κB

“…␣TOC prevents membrane polyunsaturated fatty acids from undergoing lipid peroxidation, which leads to loss of membrane integrity (34). Of note, the doses of antioxidants that were effective in inhibiting LPS-induced cytokine production in the present experiments are similar to those previously reported to be effective in other cell types (11,35,36).…”

Opening the microcirculation: can vasodilators be useful in sepsis?

“…Furthermore, NAC results in increased NO release, leading to platelet inhibition [39] and vasodilatation of small blood vessels [40]. Several murine studies have demonstrated immunomodulating effects such as decreased leukocytes adherence [41,42,43] and decreased superoxide and tumor necrosis factor α production [44]. When given as pretreatment to endotoxic dogs, NAC resulted in improved global oxygen extraction and lower lactate levels [45,46].…”

Role of Mitochondrial Oxidative Stress in Sepsis

“…GSH function is potentially enhanced by the administration of NAC, which has also itself an antioxidant and immunomodulatory activity [77][78][79][80][81][82]. Studies in humans demonstrated that the administration of NAC can significantly increase hepatosplanchnic blood flow attributed to the increase of cardiac index [83] and can augment neutrophil phagocytosis in patients diagnosed with sepsis, systemic inflammatory response syndrome (SIRS), or multiple trauma [84].…”