Abstract
Lipopolysaccharide (LPS)-induced endotoxemia triggers the secretion of proinflammatory cytokines and can cause acute lung injury (ALI). The high mobility group box 1 (HMGB1) protein plays an important role as a late mediator of sepsis and ALI. Galantamine (GAL) is a central acetylcholinesterase inhibitor that inhibits the expression of HMGB1. This study evaluated the effects of GAL by measuring levels of inflammatory mediators and observing histopathological features associated with LPS-induced ALI. Sixty 8-10 week old male Sprague-Dawley rats (200-240 g) were randomized into three groups as follows: control group, LPS group (7.5 mg/kg LPS), and LPS+GAL group (5 mg/kg GAL before LPS administration). Histopathological examination of lung specimens obtained 12 h after LPS administration was performed to analyze changes in wet-to-dry (W/D) weight ratio, myeloperoxidase (MPO) activity, and HMGB1 expression level. Additionally, plasma concentrations of tumor necrosis factor-α, interleukin-6, and HMGB1 were measured using an enzyme-linked immunosorbent assay at 0 (baseline), 3, 6, 9, and 12 h after LPS administration. Mortality in the three groups was recorded at 72 h. LPS-induced ALI was characterized by distortion of pulmonary architecture and elevation of MPO activity, W/D weight ratio, and levels of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-6, and HMGB1. Pretreatment with GAL significantly reduced the LPS-induced lung pathological changes, W/D weight ratio, levels of pro-inflammatory cytokines and MPO activity (ANOVA). Moreover, GAL treatment significantly decreased the mortality rate (ANOVA). In conclusion, we demonstrated that GAL exerted a protective effect on LPS-induced ALI in rats.
Highlights
Acute lung injury (ALI) is a leading cause of death in patients with sepsis, and has shown an annual increase in incidence over the past few years [1,2]
high mobility group box 1 (HMGB1) is reported to be involved in neutrophil accumulation, interstitial edema, disruption of epithelial integrity, leakage of proteins into the alveolar space, and increased production of pro-inflammatory cytokines associated with the pathogenesis of ALI [5,6]
In the LPS group, 50% of the rats died within 24 h while an additional 30% died within 72 h; the total mortality rate in this group was 80% in contrast to the LPS+GAL group where the mortality rate was 10%
Summary
Acute lung injury (ALI) is a leading cause of death in patients with sepsis, and has shown an annual increase in incidence over the past few years [1,2]. Despite remarkable advances in sepsis treatment, the occurrence of ALI and subsequent acute respiratory failure in critically ill patients remains unacceptably high [3]. Cumulative evidence has suggested that the process is mediated by increased pulmonary expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-a, interleukin (IL)-1, IL-6, and high mobility group box 1 (HMGB1) [4]. These pro-inflammatory cytokines are believed to trigger, amplify, and perpetuate the inflammatory response, thereby affecting gas exchange and causing refractory hypoxemia. Anti-HMGB1 antibodies prevented death in experimental mice with sepsis and the resultant ALI [7,8], indicating that therapeutic agents that attenuate HMGB1 release may have potential for the prevention and treatment of ALI
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