Differential anti-inflammatory and anti-oxidative effects of dexamethasone and N-acetylcysteine in endotoxin-induced lung inflammation

Abstract

SUMMARYInhalation of bacterial endotoxin induces an acute inflammation in the lower respiratory tract. In this study, the anti-inflammatory effects of the anti-oxidant N-acetylcysteine (NAC) and the glucocorticoid dexamethasone were investigated in mice exposed to aerosolized endotoxin (lipopolysaccharide (LPS)). Powerful reduction of neutrophils in bronchoalveolar lavage fluid (BALF) was obtained by a single i.p. injection of dexamethasone (10 mg/kg), whereas treatment with NAC only resulted in reduction of neutrophils when administered at a high dose (500 mg/kg). Measurement of cytokine and chemokine expression in lung tissue revealed a significant decrease of tumour necrosis factor-alpha, IL-1a , IL-1b , IL-6, IL-12p40, and MIP-1a mRNA when mice where treated with dexamethasone but not when treated with NAC. Analysis of oxidative burst demonstrated a remarkable reduction of oxygen radicals in BALF neutrophils after treatment with dexamethasone, whereas the effect of NAC was not significantly different from that in untreated animals. In conclusion, dexamethasone exerted both anti-inflammatory and anti-oxidative effects in acute airway inflammation, probably by blocking early events in the inflammatory cascade. In contrast, treatment with NAC resulted in a weak reduction of the inflammatory response but no inhibition of proinflammatory cytokines or reduction of oxidative burst in neutrophils. These results demonstrate dramatic differences in efficiency and also indicate that the two drugs have different actions. Combined treatment with NAC and dexamethasone revealed an additive action but no synergy was observed.

Enhanced Anti-Inflammation of Inhaled Dexamethasone Palmitate Using Mannosylated Liposomes in an Endotoxin-Induced Lung Inflammation Model

“…At as low a dose as 0.5 mg/kg, the cytokine levels were markedly attenuated in both BAL fluid and lung tissue within several hours (Rocksén et al, 2000;Haddad et al, 2001) after treatment with DPML (Figs. 4 and 5).…”

Role of the glucocorticoid‐induced leucine zipper gene in dexamethasone‐induced inhibition of mouse neutrophil migration via control of annexin A1 expression

“…We have shown here that GILZ is necessary for GC-induced inhibition of neutrophil migration into sites of inflammation. GCs contribute to the inhibition of migratory process by down-regulating the expression of adhesion molecules, such as ICAM-I, on endothelial cells and proinflammatory cytokines or chemokines, including those released by infiltrating neutrophils, such as IL-8 (38)(39)(40). In the present study, DEX treatment did not affect the expression of any surface markers that are involved in the migration process (CD11a, CD11b, TLR-2, and CXCR2), which is similar between WT and GILZ-KO neutrophils during peritonitis.…”

S100A8 Induces IL-10 and Protects against Acute Lung Injury

“…Antioxidants such as Nacetylcysteine inhibit NF-kB activation provoked by aerosolized LPS (44), and N-acetylcysteine is used clinically, for example, to boost antioxidant defense in lungs of patients with chronic obstructive pulmonary disease (45). S100A8 significantly reduced NF-kB mRNA levels that increased with LPS (Fig.…”