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Dissociation between systemic and pulmonary anti ‐ inflammatory effects of dexamethasone in humans

View Article: PubMed Central - PubMed

ABSTRACT

Aims: The local pulmonary inflammatory response has a different temporal and qualitative profile compared with the systemic inflammatory response. Although glucocorticoids substantially downregulate the systemic release of acute‐phase mediators, it is not clear whether they have comparable inhibitory effects in the human lung compartment. Therefore, we compared the anti‐inflammatory effects of a pure glucocorticoid agonist, dexamethasone, on bronchoalveolar lavage and blood cytokine concentrations in response to bronchially instilled endotoxin.

Methods: In this randomized, double‐blind and placebo‐controlled trial, 24 volunteers received dexamethasone or placebo and had endotoxin instilled into a lung segment and saline instilled into a contralateral segment, followed by bronchoalveolar lavage.

Results: Bronchially instilled endotoxin induced a local and systemic inflammatory response. Dexamethasone strongly blunted the systemic interleukin (IL) 6 and C‐reactive protein release. In sharp contrast, dexamethasone left the local release of acute‐phase mediators in the lungs virtually unchanged: bronchoalveolar lavage levels of IL‐6 were only 18% lower and levels of IL‐8 were even higher with dexamethasone compared with placebo, although the differences between treatments were not statistically significant (P = 0.07 and P = 0.08, respectively). However, dexamethasone had inhibitory effects on pulmonary protein extravasation and neutrophil migration.

Conclusions: The present study demonstrated a remarkable dissociation between the systemic anti‐inflammatory effects of glucocorticoids and its protective effects on capillary leak on the one hand and surprisingly low anti‐inflammatory effects in the lungs on the other.

No MeSH data available.


Systemic cytokine release in response to bronchial instillation of 4 ng·kg−1 lipopolysaccharide (LPS) in healthy volunteers who received dexamethasone intravenously (i.v.) (■) (n = 11) or placebo (○) (n = 13). Venous blood was obtained before drug administration (13 h and 1 h before LPS instillation), and 6 h and 24 h after LPS instillation. LPS instillation was associated with a minimal increase in TNF‐α levels (24 h) (A) and a significant increase in IL‐6 levels (P < 0.002, at 6 h) (B). IL‐8 (C) levels did not change over 24 h. Dexamethasone effectively reduced IL‐6 (B), whereas IL‐8 (C) remained unchanged and TNF‐α levels (A) were reduced moderately. In (A), data are displayed as median and interquartile range. In (B) and (C), data represent means and 95% confidence intervals. *P < 0.05, **P < 0.01 vs. baseline. #P < 0.05, ###P < 0.001 for comparison between dexamethasone and placebo treatment
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bcp12857-fig-0006: Systemic cytokine release in response to bronchial instillation of 4 ng·kg−1 lipopolysaccharide (LPS) in healthy volunteers who received dexamethasone intravenously (i.v.) (■) (n = 11) or placebo (○) (n = 13). Venous blood was obtained before drug administration (13 h and 1 h before LPS instillation), and 6 h and 24 h after LPS instillation. LPS instillation was associated with a minimal increase in TNF‐α levels (24 h) (A) and a significant increase in IL‐6 levels (P < 0.002, at 6 h) (B). IL‐8 (C) levels did not change over 24 h. Dexamethasone effectively reduced IL‐6 (B), whereas IL‐8 (C) remained unchanged and TNF‐α levels (A) were reduced moderately. In (A), data are displayed as median and interquartile range. In (B) and (C), data represent means and 95% confidence intervals. *P < 0.05, **P < 0.01 vs. baseline. #P < 0.05, ###P < 0.001 for comparison between dexamethasone and placebo treatment

Mentions: LPS instillation induced only a limited systemic inflammatory reaction. IL‐6 increased 22‐fold (6 h; P < 0.002; Figure 6B) and CRP increased 32‐fold (24 h; P < 0.002; Figure 7A), while plasma IL‐8 levels did not change over 24 h (Figure 6C) and TNF‐α increased only minimally (24 h; P = 0.01; Figure 6) (Table 3). Endotoxin instillation increased absolute neutrophil counts twofold (P = 0.002; Figure 7B) and reduced absolute lymphocyte counts by 30% (P = 0.016; Figure 7D) (Table 3).


Dissociation between systemic and pulmonary anti ‐ inflammatory effects of dexamethasone in humans
Systemic cytokine release in response to bronchial instillation of 4 ng·kg−1 lipopolysaccharide (LPS) in healthy volunteers who received dexamethasone intravenously (i.v.) (■) (n = 11) or placebo (○) (n = 13). Venous blood was obtained before drug administration (13 h and 1 h before LPS instillation), and 6 h and 24 h after LPS instillation. LPS instillation was associated with a minimal increase in TNF‐α levels (24 h) (A) and a significant increase in IL‐6 levels (P < 0.002, at 6 h) (B). IL‐8 (C) levels did not change over 24 h. Dexamethasone effectively reduced IL‐6 (B), whereas IL‐8 (C) remained unchanged and TNF‐α levels (A) were reduced moderately. In (A), data are displayed as median and interquartile range. In (B) and (C), data represent means and 95% confidence intervals. *P < 0.05, **P < 0.01 vs. baseline. #P < 0.05, ###P < 0.001 for comparison between dexamethasone and placebo treatment
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bcp12857-fig-0006: Systemic cytokine release in response to bronchial instillation of 4 ng·kg−1 lipopolysaccharide (LPS) in healthy volunteers who received dexamethasone intravenously (i.v.) (■) (n = 11) or placebo (○) (n = 13). Venous blood was obtained before drug administration (13 h and 1 h before LPS instillation), and 6 h and 24 h after LPS instillation. LPS instillation was associated with a minimal increase in TNF‐α levels (24 h) (A) and a significant increase in IL‐6 levels (P < 0.002, at 6 h) (B). IL‐8 (C) levels did not change over 24 h. Dexamethasone effectively reduced IL‐6 (B), whereas IL‐8 (C) remained unchanged and TNF‐α levels (A) were reduced moderately. In (A), data are displayed as median and interquartile range. In (B) and (C), data represent means and 95% confidence intervals. *P < 0.05, **P < 0.01 vs. baseline. #P < 0.05, ###P < 0.001 for comparison between dexamethasone and placebo treatment
Mentions: LPS instillation induced only a limited systemic inflammatory reaction. IL‐6 increased 22‐fold (6 h; P < 0.002; Figure 6B) and CRP increased 32‐fold (24 h; P < 0.002; Figure 7A), while plasma IL‐8 levels did not change over 24 h (Figure 6C) and TNF‐α increased only minimally (24 h; P = 0.01; Figure 6) (Table 3). Endotoxin instillation increased absolute neutrophil counts twofold (P = 0.002; Figure 7B) and reduced absolute lymphocyte counts by 30% (P = 0.016; Figure 7D) (Table 3).

View Article: PubMed Central - PubMed

ABSTRACT

Aims: The local pulmonary inflammatory response has a different temporal and qualitative profile compared with the systemic inflammatory response. Although glucocorticoids substantially downregulate the systemic release of acute&#8208;phase mediators, it is not clear whether they have comparable inhibitory effects in the human lung compartment. Therefore, we compared the anti&#8208;inflammatory effects of a pure glucocorticoid agonist, dexamethasone, on bronchoalveolar lavage and blood cytokine concentrations in response to bronchially instilled endotoxin.

Methods: In this randomized, double&#8208;blind and placebo&#8208;controlled trial, 24 volunteers received dexamethasone or placebo and had endotoxin instilled into a lung segment and saline instilled into a contralateral segment, followed by bronchoalveolar lavage.

Results: Bronchially instilled endotoxin induced a local and systemic inflammatory response. Dexamethasone strongly blunted the systemic interleukin (IL) 6 and C&#8208;reactive protein release. In sharp contrast, dexamethasone left the local release of acute&#8208;phase mediators in the lungs virtually unchanged: bronchoalveolar lavage levels of IL&#8208;6 were only 18% lower and levels of IL&#8208;8 were even higher with dexamethasone compared with placebo, although the differences between treatments were not statistically significant (P&nbsp;=&nbsp;0.07 and P&nbsp;=&nbsp;0.08, respectively). However, dexamethasone had inhibitory effects on pulmonary protein extravasation and neutrophil migration.

Conclusions: The present study demonstrated a remarkable dissociation between the systemic anti&#8208;inflammatory effects of glucocorticoids and its protective effects on capillary leak on the one hand and surprisingly low anti&#8208;inflammatory effects in the lungs on the other.

No MeSH data available.