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

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.

Keywords: acute respiratory distress syndrome; dexamethasone; lipopolysaccharide; lung inflammation; surfactant protein D.

Figure 1

Schematic of the experimental design. DEX, dexamethasone; LPS, lipopolysaccharide

Figure 2

Consolidated Standards of Reporting Trials flow diagram. Twenty‐eight subjects were screened, and three were excluded (two had a cough and fever a week before the first trial day, and one individual declined to participate). In one subject allocated to the placebo group, no endotoxin or saline was instilled because obstructive sleep apnoea was suspected when sedation was initialized

Figure 3

Instillation of 4 ng·kg⁻¹ lipopolysaccharide (LPS) into a lung segment in healthy volunteers increased bronchoalveolar lavage (BAL) fluid leukocyte (A) and neutrophil (B) counts compared with BAL fluid from saline‐instilled (contralateral) lung sites. BAL was performed 6 h after pulmonary LPS instillation. Pretreatment with dexamethasone intravenously (■) (n = 11) inhibited the LPS‐induced rise in BAL fluid cellularity (A) and neutrophil counts (B) compared with placebo‐ treated (○)individuals (n = 13). BAL fluid concentrations of macrophages (C) were not altered significantly by LPS or dexamethasone. Symbols and lines represent means and 95% confidence intervals. *P < 0.05, **P < 0.01 vs. saline; ^# P < 0.05, ^## P < 0.01 for comparison between dexamethasone and placebo treatment

Figure 4

Instillation of 4 ng·kg⁻¹ lipopolysaccharide (LPS) into a lung segment of healthy volunteers increased bronchoalveolar lavage (BAL) fluid total protein (A) and immunoglobulin G (IgG) (B) concentrations compared with BAL fluid from saline‐instilled (contralateral) lung sites. BAL was performed 6 h after pulmonary LPS instillation. Pretreatment with dexamethasone intravenously (■) (n = 11) inhibited the LPS‐induced rise in total protein (A) and IgG (B) concentrations compared with placebo‐treated (○) individuals (n = 13). BAL fluid concentrations of the epithelial lung injury marker surfactant protein D (C) were not altered by LPS or dexamethasone. Symbols and lines represent means and 95% confidence intervals. **P < 0.01 vs. saline; ^## P < 0.01, ^### P < 0.001 for comparison between dexamethasone and placebo treatment

Figure 5

Cytokines in bronchoalveolar fluid 6 h after pulmonary instillation of 4 ng·kg⁻¹ lipopolysaccharide (LPS) and saline into the contralateral lung from volunteers who received dexamethasone intravenously (■) (n = 11) or placebo (○) (n = 13). LPS strongly increased tumour necrosis factor‐α (TNF‐α) (A), interleukin (IL)‐6 (B) and IL‐8 levels (C). Dexamethasone gave rise to a relatively small decrease in IL‐6 (−18%) from LPS‐challenged segments in comparison with placebo (B) and failed to reduce TNF‐α (A) or IL‐8 (C) levels. Symbols and lines represent means and 95% confidence intervals. **P < 0.01, *** P ≤ 0.001 vs. saline. ^## P < 0.01, ^### P ≤ 0.001 for comparison between dexamethasone and placebo treatment

Figure 6

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

Figure 7

Changes in C‐reactive protein (A), absolute counts of neutrophils (B), plasma concentrations of surfactant protein D (C) and lymphocytes (D) 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 increases in C‐reactive protein and absolute neutrophil counts and a reduction of absolute lymphocyte counts. Dexamethasone almost completely inhibited the rise in C‐reactive protein, and this was accompanied by the expected lymphocytopenia and neutrophilia. Plasma concentrations of surfactant protein D rose significantly after endotoxin instillation in the placebo group (at 6 h and 24 h vs. baseline) and, less pronounced, in the dexamethasone group (at 24 h vs. baseline). Symbols and lines represent means and 95% confidence intervals. *P < 0.05, **P < 0.01 vs. baseline. ^### P < 0.005 for comparison between dexamethasone and placebo treatment