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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.


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
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bcp12857-fig-0003: 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

Mentions: In endotoxin‐challenged segments, leukocyte counts increased by 80% (P = 0.028; Figure 3A), total protein by 50% (P = 0.011; Figure 4A) and IgG concentrations 2.4‐fold (P < 0.01; Figure 4B) in BAL fluid compared with BAL fluid from saline‐instilled segments. The increase in the leukocyte count was due to a tenfold rise in the neutrophil count (P < 0.001; Figure 3B), whereas macrophage (Figure 3C) and lymphocyte (data not shown) counts did not change significantly. Moreover, endotoxin increased BAL fluid TNF‐α levels 100‐fold, to 52 (22–129) pg·ml−1 (P < 0.001; Figure 5A). Endotoxin increased IL‐6 levels 13‐fold (P < 0.001; Figure 5B) and IL‐8 levels fivefold (P < 0.005; Figure 5C) in BAL fluid, compared with BAL fluid after saline instillation (Table 2).


Dissociation between systemic and pulmonary anti ‐ inflammatory effects of dexamethasone in humans
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
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bcp12857-fig-0003: 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
Mentions: In endotoxin‐challenged segments, leukocyte counts increased by 80% (P = 0.028; Figure 3A), total protein by 50% (P = 0.011; Figure 4A) and IgG concentrations 2.4‐fold (P < 0.01; Figure 4B) in BAL fluid compared with BAL fluid from saline‐instilled segments. The increase in the leukocyte count was due to a tenfold rise in the neutrophil count (P < 0.001; Figure 3B), whereas macrophage (Figure 3C) and lymphocyte (data not shown) counts did not change significantly. Moreover, endotoxin increased BAL fluid TNF‐α levels 100‐fold, to 52 (22–129) pg·ml−1 (P < 0.001; Figure 5A). Endotoxin increased IL‐6 levels 13‐fold (P < 0.001; Figure 5B) and IL‐8 levels fivefold (P < 0.005; Figure 5C) in BAL fluid, compared with BAL fluid after saline instillation (Table 2).

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.