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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.


Schematic of the experimental design. DEX, dexamethasone; LPS, lipopolysaccharide
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bcp12857-fig-0001: Schematic of the experimental design. DEX, dexamethasone; LPS, lipopolysaccharide

Mentions: The ethics committee of the Medical University of Vienna approved the study protocol and the trial was conducted in accordance with the Declaration of Helsinki and registered at ClinicalTrials.gov as NCT01714427. Twenty‐four healthy nonsmokers gave written informed consent before study entry. Medical screening included medical history, physical examination, laboratory parameters, virology, chest radiography, spirometry and standard drug screening, and was unremarkable in all study participants. The trial was randomized, double blind and placebo controlled. Subjects (nine women, 15 men) were randomized into two groups – dexamethasone or placebo infusion – and additionally to instillation of 4 ng·kg−1 lipopolysaccharide (LPS) or saline into the left or right lungs. Volunteers received two separate doses of dexamethasone [40 mg in 100 ml saline (Merck, Vienna, Austria)] or placebo (physiological saline) intravenously on the first trial day 13 h prior to, and on the second trial day 1 h prior to endotoxin instillation (Figure 1). Dexamethasone is a commonly used synthetic glucocorticoid hormone with a 30‐fold higher anti‐inflammatory activity than hydrocortisone and no affinity for mineralocorticoid receptors 12. According to the summary of product characteristics, doses of 80–160 mg·day−1 are used for the treatment of noncardiogenic pulmonary oedema 13. Thus, given that its half‐life is168–324 minutes, two separate doses of 40 mg b.i.d. were deemed sufficient to reduce the lung inflammation response and putative pulmonary fluid accumulation. Endotoxin was prepared from national reference endotoxin (Escherichia coli O:113, CC‐RE‐Lot 3, NIH) by reconstitution with saline to 4 ng·kg−1 body weight in a total volume of 2 ml. A bilateral BAL was performed 6 h after endotoxin instillation. Volumes of 140 ml prewarmed saline (aliquots of 20–40 ml) were instilled into each lung site. The retrieved BAL volumes were comparable between LPS‐challenged and saline‐exposed segments [placebo: LPS 45 (35–50) ml vs. saline 54 (39–59) ml; dexamethasone: LPS 49 (43–64) ml vs. saline 53 (45–61) ml]. Vital signs (heart rate, continuous oxygen saturation and blood pressure) were monitored before the infusion of dexamethasone or placebo (13 h and 1 h before endotoxin instillation), at 20 min intervals after endotoxin instillation and for a minimum of 3 h after BAL; thereafter, subjects were allowed to leave the ward and then return the next morning for the 24‐h blood drawing, spirometry, vital sign measurements and physical examination. Blood samples were obtained at the screening visit, before drug administration (13 h and 1 h before endotoxin instillation), and 6 h and 24 h after endotoxin instillation.


Dissociation between systemic and pulmonary anti ‐ inflammatory effects of dexamethasone in humans
Schematic of the experimental design. DEX, dexamethasone; LPS, lipopolysaccharide
© Copyright Policy - creativeCommonsBy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4834593&req=5

bcp12857-fig-0001: Schematic of the experimental design. DEX, dexamethasone; LPS, lipopolysaccharide
Mentions: The ethics committee of the Medical University of Vienna approved the study protocol and the trial was conducted in accordance with the Declaration of Helsinki and registered at ClinicalTrials.gov as NCT01714427. Twenty‐four healthy nonsmokers gave written informed consent before study entry. Medical screening included medical history, physical examination, laboratory parameters, virology, chest radiography, spirometry and standard drug screening, and was unremarkable in all study participants. The trial was randomized, double blind and placebo controlled. Subjects (nine women, 15 men) were randomized into two groups – dexamethasone or placebo infusion – and additionally to instillation of 4 ng·kg−1 lipopolysaccharide (LPS) or saline into the left or right lungs. Volunteers received two separate doses of dexamethasone [40 mg in 100 ml saline (Merck, Vienna, Austria)] or placebo (physiological saline) intravenously on the first trial day 13 h prior to, and on the second trial day 1 h prior to endotoxin instillation (Figure 1). Dexamethasone is a commonly used synthetic glucocorticoid hormone with a 30‐fold higher anti‐inflammatory activity than hydrocortisone and no affinity for mineralocorticoid receptors 12. According to the summary of product characteristics, doses of 80–160 mg·day−1 are used for the treatment of noncardiogenic pulmonary oedema 13. Thus, given that its half‐life is168–324 minutes, two separate doses of 40 mg b.i.d. were deemed sufficient to reduce the lung inflammation response and putative pulmonary fluid accumulation. Endotoxin was prepared from national reference endotoxin (Escherichia coli O:113, CC‐RE‐Lot 3, NIH) by reconstitution with saline to 4 ng·kg−1 body weight in a total volume of 2 ml. A bilateral BAL was performed 6 h after endotoxin instillation. Volumes of 140 ml prewarmed saline (aliquots of 20–40 ml) were instilled into each lung site. The retrieved BAL volumes were comparable between LPS‐challenged and saline‐exposed segments [placebo: LPS 45 (35–50) ml vs. saline 54 (39–59) ml; dexamethasone: LPS 49 (43–64) ml vs. saline 53 (45–61) ml]. Vital signs (heart rate, continuous oxygen saturation and blood pressure) were monitored before the infusion of dexamethasone or placebo (13 h and 1 h before endotoxin instillation), at 20 min intervals after endotoxin instillation and for a minimum of 3 h after BAL; thereafter, subjects were allowed to leave the ward and then return the next morning for the 24‐h blood drawing, spirometry, vital sign measurements and physical examination. Blood samples were obtained at the screening visit, before drug administration (13 h and 1 h before endotoxin instillation), and 6 h and 24 h after endotoxin instillation.

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.