Attenuation of lung inflammation by adrenergic agonists in murine acute lung injury.
BACKGROUND
Acute lung injury leading to a systemic inflammatory response greatly increases mortality in critically ill patients. Cardiovascular management of these patients frequently involves beta-adrenergic agonists. These agents may alter the inflammatory response. Therefore, the authors tested the hypothesis that beta-adrenergic agonists alter the pulmonary inflammatory response during acute lung injury in mice.


METHODS
Five-week-old CD-1 mice received continuous infusions of 10 microg x kg(-1) x min(-1) dobutamine, 6 microg x kg(-1) x min(-1) dopexamine, or vehicle via intraperitoneal mini osmotic pumps, followed immediately by intratracheal instillation of approximately 2 microg/kg endotoxin (or phosphate-buffered saline control). Six hours later the mice were killed, and lung lavage was performed. Interleukin-6 and -10 concentrations in lung homogenates were measured using enzyme-linked immunosorbent assay. Interleukin-6 and macrophage inflammatory protein-2 mRNA was measured using reverse-transcription polymerase chain reaction.


RESULTS
Interleukin-6 protein and mRNA significantly increased after intratracheal endotoxin (P < 0.001), and the fraction of neutrophils in lung lavage fluid increased in endotoxin-treated (41 +/- 25%) versus control mice (2 +/- 4%, P < 0.05). Treatment of endotoxic mice with dobutamine significantly decreased interleukin-6 protein (P < 0.05) and mRNA (P < 0.05) expression. Dopexamine had similar but less pronounced effects. Dobutamine decreased interleukin-10 expression, whereas dopexamine did not. In endotoxemic mice, both dobutamine and dopexamine decreased induction of macrophage inflammatory protein-2 mRNA (P < 0.05) and reduced the fraction of neutrophils in lung lavage fluid (P < 0.05).


CONCLUSIONS
In endotoxin-induced acute lung injury, beta-adrenergic agonists can significantly decrease proinflammatory cytokine expression, decrease induction of chemokine mRNA, and decrease the resultant neutrophil infiltrate in the lung.
Dhingra
V K
VK
University of British Columbia Program of Critical Care Medicine and McDonald Research Laboratories, St. Paul's Hospital, Vancouver, Canada.
Uusaro
A
A
Holmes
C L
CL
Walley
K R
KR
D000208:Acute Disease; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D054426:Chemokine CXCL2; D004280:Dobutamine / Q000008:administration & dosage / Q000627:therapeutic use; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007275:Injections, Intravenous; D015850:Interleukin-6 / Q000096:biosynthesis; D055370:Lung Injury; D051379:Mice; D015846:Monokines / Q000096:biosynthesis; D020556:Neutrophil Infiltration / Q000502:physiology; D009929:Organ Size; D011014:Pneumonia / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000318:Adrenergic beta-Agonists; D054426:Chemokine CXCL2; D015850:Interleukin-6; D015846:Monokines; D012333:RNA, Messenger; D004280:Dobutamine