Attenuation of lung inflammation by adrenergic agonists in murine acute lung injury

Abstract

Background: Acute lung injury leading to a systemic inflammatory response greatly increases mortality in critically ill patients. Cardiovascular management of these patients frequently involves β-adrenergic agonists. These agents may alter the inflammatory response. Therefore, the authors tested the hypothesis that β-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 μg · kg-1 · min-1 dobutamine, 6 μg · kg-1 · min-1 dopexamine, or vehicle via intraperitoneal mini osmotic pumps, followed immediately by intratracheal instillation of approximately 2 μg/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, β-adrenergic agonists can significantly decrease proinflammatory cytokine expression, decrease induction of chemokine mRNA, and decrease the resultant neutrophil infiltrate in the lung.