Am. J. Respir. Crit. Care Med., Volume 160, Number 5, November 1999, 1703-1710

Effect of Adrenoreceptors on Endotoxin-induced Cytokines and Lipid Peroxidation in Lung Explants

HAIBO ZHANG, YOUNG KYOON KIM, ANAND GOVINDARAJAN, ATSUSHI BABA, MATTHEW BINNIE, V. MARCO RANIERI, MINGYAO LIU, and ARTHUR S. SLUTSKY

Division of Respiratory Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital; Division of Thoracic Surgery, The Toronto Hospital; and Departments of Medicine and Surgery, University of Toronto, Toronto, Ontario, Canada

Lung tissue may be an important source of systemic inflammation associated with sepsis and the acute respiratory distress syndrome (ARDS). An ex vivo model of freshly explanted lung tissue in culture was developed to evaluate the ability of lipopolysaccharide (LPS) to directly stimulate lung tissues under conditions where indirect mechanisms such as recruitment of blood-derived inflammatory cells could not be implicated. Under control conditions, lung explants produced a high level of macrophage inflammatory protein-2 (MIP-2). Eight hours after LPS challenge, there were marked increases in the production of tumor necrosis factor- (TNF-) from 0.18 ± 0.04 to 4.13 ± 0.23 ng/ml/g tissue (p < 0.05), MIP-2 from 60.0 ± 7.4 to 165.6 ± 10.3 ng/ml/g tissue (p < 0.05), and tissue lipid peroxidation (malonaldehyde from 27.6 ± 2.5 to 48.4 ± 17.5 µM/g tissue; and 4-hydroxyalkenal from 34.0 ± 3.0 to 59.7 ± 18.8 µM/g tissue, both p < 0.05) from lung explants. Treatment with the -adrenoreceptor agonist isoproterenol (1 ng/ml) attenuated LPS-induced release of TNF- and lipid peroxidation in association with an increase in intracellular cAMP levels. The adenylate cyclase activator, forskolin, also inhibited LPS-induced changes in TNF- and lipid peroxidation. In conclusion, increasing intracellular levels of cAMP through -adrenoreceptor activation can attenuate the acute inflammatory response induced in the lung by LPS. LPS did not significantly impair the -adrenoreceptor reactivity in lung explants. Lung explants allow for the quantitative assessment of pulmonary inflammatory responses independent of influences from the circulation, and thus may be a useful ex vivo model to investigate cellular and molecular mechanisms of lung injury. Zhang H, Kim YK, Govindarajan A, Baba A, Binnie M, Ranieri VM, Liu M, Slutsky AS. Effect of adrenoreceptors on endotoxin-induced cytokines and lipid peroxidation in lung explants.

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