Effect of adrenoreceptors on endotoxin-induced cytokines and lipid peroxidation in lung explants

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-de rived 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-alpha: (TNF-alpha) 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 (malona ldehyde from 27.6 +/- 2.5 to 48.4 +/- 17.5 mu M/g tissue; and 4-hydroxyalke nal from 34.0 +/- 3.0 to 59.7 +/- 18.8 mu M/g tissue, both p < 0.05) from l ung explants. Treatment with the beta-adrenoreceptor agonist isoproterenol (1 ng/ml) attenuated LPS-induced release of TNF-alpha and lipid peroxidatio n in association with an increase in intracellular cAMP levels. The adenyla te cyclase activator, forskolin, also inhibited LPS-induced changes in TNF- alpha and lipid peroxidation. In conclusion, increasing intracellular level s of cAMP through beta-adrenoreceptor activation can attenuate the acute in flammatory response induced in the lung by LPS. LPS did not significantly i mpair the beta-adrenoreceptor reactivity in lung explants. Lung explants al low for the quantitative assessment of pulmonary inflammatory responses ind ependent of influences from the circulation, and thus may be a useful ex vi vo model to investigate cellular and molecular mechanisms of lung injury.