Role of B-adrenergic Receptors in Endotoxemia-induced Inflammation and Mortality

During endotoxemia, LPS exposure induces the production of inflammatory cytokines. Pro-inflammatory cytokines at systemic levels cause production of other inflammatory molecules and subsequent inflammation. LPS also induces the production of anti-inflammatory cytokines and molecules which help to resolve the inflammatory response. The sympathetic nervous system increases the production and secretion of catecholamines after exposure to LPS. Catecholamines have the ability to modulate inflammatory responses via the stimulation of adrenergic receptors. Pharmacological agonist stimulation of - adrenergic receptors increases survival, reduces morbidity and abates inflammatory responses as indicated by a decrease in LPS-induced production of pro-inflammatory cytokines. The effects of -adrenergic receptor activation by endogenous catecholamines upon LPS-induced mortality and inflammation have not been described. Therefore, mice with disrupted -1,-2, and -3 adrenergic receptors (-less) were used to determine how endogenous catecholamine stimulation of -adrenergic receptors modulates endotoxemia. Forty-eight hours post exposure to LPS, -less mice have 50% mortality while wildtype mice have 100urvival and -less mice exhibit more morbidity than wildtype mice at all observed time points. In addition -less mice have a greater inflammatory response as indicated by having twice as much systemic pro-inflammatory cytokine, TNF-, and half as much anti-inflammatory cytokine, IL-10, as the wildtype mice. These results indicate that -adrenergic receptors protect from LPS-induced mortality, morbidity, and inflammatory response. To determine the contribution of the stimulation of -adrenergic receptors expressed on ii radiosensitive and radio resistant cells in the protection from endotoxemia, bone marrow chimeras were generated using -less and wildtype mice. Although both radiosensitive and radioresistant cells contribute, the stimulation of - adrenergic receptors expressed on radioresistant cells plays the predominate role in protection from LPS-induced mortality, morbidity and production of TNF-. To determine the contribution of the stimulation of individual -adrenergic receptors in protection against endotoxemia, 1/2 -/- mice were examined in the LPS-induced endotoxemia paradigm. The 1/2 -/- mice had higher mortality and exhibited greater morbidity and a larger inflammatory response than wildtype after LPS exposure. In conclusion endogenous catecholamine stimulation of 1/2 adrenergic receptors on radioresistant cells is responsible for the majority of the protection from endotoxemia.

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