The crucial role of systemic responses in the innate (non-adaptive) host defense.

We suggest that successful defense against microbial invasion requires both local inflammation and systemic anti-inflammation. The key systemic responses involve the hypothalamic-pituitary-adrenocortical axis, the sympathetic-adrenomedullary axis, acute phase protein production, thermoregulation and alterations in leukocyte responsiveness to agonists such as bacterial endotoxin. These integrated responses raise blood and tissue concentrations of several anti-infective molecules, mobilize leukocytes into the circulation, and increase blood flow to injured or infected sites. They also neutralize cytokines, proteases and oxidants that enter the bloodstream from inflamed local sites and forestall endothelial activation in distant vessels. Together, these forces help concentrate activated phagocytes at injured or infected local sites while preventing potentially damaging inflammation in uninvolved tissues.