Studies were performed to define the accumulation of cytokines and other mediators of inflammation in experimental models of inflammation in normal human subjects and in patients with abnormalities of host defenses or inflammation. Skin blisters created by suction and heat were used to study local inflammation in the skin. This blister system has been used by us to characterize the accumulation of inflammatory mediators. Studies of skin blisters in patients with abnormal inflammatory responses revealed dramatic increases in TNF-alpha in patients with acute vasculitis in association with Wegeners granulomatosis, in patients with systemic mastocytosis, and in the syndrome of hyperimmunoglobulin E and recurrent infections (Job's syndrome). Increases in TNF-alpha correlated well with disease activity suggesting that targeting drug development for modulation of this cytokine will have specific merit in these disease states. Normal blister exudate neutrophils synthesize large amounts of IL-8, compared with control peripheral blood neutrophils. Studies of normals and patients with excessive inflammation revealed a tight linear relationship between the level of IL-8 and the number of inflammatory neutrophils in the exudate. Exudate neutrophils synthesize IL-8 which is stored in a compartment different from specific or azurophil granules, but is co-eluted with an alkaline phosphatase rich plasma membrane fraction. Exposure of blood neutrophils to the calcium ionophore A23187 mimicked exudation and increased neutrophil IL-8 concentration 200-fold.
