Cytokines, macrophages, and leukocytes in brain ischemia

Monocytes, TNF-α, and IL-1 in stroke initiation. We have been interested in the potential relationship between the localized Shwartzman phenomenon and acute stroke. This phenomenon was initially described in 1928 during efforts to develop a vaccine for typhoid fever.1 The essence of this phenomenon is that vessel segments exposed to interleukin-1 (IL-1) and tumor necrosis factor alpha(TNF-α)2 become activated and such that the occurrence of an additional step causes local thrombosis or vessel damage with hemorrhage. the step involves activation of the coagulation system or inflammation with activation of complement.3 If a mechanism similar to the Shwartzman phenomenon were to operate in the genesis of stroke, a vessel segment periodically exposed to effective levels of the cytokines TNF-α and IL-1 would be brought into a state in which its endothelium would be activated,4,5 and the vessel segment could be considered prepared and ready to be triggered for a period of hours. If, during this critical interval, the coagulation or complement system should become activated (the provocative stimulus), the prepared vessel segment could undergo thrombosis or a sequence of events leading to hemorrhage. Our first series of experiments addressed the issue of whether or not various risk factors for stroke effectively prepared the brainstem vasculature of rats for a localized Shwartzman reaction.6 Lipopolysaccharide (LPS) was injected intracisternally or intravenously into rats, with and without identifiable stroke risk factors, and the incidence of brainstem stroke was quantified. Rats with hypertension, hypertension plus genetic stroke proneness, advanced age, and streptozotocin-induced diabetes reacted with a significantly higher incidence of strokes than rats devoid of such stroke risk factors. For further analysis, we generated a working hypothesis that hypertension creates a state in which there is an increased probability for an interaction between monocytes or macrophages and …