Activation of several cascade systems, e.g. coagulation, fibrinolysis, kallikreinkinin, complement and eicosanoid systems, has been implicated in the etiology of septic-lung microvascular injury. A chronic lung lymph fistula preparation in sheep (n = 9) was used to study coagulation, kallikrein-kinin and eicosanoids during Escherichia coli septicemia. Lung lymph flow and lymph composition indicated an increased lung microvascular permeability approximately 2 h after infusion of bacteria. Stable prothrombin and antithrombin III levels in lymph contradicted local activation of the coagulation cascade in the lung and systemic activation was not evident until 4 h after bacteria infusion. Lymph thromboxane B2 and 6-keto PGF1 alpha peaked early (1 h). Reduced lymph prekallikrein and kallikrein inhibitors indicated local activation of this system in the lung. Systemic activation of kallikrein could not be demonstrated. Thus, (1) changes in systemic blood may not adequately reflect local events and (2) studies of proteolytic enzymes and other inflammatory mediators in lung may contribute to clarifying the etiology of microvascular injury.