The authors measured the peripheral blood pro-inflammatory cytokine responses (tumor necrosis factor-alpha [TNF-alpha] and interleukin-6 [IL-6]) and related end organ responses ti intraperitoneal zymosan-saline suspension over 5 days in CD-1 mice. Other indicators of local and systemic inflammation included wet:dry weight ratios of lung, liver, kidneys, spleen, and bowel; peripheral blood hematocrit, white blood cell count, and platelet count; lung myeloperoxidase activity; lung protein leak; and bacterial translocation to liver, spleen, and mesenteric lymph nodes. The initial event in responses to zymosan A injection was a sharp rise in the peripheral blood TNF-alpha level, which crested within 1 h of injection. This response was followed by a peripheral blood leukocytosis also within 1 h, and a peak lung myeloperoxidase activity within 1-2 h of injection. The maximum lung permeability index occurred 8 h after injection (zymosan, .398 +/- .019 [n = 10]; saline vehicle, .266 +/- .007 [n = 10], p < .001) followed by the maximum lung wet:dry weight ratio, which occurred 18 h after injection. The peak wet:dry weight ratios for the other organs occurred between 12 and 24 h after injection as well. Peripheral blood IL-6 maxima followed TNF-a maxima after lags of several hours. The release of pre-formed TNF-a is likely the most proximal event following injection of zymosan, and may set in motion the processes that result in end-organ injury and secondary multiple organ dysfunction, particularly activation of leukocytes. The precise roles of TNF-alpha and IL-6 in the pathogenesis of end-organ injury, however, are not addressed.