Granulocytes as Mediators in Pulmonary Edema

The precise role of white blood cells (WBC) in lung injury has long been a matter of great interest. Granulocytes were first suspected of involvement when microscopic tissue sections from patients dying with "shock lung" revealed inordinate numbers of granulocytes. These cells were found to be plugging capillaries and occasionally passing transmurally into lung interstitium. However, no cause and effect realtionship could be established; that is, it was not clear whether the granulocytes were responsible for the lung damage or whether there were chemataxins produced by the injured lung causing granulocyte sequestration. In 1968, Kaplow and Goffinet discovered the phenomenon of sudden but transient neutropenia which occurs with cellophane membrane hemodialysis. Further investigation of this process has demonstrated neutrophils deposited in the pulmonary microvasculature during the neutropenia. Complement activation is thought to be involved, and indeed fragments of the C5a portion of complement cause in vitro aggregation of granulocytes. Infusion of Gram-negative bacteria, complement, endotoxin, glass beads, fat emulsion, and many other materials into sheep prepared with chronic lung lymph fistulas has produced hypoxemia, pulmonary hypertension, increases in protein-rich lung lymph, leukopenia, and pulmonary leukostasis. Hydroxyurea-induced depletion of WBCs, especially granulocytes, markedly attenuates the pulmonary lymph flow response without affecting the early pulmonary hypertension. From this data, it has been concluded that activated granulocytes are required for the increase in microvascular permeability induced by endotoxin. The mechanisms by which activated granulocytes produce lung injury has recently been the subject of intensive investigation. The phenomenon of leukocyte activation in the presence of bacteria was discovered in 1933 by Baldri( [