Therapeutic ramifications of the interaction of complement, granulocytes, and platelets in the production of acute lung injury.
Evidence is reviewed that activation of complement through its ability to cause adhesion of granulocytes to the pulmonary endothelium (margination) and aggregation and embolization of these cells to the lung microvasculature is an important cause of pulmonary injury. Agents capable of diminishing such stimulated adhesiveness might be rational therapeutic adjuncts in vascular-damaging syndromes and are being investigated. To date, corticosteroids, such as methylprednisolone (in enormous doses), and certain nonsteroidal anti-inflammatory drugs, such as ibuprofen, have been shown to diminish granulocyte stickiness in vitro and diminish complement-mediated tissue damage in vivo. Moreover, platelets amplify complement/granulocyte-induced endothelial damage by releasing serotonin, which, in turn, potentiates granulocyte adhesion to endothelium. This potentiation is abrogated by the serotonin antagonists imiprimine and methysergide. Since these diverse agents inhibit granulocyte-adhesion phenomena by different mechanisms, they might predictably be synergistic in their beneficial effect. This prediction is validated for methylprednisolone and ibuprofen, for which we report a threefold synergism in preventing complement-mediated granulocyte aggregation in vitro. Preliminary studies indicate utility of this synergism in vivo as well, in that the degree of myocardial infarction [a complement-activating phenomenon) is diminished in coronary-ligated animals in which rather small doses of the two drugs administered together.
D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D003167:Complement Activation; D003182:Complement C5 / Q000502:physiology; D006098:Granulocytes / Q000502:physiology; D008833:Microcirculation / Q000648:ultrastructure; D011652:Pulmonary Circulation; D012128:Respiratory Distress Syndrome / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology*; D012756:Sheep
D000305:Adrenal Cortex Hormones; D003182:Complement C5