Accelerated Hematopoietic Recovery and Protective Effect of the Cyclooxygenase Inhibitor Indomethacin in Bacterial Infection of Neutropenic Mice

Abstract

The effects of indomethacin administration on Pseudomonas aeruginosa infection were investigated in neutropenic mice. Cyclophosphamide-treated mice received the drug at 2.5 to 12 mg/kg according to different regimens, to be challenged with a lethal intraperitoneal inoculum of P. aeruginosa 5 days after myelosuppression. A single exposure of the neutropenic mice to 7 mg/kg indomethacin during the first 6 to 48 hr after myelosuppression was found to optimally restore the animals' antibacterial resistance, both in terms of survival of infected mice and clearance of the organisms from the peritoneal cavity. However, when administered 24 hr before challenge, the same drug dosage had no effect in enhancing survival. Cure was associated with accelerated hematopoietic recovery, as revealed by peripheral blood leukocyte counts, spleen weight and cellularity, cellular response to infection in the peritoneal cavity, and enumeration in vitro of bone marrow and splenic granulocyte-macrophage colony-forming cells. Following indomethacin administration, a rapid burst in the levels of colony-stimulating activity was detected in the bloodstream, and exposure of splenic macrophages or marrow cells to indomethacin in vitro was found to result in enhanced expression of transcripts specific for granulocyte-macrophage colony-stimulating factor. These data support the notion that the administration of cyclooxygenase inhibitors may be useful in promoting hematopoiesis and reducing the risk of opportunistic infections in myelosuppressed hosts.