Effects of high-dose methotrexate on rat alveolar and inflammatory macrophage populations

Methotrexate (MTX) is used clinically in high doses to treat a variety of neoplastic diseases. Although it has been recognized that such aggressive chemotherapy can result in suppression of cellular host defense mechanisms, phagocytic cell function during MTX therapy remains poorly understood. The present study was designed to examine the effects of a single high dose of MTX on alveolar and inflammatory peritoneal cell populations in the rat. Male Sprague-Dawley rats were treated with a single intraperitoneal injection of MTX (25 or 50 mg/kg) and subsequent alterations in the composition of peripheral blood white cells (WBC), a peritoneal inflammatory exudate, and the resident alveolar macrophage (AM) were measured 1-4 days after MTX treatment. A severe depression in the polymorphonuclear leukocyte (PMNL) and monocyte populations in the peripheral blood was observed 72 and 96 h after either dose of MTX. Similarly, the total number of peritoneal exudate cells, collected 72 h after a caseinate inflammatory stimulus, was reduced by 50% after MTX treatment. When the cellular composition of the peritoneal exudate was examined, it was observed that macrophage and lymphocyte numbers were selectively depressed. In addition, the number of AM obtained by lung lavage was significantly reduced 72 and 96 h after MTX injection. Although both peritoneal and alveolar macrophage numbers were diminished, in vitro phagocytic activity was not impaired 72 h after MTX injection. These studies demonstrate that a single, clinically relevant dose of MTX, in addition to depressing PMNL and monocyte levels in the peripheral blood, can also impair the accumulation of macrophages at a site of tissue injury and the influx of macrophages into lung alveoli. These findings suggest that the capacity of the mononuclear phagocyte system to respond to an infectious or tumor cell challenge may be severely compromised during MTX treatment.