ALVEOLAR MACROPHAGE RELEASE OF TUMOR-NECROSIS-FACTOR DURING MURINE PNEUMOCYSTIS-CARINII PNEUMONIA

Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine pr oduced principally by mononuclear cells, is released in response to a variety of pulmonary pathogens. We hypothesized that release of TNF in the lung is a normal part of the host response to intratracheal chall enge with Pneumocystis carinii. To test this hypothesis, we measured T NF in bronchoalveolar lavage fluid (BALF) in normal and CD4-depleted m ice at various intervals in acute and chronically infected animals. To assess the cell of origin and the control of TNF release in the lung, we measured mRNA for TNF by a competitive polymerase chain reaction a nd assessed the capacity of adherence-enriched cells to produce TNF in vitro in response to lipopolysaccharide. Our data demonstrate that TN F peaks at 3 h in both control and CD4-depleted mice after acute chall enge with P carinii and this increase in TNF precedes the influx of in flammatory cells into the lung. TNF levels in BALF return to undetecta ble levels by day 3. In chronically infected animals, there is a 5-fol d increase in mRNA for TNF in adherent cells which is associated with an increased capacity to release TNF in vitro. These data suggest that TNF is a normal host response to P carinii infection; however, there is no difference in acute TNF release between control animals that cle ar their infection and CD4-depleted animals that develop chronic infec tion. TNF is upregulated in chronically infected animals, but CD4 depl etion results in the loss of additional host factors essential for res olution of this infection.