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Alveolar macrophage release of tumor necrosis factor during murine Pneumocystis carinii pneumonia
Abstract:
Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine produced 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 challenge with Pneumocystis carinii. To test this hypothesis, we measured TNF in bronchoalveolar lavage fluid (BALF) in normal and CD4-depleted mice 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 and assessed the capacity of adherence-enriched cells to produce TNF in vitro in response to lipopolysaccharide. Our data demonstrate that TNF peaks at 3 h in both control and CD4-depleted mice after acute challenge with P. carinii and this increase in TNF precedes the influx of inflammatory cells into the lung. TNF levels in BALF return to undetectable levels by day 3. In chronically infected animals, there is a 5-fold 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 clear their infection and CD4-depleted animals that develop chronic infection. TNF is upregulated in chronically infected animals, but CD4 depletion results in the loss of additional host factors essential for resolution of this infection.
Insights
Tumor necrosis factor-alpha (TNF-alpha) is a normal host response to Pneumocystis carinii lung infection. While acute TNF-alpha release is similar in normal and CD4-depleted mice, chronic infection shows increased TNF-alpha, suggesting its role in host defense.
Area of Science:
- Immunology
- Pulmonology
- Microbiology
Background:
- Tumor necrosis factor-alpha (TNF-alpha) is a key proinflammatory cytokine involved in host defense against pathogens.
- Pulmonary infections, including Pneumocystis carinii pneumonia (PCP), trigger cytokine release in the lung.
- The role of TNF-alpha in the host response to P. carinii remains incompletely understood.
Purpose of the Study:
- To investigate the hypothesis that TNF-alpha release is a normal host response to intratracheal challenge with P. carinii.
- To characterize the kinetics and cellular origin of TNF-alpha production in the lung during P. carinii infection.
- To compare TNF-alpha responses in normal and CD4-depleted mice, which exhibit different infection outcomes.
Main Methods:
- Measurement of TNF-alpha levels in bronchoalveolar lavage fluid (BALF) from normal and CD4-depleted mice at various time points post-infection.
- Quantification of TNF-alpha mRNA in lung cells using competitive polymerase chain reaction.
- Assessment of TNF-alpha production by adherence-enriched cells in vitro stimulated with lipopolysaccharide.
Main Results:
- TNF-alpha levels peaked at 3 hours after acute P. carinii challenge in both normal and CD4-depleted mice, preceding inflammatory cell influx.
- TNF-alpha levels returned to baseline by day 3 in acutely infected animals.
- Chronically infected animals showed a 5-fold increase in TNF-alpha mRNA in adherent cells with enhanced in vitro production capacity.
- No significant difference in acute TNF-alpha release was observed between mice that cleared the infection and those that developed chronic infection due to CD4 depletion.
Conclusions:
- TNF-alpha represents a normal and early host response to P. carinii infection in the lung.
- While TNF-alpha is upregulated during chronic P. carinii infection, CD4 depletion impairs the resolution of infection by affecting other essential host factors.
- The data suggest a complex interplay between TNF-alpha, CD4+ T cells, and pathogen clearance in P. carinii infections.