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Alveolar Macrophage Apoptosis Contributes to Pneumococcal Clearance in a Resolving Model of Pulmonary Infection

David H. Dockrell, Helen M. Marriott, Lynne R. Prince, Victoria C. Ridger, Paul G. Ince, Paul G. Hellewell and Moira K. B. Whyte
J Immunol November 15, 2003, 171 (10) 5380-5388; DOI: https://doi.org/10.4049/jimmunol.171.10.5380
David H. Dockrell
Genomic Medicine and
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Helen M. Marriott
Genomic Medicine and
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Lynne R. Prince
Genomic Medicine and
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Victoria C. Ridger
Clinical Sciences North, University of Sheffield School of Medicine and Biomedical Sciences, Sheffield, United Kingdom
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Paul G. Ince
Genomic Medicine and
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Paul G. Hellewell
Clinical Sciences North, University of Sheffield School of Medicine and Biomedical Sciences, Sheffield, United Kingdom
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Moira K. B. Whyte
Genomic Medicine and
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  • FIGURE 1.
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    FIGURE 1.

    Characterization of microbiologic features of i.t. instillation of low and high inocula of pneumococci. A, Bacteria in lung homogenates 24 h after i.t. instillation of 104 CFU type 1 or 2 (low Spn 1, low Spn 2) or 107 CFU type 1 or 2 (high Spn 1, high Spn 2) pneumococci, low Spn 1 vs high Spn 1, p < 0.05 (∗); low Spn 2 vs high Spn 2, p < 0.01 (∗∗), Kruskal-Wallis with Dunn’s post test. Bacteria were undetectable in the lungs of 69% of mice infected with low Spn 1 compared with 25% infected with high Spn 1 (p = 0.026) and 57% of mice infected with low Spn 2 compared with 0% infected with high Spn 2 (p = 0.007, Fisher’s exact test). B, Bacteria in blood 24 h after infection, low Spn 1 vs high Spn 1, p < 0.05 (∗); low Spn 2 vs high Spn 2, p < 0.01 (∗∗), Kruskal-Wallis with Dunn’s post test. Ninety-two percent of the mice were abacteremic following infection with low Spn 1 compared with 20% following high Spn 1 (p = 0.008) and 57% of the mice following infection with low Spn 2 compared with 8% following high Spn 2 (p = 0.031, Fisher’s exact test). C, The percentage of mice with detectable bacteria in the lung 2–192 h after infection with low Spn 1 (n = 4–16) for each time point. D, Cumulative survival after instillation of low Spn 1 or mock infection (PBS; n = 8 in each group); low Spn 1 vs PBS (p = 0.134, log rank analysis).

  • FIGURE 2.
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    FIGURE 2.

    Characterization of inflammatory features in the lung of low- and high-dose pneumococcal infection. A, Absolute numbers of PMN (#PMN) in BAL 24 h after i.t. instillation of 104 CFU type 1 or 2 (low Spn 1, low Spn 2) or 107 CFU type 1 or 2 (high Spn 1, high Spn 2) pneumococci or mock infection (PBS, n = 9), mean + SEM. Low Spn 1 (n = 7) vs high Spn 1 (n = 10), p < 0.05 (∗); low Spn 2 (n = 7) vs high Spn 2 (n = 9), p < 0.05 (∗), Kruskal-Wallis with Dunn’s post test. B, Representative appearances of lung sections stained with H&E from mice 24 h after i.t. instillation of PBS (top left), low Spn 1 (top right), or high Spn 2 (bottom left), all ×10 objective. An enlargement of the marked area of inflammation from high Spn 2 is shown bottom right (×40 objective) to demonstrate PMN recruitment. C, #PMN in BAL 2–192 h after instillation of low Spn 1 (n = 3–9 for each time point, mean + SEM).

  • FIGURE 3.
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    FIGURE 3.

    AM depletion modifies the course of low-dose pneumococcal infection in the lung. A, Absolute number of AM (# AM) in BAL 72 h after intranasal instillation of PBS (PBSAM+), liposome-encapsulated clodronate (AM−), or liposome-encapsulated PBS (LipAM+), mean + SEM. #AM was reduced by 68% in AM− compared with PBSAM+. AM− (n = 19) vs PBSAM+ (n = 19), p < 0.001 (∗∗∗); AM− vs LipAM+ (n = 19), p < 0.001 (∗∗∗), Kruskal-Wallis with Dunn’s post test. B, Bacteria in lung homogenates 24 h after i.t. instillation of 104 CFU type 1 pneumococci (Spn) in PBSAM+, AM−, or LipAM+. Bacteria were undetectable in the lung of 81% of the PBSAM+ group, 9% of the AM− group, and 42% of the LipAM+ group. AM− vs PBSAM+, p < 0.001 (∗∗∗); AM− vs LipAM+, p < 0.05 (∗), Kruskal-Wallis with Dunn’s post test. C, Absolute numbers of PMN (# PMN) in BAL 24 h after i.t. instillation of low-dose Spn 1 (Spn) or PBS in PBSAM+, AM−, or LipAM+ (mean + SEM). AM−/Spn vs AM−/PBS, p < 0.01 (∗∗); AM−/Spn vs PBSAM+/Spn, p < 0.01 (∗∗); AM−/Spn vs LipAM+/Spn, p < 0.05 (∗), Kruskal-Wallis with Dunn’s post test. D, Cumulative survival after infection with low-dose Spn 1 in PBSAM+, AM−, or LipAM+ (n = 12 in each group). PBSAM+ and LipAM+ had identical 100% survival (AM+), which was not significantly different from survival in the AM− group (p = 0.135, log rank analysis).

  • FIGURE 4.
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    FIGURE 4.

    Infection with pneumococci is associated with increased numbers of apoptotic cells in the lung. A, Representative lung sections (×40 objective) stained by TUNEL and propidium iodide from mice 24 h after mock infection (PBS, left panel) or infection with 104 CFU type 1 pneumococci (low Spn, right panel); apoptotic TUNEL+ cells appear green. B, Quantification of the number of TUNEL+ cells in lung sections from low Spn 1 or PBS 24 h after infection. Mean + SEM TUNEL+ cells per lung field (×100 objective), low Spn 1 vs PBS, p < 0.05 (∗), Mann-Whitney U test; results are representative of three experiments. C, Cytospins obtained from the BAL 24 h after infection with low Spn 1 demonstrate apoptotic cells (left panel) and apoptotic bodies in macrophages (right panel). D, Total number of apoptotic events (apoptotic cells and bodies) in cytospins of BAL from mice 24 h after instillation of low-dose type 1 (low Spn 1, n = 9), high-dose type 1 (high Spn 1, n = 6) pneumococci or mock infection (PBS, n = 8), mean + SEM. PBS vs low Spn 1, p < 0.05 (∗); PBS vs high Spn 1, p < 0.001 (∗∗∗); low Spn 1 vs high Spn 1, p < 0.05 (∗), Kruskal-Wallis with Dunn’s post test.

  • FIGURE 5.
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    FIGURE 5.

    Increased numbers of apoptotic macrophages are found in the lung after infection with pneumococci. A, Representative appearance of lung sections stained with H&E from mice 24 h after i.t. instillation of 104 CFU type 1 pneumococci (low Spn 1) showing an apoptotic macrophage (arrow) and normal macrophages (arrowheads) viewed by differential interference contrast microscopy (×40 objective). B, Cytospin of BAL 24 h after low Spn 1 infection stained with F4/80 FITC and Ho33342. Macrophages show positive F4/80 staining (green cells), one of which demonstrates a fragmented nucleus by Ho33342 staining (arrow). C, Representative dot plots depicting percentage of macrophage apoptosis in BAL 24 h after i.t. instillation of PBS or infection with low-dose Spn. FL2 represents Annexin VPE and FL-4 TOP-RO-3 staining. Apoptotic cells were Annexin VPE+/TO-PRO-3− and the percentage of apoptotic cells are recorded in the upper left quadrant. Cells treated with EDTA during staining are shown in the right-hand panel as a negative control for annexin V binding. D, Percentage of macrophage apoptosis (Annexin VPE+/TO-PRO-3−, flow cytometry) in BAL 24 h after i.t. instillation of low Spn 1 (n = 11), 107 CFU type 1 pneumococci (high Spn 1, n = 10), or mock infection (PBS, n = 11). Mean + SEM, PBS vs low Spn 1, p < 0.05 (∗); PBS vs high Spn 1, p < 0.01 (∗∗), Kruskal-Wallis with Dunn’s post test.

  • FIGURE 6.
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    FIGURE 6.

    Inhibition of macrophage apoptosis is associated with increased bacteremia after low-dose pneumococcal infection. A, Percentage of apoptotic AM in BAL (AnnexinVPE+/TO-PRO-3−, flow cytometry) 24 h after infection with 104 CFU type 1 pneumococci (Spn) or mock infection (PBS) and treatment with zVADfmkfmk (zVADfmk) or vehicle control (2% DMSO, n = 7–9/group). Mean + SEM, Spn/DMSO vs Spn/zVADfmk, p < 0.05, Mann-Whitney U test (∗). B, Bacterial killing at 6 h by BMDM infected in vitro with type 1 pneumococci in the absence or presence of zVADfmk or zFAfmk (zFAfmk), zVADfmk vs zFAfmk, p < 0.05, Friedman test with Dunn’s post test comparison (∗). C, Bacteria in lung homogenates 24 h after i.t. instillation of Spn and i.p. 2% DMSO or zVADfmk. D, Bacteria in blood 24 h after infection and i.p. 2% DMSO or zVADfmk. One hundred percent of the Spn/DMSO group were abacteremic compared with 54% of the Spn/zVADfmk group, p = 0.046, Fisher’s exact test (∗). E, Cumulative survival after infection with Spn and i.p. DMSO or zVADfmk (n = 12 mice/group). There was no significant difference in survival, two deaths in the DMSO group compared with four in the zVADfmk group (p = 0.13, log rank analysis).

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The Journal of Immunology: 171 (10)
The Journal of Immunology
Vol. 171, Issue 10
15 Nov 2003
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Alveolar Macrophage Apoptosis Contributes to Pneumococcal Clearance in a Resolving Model of Pulmonary Infection
David H. Dockrell, Helen M. Marriott, Lynne R. Prince, Victoria C. Ridger, Paul G. Ince, Paul G. Hellewell, Moira K. B. Whyte
The Journal of Immunology November 15, 2003, 171 (10) 5380-5388; DOI: 10.4049/jimmunol.171.10.5380

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Alveolar Macrophage Apoptosis Contributes to Pneumococcal Clearance in a Resolving Model of Pulmonary Infection
David H. Dockrell, Helen M. Marriott, Lynne R. Prince, Victoria C. Ridger, Paul G. Ince, Paul G. Hellewell, Moira K. B. Whyte
The Journal of Immunology November 15, 2003, 171 (10) 5380-5388; DOI: 10.4049/jimmunol.171.10.5380
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