CD47 deficiency protects mice from lipopolysaccharide-induced acute lung injury and Escherichia coli pneumonia - PubMed (original) (raw)

CD47 deficiency protects mice from lipopolysaccharide-induced acute lung injury and Escherichia coli pneumonia

Xiao Su et al. J Immunol. 2008.

Abstract

CD47 modulates neutrophil transmigration toward the sites of infection or injury. Mice lacking CD47 are susceptible to Escherichia coli (E. coli) peritonitis. However, less is known concerning the role of CD47 in the development of acute lung inflammation and injury. In this study, we show that mice lacking CD47 are protected from LPS-induced acute lung injury and E. coli pneumonia with a significant reduction in pulmonary edema, lung vascular permeability, and bacteremia. Reconstitution of CD47(+/-) mice with CD47(-/-) neutrophils significantly reduced lung edema and neutrophil infiltration, thus demonstrating that CD47(+) neutrophils are required for the development of lung injury from E. coli pneumonia. Importantly, CD47-deficient mice with E. coli pneumonia had an improved survival rate. Taken together, deficiency of CD47 protects mice from LPS-induced acute lung injury and E. coli pneumonia. Targeting CD47 may be a novel pathway for treatment of acute lung injury.

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Conflict of interest statement

Disclosures

The authors have no financial conflict of interest.

Figures

FIGURE 1

FIGURE 1

Lack of CD47 affected LPS-induced acute lung injury at 4 and 24 h. A and B, Excess lung water and lung vascular permeability were reduced in the CD47 knockout mice at 24 h. *, p < 0.05 vs CD47−/−; #, p < 0.05 vs baseline. C and D, Less hemoconcentration in the CD47-deficient mice at 4 and 24 h. *, p < 0.05 or **, p < 0.01 vs CD47−/−. E and F, Plasma MIP-2 level was reduced and plasma IL-12 was elevated at 24 h. *, p < 0.05; #, p < 0.05 vs baseline. n = 3 for baseline; n = 6–9 for the other group. Data were pooled from three experiments. Data are mean ± SD.

FIGURE 2

FIGURE 2

Deficiency of CD47 reduced neutrophil count in the blood and BAL in the LPS-induced acute lung injury at 4 and 24 h. A, Leukocyte in the blood; B, Neutrophils in the blood; C, Leukocyte in the BAL; D, Neutrophils in the BAL. *, p < 0.05 vs CD47−/−; #, p < 0.05 vs baseline. Lack of CD47 decreased protein concentration in the BAL, decreased BAL MIP-2 and TNF-α at 4 h, but did not affect the cytokine production in the BAL at 24 h in LPS-induced acute lung injury. E, Protein concentration in the BAL. F–H, MIP-2, TNF-α, and IL-12 in the BAL. *, p < 0.05 vs CD47−/−; #, p < 0.05 vs baseline. n = 3 for baseline; n = 4–5 for the other group. Data were pooled from four experiments. Data are mean ± SD.

FIGURE 3

FIGURE 3

Deficiency of CD47 reduced lung injury in the E. coli pneumonia experiments at 4 h. A and B, Excess lung water and lung vascular permeability were reduced at 4 h. C and D, Hemoconcentration was attenuated in the CD47 deficient group. E–G, Lack of CD47 resulted in lower protein concentration, neutrophil counts, and MIP-2 levels in the BAL at 4 h. *, p < 0.05 or **, p < 0.01 vs CD47−/−; #, p < 0.05 vs baseline. n = 3 for baseline; n = 5–6 for the other group. Data were pooled from three experiments. Data are mean ± SD.

FIGURE 4

FIGURE 4

The number of neutrophils and E. coli colonies in the lung and blood stream in the E. coli pneumonia experiments at 4 h. A and B. Leukocyte and neutrophil counts in the blood with or without E. coli pneumonia. *, p < 0.05 vs CD47−/−; #, p < 0.05 vs baseline. Data are mean ± SD. C and D, E. coli colonies in the lung homogenate (C) and blood (D) 4 h after initiation of infection. *, p < 0.05 for CD47−/− vs CD47+/− mice with pneumonia. n = 3 for baseline; n = 7–9 for the other group. Data were pooled from four experiments. Data are mean ± SD.

FIGURE 5

FIGURE 5

Deficiency of CD47-reduced lung injury in the E. coli pneumonia experiments at 48 h. A and B, Excess lung water and neutrophil counts were reduced at 48 h. C and D, Hemoconcentration was attenuated in the CD47-deficient group at 48 h. E–H, Lack of CD47 resulted in lower MPO activity in the lung homogenate, but did not affect MIP-2 and IL-12 levels in lung homogenate, and IL-12 in the plasma at 48 h. *, p < 0.05 for CD47+/− vs CD47−/−; #, p < 0.05 vs baseline. n = 3 for baseline; n = 4–6 for the other group. Data were pooled from three experiments. Data are mean ± SD.

FIGURE 6

FIGURE 6

Neutrophil reconstitution experiments to demonstrate that CD47 expression on the neutrophils contributes to greater lung inflammation and injury in the E. coli pneumonia. A and B, Reconstitution of CD47+/− mice with CD47−/− neutrophils reduced excess lung water and lung vascular permeability compared with CD47+/− mice with CD47+/− neutrophils. Reconstitution of CD47−/− mice with CD47+/− neutrophils increased excess lung water and lung vascular permeability compared with CD47−/− mice with CD47−/− neutrophils. C, Reconstitution of CD47+/− mice with CD47−/− neutrophils significantly decreased lung homogenate MPO, an index of neutrophil infiltration. D, Reduced plasma MIP-2 production in the CD47+/− mice reconstituted with CD47−/− neutrophils. E, Reconstitution of CD47+/− mice with CD47−/− neutrophils significantly decreased lung homogenate MPO, an index of neutrophil infiltration after flushing away sequestered neutrophils in the pulmonary circulation. n = 3 for baseline; n = 4–6 for the other group. Data were pooled from six experiments. Data are mean ± SD.

FIGURE 7

FIGURE 7

Lack of CD47 improved survival at 72 h after mice were intratracheally challenged with 5 × 106 CFU live E. coli. *, p < 0.05 using a log-rank test; n = 17 in the CD47+/− group; n = 14 in the CD47−/− group. Data were pooled from two experiments.

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