Search

To investigate the role of CD11c+cells in endotoxin-induced acute lung injury, wild-type or CD11c-diphtheria toxin receptor transgenic mice were treated with intraperitoneal diphtheria toxin (5 ng/g b.wt.) in the presence or absence of intratracheal lipopolysaccharide (51 μg). Lipopolysaccharide treatment resulted in 100% mortality in CD11c-depleted animals but not in control animals. Analysis of local lung tissue revealed no differences in acute lung injury severity; however, analysis of distal tissues revealed severe damage and necrosis to multiple organs (liver, spleen, and kidneys) in CD11c-diphtheria toxin receptor mice but not in wild-type mice. In addition, dramatic increases in systemic levels of liver enzymes (alanine aminotransferase, 657 U/L, aspartate aminotransferase, 1401 U/L), blood urea (53 mg/dl), and 8-iso-prostaglandin F2α, a marker of oxidative stress (350 pg/ml), were observed. These data demonstrate that CD11c+cells play a critical role in protecting the organs from systemic injury caused by a pulmonary endotoxin challenge.

ABSTRACTC57BL/6 mice develop an allergic bronchopulmonary mycosis following intratracheal inoculation of Cryptococcus neoformans24067. We determined that only low levels of tumor necrosis factor alpha (TNF-α) are produced in the lungs following infection. Thus, the objective of the present studies was to determine whether treatment with a TNF-α-expressing adenoviral vector (adenoviral vector with the murine TNF-α transgene under the control of the human cytomegalovirus promoter [AdTNFα]) could switch the type 2 (T2) T-cell response/T1 T-cell response balance toward the T1 T-cell response. AdTNFα induced an increase in TNF-α expression at days 3 and 7. At days 7 to 14, the number of cryptococcal lung CFU continued to increase in both untreated and control adenoviral vector (empty adenovirus type 5 backbone)-treated mice, but the number was ultimately 100-fold lower following AdTNFα treatment. AdTNFα markedly increased neutrophil and macrophage numbers, and pulmonary eosinophilia did not develop. CXCL1, CXCL2, and gamma interferon were also up-regulated, while eotaxin, interleukin-4 (IL-4), and IL-5 were down-regulated. AdTNFα treatment also increased the number of CD80+and CD40+cells and decreased the number of CD86+cells (CD11b+and CD11c+) in the lungs. Major histocompatibility complex class II levels on CD11b+cells were increased. Whole-lung expression of inducible nitric oxide synthase was increased, while YM2 expression and acidic mammalian chitinase expression were decreased. None of these effects were observed with the control (empty) adenoviral vector. Overall, these results support the hypothesis that early TNF-α expression promotes a shift in T-cell and macrophage polarization from T2/alternatively activated macrophages toward T1/classically activated macrophages, resulting in control of the fungal infection and prevention of the allergic response.