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Role of alveolar macrophages in Candida-induced acute lung injury
Y Kubota1, Y Iwasaki, H Harada
1Second Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan. ykubota@oak.ocn.ne.jp
Abstract:
Recent studies have shown that alveolar macrophages (AMs) not only act as phagocytes but also play a central role as potent secretory cells in various lung diseases, including pneumonia and acute respiratory distress syndrome. The behavior of AMs during disseminated candidiasis, however, is insufficiently elucidated. This study is the first to report disseminated candidiasis in AM-depleted mice and to analyze the effect of AMs on Candida-induced acute lung injury. While all AM-sufficient mice died by day 2 after infection with Candida albicans, no mortality was observed among AM-depleted mice. Unexpectedly, the CFU numbers of C. albicans isolated from the lungs of AM-depleted mice were significantly higher than those for C. albicans isolated from AM-sufficient mice. The lung wet-to-dry weight ratio was lower for AM-depleted mice than for AM-sufficient mice, although this difference was not significant. We found that bronchoalveolar lavage fluid (BALF) from AM-depleted mice in candidemia contained fewer neutrophils than BALF from AM-sufficient mice. In addition, myeloperoxidase activities in lung homogenates of AM-depleted mice were significantly lower than those in homogenates of AM-sufficient mice. A significant decrease in levels of murine macrophage inflammatory protein 2 (MIP-2), a potent chemoattractant for neutrophils, was noted in lung homogenates from AM-depleted mice compared with levels in homogenates from AM-sufficient mice. Immunohistochemical studies using anti-MIP-2 antibodies revealed that AMs were the cellular source of MIP-2 within the lung during candidemia. We observed that AM depletion decreased levels of AM-derived neutrophil chemoattractant, alleviated acute lung injury during candidemia, and prolonged the survival of mice in candidemia, even though clearance of C. albicans from the lungs was reduced.
Insights
Alveolar macrophages (AMs) protect against Candida-induced lung injury by recruiting neutrophils. Depleting AMs paradoxically improved survival in mice with disseminated candidiasis, despite increased fungal load.
Area of Science:
- Immunology
- Pulmonology
- Microbiology
Background:
- Alveolar macrophages (AMs) are crucial in lung immunity, acting as phagocytes and secretory cells in diseases like pneumonia.
- The role of AMs in disseminated candidiasis and their impact on Candida-induced acute lung injury remain unclear.
- This study investigates the function of AMs during Candida albicans infection in mice.
Purpose of the Study:
- To investigate the role of AMs in disseminated candidiasis.
- To analyze the effect of AM depletion on Candida-induced acute lung injury.
- To determine the impact of AMs on neutrophil recruitment and survival during candidemia.
Main Methods:
- Disseminated candidiasis was induced in AM-depleted and AM-sufficient mice.
- Fungal burden (CFU), lung wet-to-dry weight ratio, neutrophil infiltration (via BALF and MPO activity), and MIP-2 levels were assessed.
- Immunohistochemistry was used to identify the cellular source of MIP-2.
Main Results:
- AM-depleted mice showed no mortality compared to 100% mortality in AM-sufficient mice.
- AM depletion led to higher fungal burden but reduced lung injury markers (lower W/D ratio, fewer neutrophils, lower MPO activity).
- AMs were identified as the primary source of MIP-2, a neutrophil chemoattractant, in the lungs during candidemia.
Conclusions:
- AM depletion alleviates acute lung injury and prolongs survival in disseminated candidiasis, despite impaired fungal clearance.
- AMs contribute to lung injury by releasing MIP-2, which recruits neutrophils.
- Targeting AM-mediated neutrophil recruitment could be a therapeutic strategy for invasive fungal infections.