Acute phase protein α1-antitrypsin reduces the bacterial burden in mice by selective modulation of innate cell responses

Abstract

Background: Severe bacterial infection can cause sepsis, multiple organ dysfunction syndrome (MODS), and death. Human α1-antitrypsin (hAAT) is an antiinflammatory, immune-modulating, and tissue-protective circulating serine-protease inhibitor, with levels that increase during acute-phase responses. It is currently being evaluated as a therapeutic agent for individuals with diabetes and graft-versus-host disease. However, the concern of opportunistic bacterial infections has yet to be addressed. Therefore, we investigated host immune cell responses during acute bacterial infections under conditions of elevated hAAT levels.

Methods: Peritonitis and sepsis models were created using wild-type mice and hAAT-transgenic mice. Bacterial loads, MODS, leukopenia, neutrophil infiltration, immune cell activation, circulating cytokine levels, and survival rates were then assessed.

Results: hAAT significantly reduced infection-induced leukopenia and liver, pancreas, and lung injury, and it significantly improved 24-hour survival rates. Unexpectedly, bacterial load was reduced. Levels of early proinflammatory mediators and neutrophil influx were increased by hAAT soon after infection but not during sterile peritonitis.

Conclusions: hAAT reduces the bacterial burden after infection. Since hAAT does not block bacterial growth in culture, its effects might rely on host immune cell modulation. These outcomes suggest that prolonged hAAT treatment in patients without hAAT deficiency is safe. Additionally, hAAT treatment may be considered a preemptive therapeutic measure for individuals who are at risk for bacterial infections.

Keywords: cell infiltration; cytokines; inflammation; innate immunity; macrophages; neutrophils; sepsis.