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Harvesting Murine Alveolar Macrophages and Evaluating Cellular Activation Induced by Polyanhydride Nanoparticles
Published on: June 8, 2012
Polyamine-mediated apoptosis of alveolar macrophages during Pneumocystis pneumonia
Mark E Lasbury1, Salim Merali, Pamela J Durant
1Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. melasbur@iupui.edu
Abstract:
The number of alveolar macrophages is decreased during Pneumocystis pneumonia (Pcp), partly because of activation of apoptosis in these cells. This apoptosis occurs in both rat and mouse models of Pcp. Bronchoalveolar lavage (BAL) fluids from Pneumocystis-infected animals were found to contain high levels of polyamines, including spermidine, N1-acetylspermine, and N1-acetylspermidine. These BAL fluids and exogenous polyamines were able to induce apoptosis in alveolar macrophages. Apoptosis of alveolar macrophages during infection, after incubation with BAL fluids from Pneumocystis-infected animals, or after incubation with polyamines was marked by an increase in intracellular reactive oxygen species, activation of caspases-3 and -9, DNA fragmentation, and leakage of mitochondrial cytochrome c into the cytoplasm. When polyamines were depleted from the BAL fluids of infected animals, the ability of these BAL fluids to induce apoptosis was lost. Interestingly, the apoptosis inducing activity of the polyamine-depleted BAL fluids was restored when polyamines were added back. The results of this study suggested that Pneumocystis infection results in accumulation of high levels of polyamines in the lung. These polyamines activate apoptosis of alveolar macrophages, perhaps because of the ROS that are produced during polyamine metabolism.
Insights
Pneumocystis pneumonia (Pcp) triggers lung polyamine accumulation, inducing alveolar macrophage apoptosis. This cell death is linked to reactive oxygen species (ROS) and caspase activation during Pcp infection.
Area of Science:
- Immunology
- Cell Biology
- Microbiology
Background:
- Pneumocystis pneumonia (Pcp) is characterized by a reduction in alveolar macrophages.
- Apoptosis (programmed cell death) contributes to this macrophage depletion in Pcp models.
- Bronchoalveolar lavage (BAL) fluids from infected animals show elevated polyamine levels.
Purpose of the Study:
- To investigate the role of polyamines in Pcp-induced alveolar macrophage apoptosis.
- To elucidate the mechanisms by which polyamines induce apoptosis in these cells.
Main Methods:
- Analysis of BAL fluids from Pcp-infected rat and mouse models for polyamine content.
- Incubation of alveolar macrophages with BAL fluids and exogenous polyamines.
- Assessment of apoptosis markers including reactive oxygen species (ROS), caspase activation (caspase-3, -9), DNA fragmentation, and cytochrome c release.
- Experimental depletion and repletion of polyamines in BAL fluids.
Main Results:
- BAL fluids from Pcp-infected animals contained high levels of spermidine, N1-acetylspermine, and N1-acetylspermidine.
- Both BAL fluids and exogenous polyamines induced apoptosis in alveolar macrophages.
- Polyamines mediated apoptosis through increased ROS, caspase activation, DNA fragmentation, and mitochondrial cytochrome c release.
- Depletion of polyamines from BAL fluids abolished their apoptosis-inducing capacity, which was restored upon polyamine readdition.
Conclusions:
- Pneumocystis infection leads to increased pulmonary polyamine levels.
- These elevated polyamines are key mediators of alveolar macrophage apoptosis during Pcp.
- Polyamines likely induce apoptosis via ROS production and subsequent activation of intrinsic apoptotic pathways.
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