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Generation of a Chronic Obstructive Pulmonary Disease Model in Mice by Repeated Ozone Exposure
Published on: August 25, 2017
Chronic exposure to diesel particles worsened emphysema and increased M2-like phenotype macrophages in a PPE-induced
Alyne Riani Moreira1, Thamyres Barros Pereira de Castro2,3, Júlia Benini Kohler1
1Department of Clinical Medicine (LIM 20), School of Medicine, University of Sao Paulo, Sao Paulo, Brazil.
Abstract:
Chronic exposure to ambient levels of air pollution induces respiratory illness exacerbation by increasing inflammatory responses and apoptotic cells in pulmonary tissues. The ineffective phagocytosis of these apoptotic cells (efferocytosis) by macrophages has been considered an important factor in these pathological mechanisms. Depending on microenvironmental stimuli, macrophages can assume different phenotypes with different functional actions. M1 macrophages are recognized by their proinflammatory activity, whereas M2 macrophages play pivotal roles in responding to microorganisms and in efferocytosis to avoid the progression of inflammatory conditions. To verify how exposure to air pollutants interferes with macrophage polarization in emphysema development, we evaluated the different macrophage phenotypes in a PPE- induced model with the exposure to diesel exhaust particles. C57BL/6 mice received intranasal instillation of porcine pancreatic elastase (PPE) to induce emphysema, and the control groups received saline. Both groups were exposed to diesel exhaust particles or filtered air for 60 days according to the groups. We observed that both the diesel and PPE groups had an increase in alveolar enlargement, collagen and elastic fibers in the parenchyma and the number of macrophages, lymphocytes and epithelial cells in BAL, and these responses were exacerbated in animals that received PPE instillation prior to exposure to diesel exhaust particles. The same response pattern was found inCaspase-3 positive cell analysis, attesting to an increase in cell apoptosis, which is in agreement with the increase in M2 phenotype markers, measured by RT-PCR and flow cytometry analysis. We did not verify differences among the groups for the M1 phenotype. In conclusion, our results showed that both chronic exposure to diesel exhaust particles and PPE instillation induced inflammatory conditions, cell apoptosis and emphysema development, as well as an increase in M2 phenotype macrophages, and the combination of these two factors exacerbated these responses. The predominance of the M2-like phenotype likely occurred due to the increased demand for efferocytosis. However, M2 macrophage activity was ineffective, resulting in emphysema development and worsening of symptoms.
Insights
Chronic air pollution and lung injury increase M2 macrophages, worsening emphysema. Ineffective efferocytosis by these macrophages contributes to disease progression, highlighting a key mechanism in respiratory illness.
Area of Science:
- Pulmonary immunology
- Environmental toxicology
- Cell biology
Background:
- Chronic air pollution exacerbates respiratory illnesses by increasing inflammation and apoptosis in lung tissues.
- Ineffective efferocytosis (clearance of apoptotic cells) by macrophages is a key factor in these pathological processes.
- Macrophages exhibit diverse phenotypes (M1 proinflammatory, M2 efferocytosis/anti-inflammatory) influenced by microenvironmental cues.
Purpose of the Study:
- To investigate how air pollutant exposure affects macrophage polarization during emphysema development.
- To evaluate macrophage phenotypes in a porcine pancreatic elastase (PPE)-induced emphysema model with diesel exhaust particle (DEP) exposure.
Main Methods:
- C57BL/6 mice were induced with emphysema using intranasal PPE or saline.
- Groups were exposed to diesel exhaust particles (DEP) or filtered air for 60 days.
- Macrophage phenotypes (M1/M2), apoptosis (Caspase-3), and lung tissue/BAL cell counts were analyzed via RT-PCR, flow cytometry, and histology.
Main Results:
- Both DEP exposure and PPE instillation increased alveolar enlargement, fibrosis, and inflammatory cell counts in bronchoalveolar lavage (BAL).
- Combined PPE and DEP exposure exacerbated these responses, along with increased apoptosis (Caspase-3 positive cells).
- An increase in M2 macrophage phenotype markers was observed, while M1 markers showed no significant difference.
Conclusions:
- Chronic DEP exposure and PPE instillation induce inflammation, apoptosis, and emphysema, with combined exposure worsening these effects.
- The study observed a shift towards M2 macrophages, likely due to increased efferocytosis demand.
- Despite the M2 predominance, efferocytosis remained ineffective, leading to emphysema progression and symptom exacerbation.
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