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Organizing empyema induced in mice by Streptococcus pneumoniae: effects of plasminogen activator inhibitor-1
Torry A Tucker1, Ann Jeffers2, Jake Boren2
1The Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, 11937 US HWY 271, Biomedical Research Building, Lab C-5, Tyler, TX, 75708, USA. torry.tucker@uthct.edu.
Background:
Pleural infection affects about 65,000 patients annually in the US and UK. In this and other forms of pleural injury, mesothelial cells (PMCs) undergo a process called mesothelial (Meso) mesenchymal transition (MT), by which PMCs acquire a profibrogenic phenotype with increased expression of α-smooth muscle actin (α-SMA) and matrix proteins. MesoMT thereby contributes to pleural organization with fibrosis and lung restriction. Current murine empyema models are characterized by early mortality, limiting analysis of the pathogenesis of pleural organization and mechanisms that promote MesoMT after infection.
Methods:
A new murine empyema model was generated in C57BL/6 J mice by intrapleural delivery of Streptococcus pneumoniae (D39, 3 × 10(7)-5 × 10(9) cfu) to enable use of genetically manipulated animals. CT-scanning and pulmonary function tests were used to characterize the physiologic consequences of organizing empyema. Histology, immunohistochemistry, and immunofluorescence were used to assess pleural injury. ELISA, cytokine array and western analyses were used to assess pleural fluid mediators and markers of MesoMT in primary PMCs.
Results:
Induction of empyema was done through intranasal or intrapleural delivery of S. pneumoniae. Intranasal delivery impaired lung compliance (p < 0.05) and reduced lung volume (p < 0.05) by 7 days, but failed to reliably induce empyema and was characterized by unacceptable mortality. Intrapleural delivery of S. pneumoniae induced empyema by 24 h with lung restriction and development of pleural fibrosis which persisted for up to 14 days. Markers of MesoMT were increased in the visceral pleura of S. pneumoniae infected mice. KC, IL-17A, MIP-1β, MCP-1, PGE2 and plasmin activity were increased in pleural lavage of infected mice at 7 days. PAI-1(-/-) mice died within 4 days, had increased pleural inflammation and higher PGE2 levels than WT mice. PGE2 was induced in primary PMCs by uPA and plasmin and induced markers of MesoMT.
Conclusion:
To our knowledge, this is the first murine model of subacute, organizing empyema. The model can be used to identify factors that, like PAI-1 deficiency, alter outcomes and dissect their contribution to pleural organization, rind formation and lung restriction.
Insights
A new mouse model for pleural infection (empyema) allows researchers to study lung fibrosis. This model helps identify factors influencing disease progression and outcomes in pleural injury.
Area of Science:
- Pulmonary Medicine
- Cell Biology
- Pathology
Background:
- Pleural infection (empyema) impacts numerous patients annually, leading to pleural fibrosis and lung restriction.
- Mesothelial cells (PMCs) transform into a profibrogenic phenotype (mesothelial-to-mesenchymal transition or MesoMT), contributing to pleural scarring.
- Existing animal models for empyema have high early mortality, hindering the study of pleural organization and MesoMT mechanisms.
Purpose of the Study:
- To develop a novel murine model for subacute, organizing empyema.
- To characterize the physiological and pathological consequences of empyema in mice.
- To investigate the mechanisms driving MesoMT in the context of pleural infection.
Main Methods:
- A new empyema model was established using intrapleural delivery of Streptococcus pneumoniae in C57BL/6J mice.
- Computed tomography (CT) scanning and pulmonary function tests assessed lung function.
- Histology, immunohistochemistry, immunofluorescence, ELISA, and western blot analyses evaluated pleural injury, mediators, and MesoMT markers.
Main Results:
- Intrapleural bacterial delivery induced empyema, lung restriction, and persistent pleural fibrosis within 14 days.
- Markers of MesoMT were elevated in the visceral pleura of infected mice.
- Specific mediators like KC, IL-17A, MIP-1β, MCP-1, PGE2, and plasmin activity increased in pleural fluid; PAI-1 deficiency worsened outcomes.
Conclusions:
- This study presents the first murine model of subacute, organizing empyema.
- The model facilitates the identification of factors influencing pleural organization, rind formation, and lung restriction.
- It enables dissection of the contribution of specific factors, such as PAI-1 deficiency, to empyema pathogenesis.
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