Abstract
BackgroundPleural 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.MethodsA new murine empyema model was generated in C57BL/6 J mice by intrapleural delivery of Streptococcus pneumoniae (D39, 3 × 107–5 × 109 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.ResultsInduction 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.ConclusionTo 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.
Highlights
Pleural infection affects about 65,000 patients annually in the US and UK
Intranasal administration of S. pneumoniae did not reliably induce survivable empyema To create a model of pneumonia complicated by empyema, we initially challenged C57BL/6 mice with intranasal administration of S. pneumoniae
Pneumoniae‐mediated pleural injury is characterized by prominent visceral pleural MesoMT We previously showed that MesoMT of visceral pleural mesothelial cells likely contributes to the formation of the pleural rind associated with non-specific pleuritis in human tissues [9]
Summary
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. Of the roughly 4 million cases of pneumonia annually diagnosed in the US, about half develop a parapneumonic effusion [1] In many cases, these effusions can evolve with formation of complicated parapneumonic effusions or frank empyema, which is characterized by overt infection or intrapleural. About 40,000 US patients annually may require pleural drainage to prevent morbidity associated with complicated parapneumonic effusions/empyema in the US each year [6]. Current surgical treatment is invasive and alternative treatment with intrapleural administration of fibrinolysins is associated with variable outcomes in adults [7] These considerations justify the search for more effective interventions, which rely on better understanding of the pathogenesis of pleural organization and remodeling [8]
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