OC 56.4 - Thrombophilia leads to bronchus-associated lymphoid tissue (BALT) formation and obstetric lung injury in mice

Background: Pulmonary complications are a common reason for admission to the intensive care unit during pregnancy, accounting for 9–44% of deaths in admitted pregnant women. While the mechanisms that result in obstetric respiratory complications are poorly understood, their etiology frequently involves exaggerated activation of coagulation. Pregnancy itself is an acquired physiological state of hypercoagulability and could promote pulmonary disease in predisposed individuals. Yet, studies directly examining the role of coagulation in the pathogenesis of obstetric lung disease are scant.

Aims: We evaluated the lungs of Endothelial Protein C Receptor (EPCR)-deficient pregnant dams for signs of pathology and pregnancy-associated inflammatory changes. We further compared these results with other murine thrombophilia models.

Methods: Methods included histological sectioning, immunostaining, and quantitative real time PCR analyses.

Results: We report that EPCR-deficient mice showed clustering of CD45+ve immune cells in the alveolar parenchyma that resembled BALT formation. Immunohistochemical analysis of BALT structures demonstrated B- and T-cell recruitment and organization (Figure 1). Genes upregulated in lungs of EPCR-deficient pregnant mice included transcripts that are essential for BALT induction, organization, and maintenance (Figure 2). EPCR-deficient mice additionally showed decreased alveolar parenchymal complexity that worsened with pregnancy. We further report that lungs of thrombomodulin-deficient, Tissue factor Pathway Inhibitor (TFPI)-deficient and factor V Leiden mice also exhibited loss of alveolar complexity, immune cell infiltration and/or BALT formation.

Conclusion(s): These data uncover a novel phenomenon where EPCR deficiency leads to lung lymphocyte accumulation and injury exacerbated by pregnancy. They suggest that EPCR polymorphisms or functional EPCR deficiency due to inflammation-induced receptor shedding or the presence of inhibitory autoantibodies might increase susceptibility to obstetric lung disease. Further, our study implicates lungs as a prominent organ affected by inflammatory pathology arising from a hypercoagulable state. Thrombophilia is a risk factor for placenta-mediated pregnancy complications and may indeed also be an unrecognized risk factor for obstetric lung injury.