Mast Cell-Derived PAI-1 Promotes Airway Inflammation and Remodeling in a Murine Model of Asthma
Monday, March 7, 2016: 3:00 PM
Room 502B (Convention Center)
Ara Jo, , , , , , ,
Rationale: We previously reported that plasminogen activator inhibitor-1 (PAI-1) promotes airway remodeling in a murine model of asthma and mast cells (MCs) are an important source of PAI-1 in asthmatic airways. In this study, we hypothesized that MC-derived PAI-1 plays a major role in airway remodeling. 

Methods: MC-deficient C57BL/6J- Kitw-sh/w-sh mice reconstituted with bone marrow cultured MCs (BMCMCs) from PAI-1-/- and wild type (WT) mice. These mice were sensitized and challenged with ovalbumin (OVA) or phosphate buffer saline (PBS) exposure for 4 weeks. Airway hyperreactivity was measured by a whole body plethysmography after the final OVA challenge. After sacrificing the mice, bronchoalveolar lavage fluids (BALF) and lung tissues were collected. Tissues were embedded in paraffin, sectioned, and processed with H&E, PAS and trichrome staining.

Results: The numbers of total inflammatory cells and eosinophils in BALF from PAI1−/− BMMC-reconstituted Kitw-sh/w-sh mice were significantly decreased compared with those from WT BMMC-reconstituted Kitw-sh/w-sh mice following OVA challenge (12.26±4.00 vs 25.06±10.42, p<0.01 and 1.44±0.80 vs 3.10±0.69, p<0.01, respectively). In addition, PAI1−/− BMMC-reconstituted Kitw-sh/w-sh mice showed decreased goblet cell hyperplasia and peribronchial collagen deposition compared with WT BMMC-reconstituted Kitw-sh/w-sh mice following OVA challenge. Airway hyperresponsiveness of PAI1−/− BMMC-reconstituted Kitw-sh/w-sh mice was significantly decreased compared to that of WT BMMC-reconstituted Kitw-sh/w-sh mice with OVA challenge.

Conclusions: This study demonstrates that MC-derived PAI-1 promotes airway inflammation, goblet cell hyperplasia and peribronchial collagen deposition in a murine model of asthma, suggesting MC as a major source of PAI-1 and MC-derived PAI-1 as a novel therapeutic target for airway remodeling in asthma.