Plasminogen activator inhibitor-1 promotes airway remodeling in a murine model of chronic asthma

Abstract

3 ( ~ Plasminngen Activator Inhibitor-1 Promotes Airway Remodeling in • ,F a Murine Model of Chronic Asthma Chad K Oh* Barbara Ariue§, Rodrigo F Alban* Seong H Cho* *Harbor-UCLA Medical Center, Torrance, CA §Pediatric Allergy/Immunology, Harbor-UCLA Medical Center, Torrance, CA The irreversible destruction of the normal airway structure with abnormal fibroproliferation is the hallmark of airway remodeling. The pathogenesis of airway remodeling is not known, although airway inflammation and abnormal tissue repair are involved. The inhibition of matrix metalloproteinase (MMP) activity and fibrinolysis cause abnormal tissue repair in airway remodeling. Plasminogen activator inhibitor (PAI)-I is the key inhibitor of MMP activity and fibrinolysis. We previously reported that PAI-I production is increased in human mast cells stimulated by IgEreceptor cross-linking and in lung mast cells of asthmatic patient. In the present study, we used the ovalbumin (OVA)-sensitized mouse model of chronic asthma to determine the causative effect of PAI-I in development of airway remodeling. C57BL/6J mice were challenged with OVA by inhalation for 4 weeks. PAI-I mRNA expression in lung tissue from these mice was increased after OVA challenge. The PAI-1 protein levels in lung tissue and bronchoalveolar lavage fluids were also increased 4-fold and 5fold, respectively, after OVA challenge. The accumulation of collagen and fibrin in the airways of C57BL/6J-PAI-I (-/-) mice was considerably less than that of PAI-1 (+/+), although the inflammatory response and the number of infiltrating eosinophils in the bronchial wall were not different between PAl1 (-/-) mice and PAl1 (+/+) mice. This is the first direct in vivo evidence indicating that PAI-I promotes airway remodeling and that the PAl1-dependent airway remodeling process occurs at least in part independently of inflammation. The inhibition of PAI-1 activity could represent a novel therapeutic approach in the management of airway remodeling.