A Plasminogen Activator Inhibitor-1 Inhibitor Reduces Airway Remodeling in a Murine Model of Chronic Asthma

Abstract

We previously reported that plasminogen activator inhibitor (PAI)-1 deficiency prevents collagen deposition in the airways of ovalbumin (OVA)-challenged mice. In this study, we explored the therapeutic utility of blocking PAI-1 in preventing airway remodeling, using a specific PAI-1 inhibitor, tiplaxtinin. C57BL/6J mice were immunized with intraperitoneal injections of OVA on Days 0, 3, and 6. Starting on Day 11, mice were challenged with phosphate-buffered saline or OVA by nebulization three times per week for 4 weeks. Tiplaxtinin was mixed with chow and administered orally from 1 day before the phosphate-buffered saline or OVA challenge. Lung tissues were harvested after challenge and characterized histologically for infiltrating inflammatory cells, mucus-secreting goblet cells, and collagen deposition. Airway hyperresponsiveness was measured using whole-body plethysmography. Tiplaxtinin treatment significantly decreased levels of PAI-1 activity in bronchoalveolar lavage fluids, which indicates successful blockage of PAI-1 activity in the airways. The number of infiltrated inflammatory cells was reduced by tiplaxtinin treatment in the lungs of the OVA-challenged mice. Furthermore, oral administration of tiplaxtinin significantly attenuated the degree of goblet cell hyperplasia and collagen deposition in the airways of the OVA-challenged mice, and methacholine-induced airway hyperresponsiveness was effectively reduced by tiplaxtinin in these animals. This study supports our previous findings that PAI-1 promotes airway remodeling in a murine model of chronic asthma, and suggests that PAI-1 may be a novel target of treatment of airway remodeling in asthma.Keywords: asthma; airway remodeling; collagen deposition; plasminogen activator inhibitor-1; tiplaxtinin Allergic asthma is now the most common chronic disease of children, and one of the most common respiratory diseases in adults. The hallmark of asthma is chronic airway inflammation with multiple pulmonary pathologies, including airway hyperresponsiveness (AHR), eosinophilic infiltration, mucus hypersecretion, and subepithelial fibrosis (1, 2).Plasminogen activator inhibitor (PAI)-1 is a member of the serine protease inhibitor gene family, and the major physiologic inhibitor of the serine proteases, urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA). Because uPA and tPA play important roles in damping tissue matrix deposition, high levels of PAI-1 lead to excess extracellular matrix formation (3). Under normal conditions, PAI-1 is present in plasma and tissues at low concentrations. Elevated levels of PAI-1 are often observed in a variety of pathologic conditions and clinical settings, such as infection, stroke, myocardial infarction, diabetes, obesity, sepsis, and cancers (4, 5). We previously reported that the levels of PAI-1 were elevated in the airways of a murine model of chronic asthma, and that PAI-1 deficiency was associated with reduced airway fibrosis in these mice (6). We also demonstrated that PAI-1 expression wa...

Inhibition of SERPINE1 Function Attenuates Wound Closure in Response to Tissue Injury: A Role for PAI-1 in Re-Epithelialization and Granulation Tissue Formation

“…Tiplaxtinin (PAI-039), the most well studied small-molecule inhibitor, attenuates asthmatic episodes, reduces both hyperlipidemia and hyperglycemia, suppresses angiogenesis and has recently been identified as a potent inhibitor of carotid stenosis by stimulating vascular smooth muscle cell apoptosis [13][14][15][16][17][18][19][20]. Similarly, other compounds that share a similar binding site on PAI-1 as tiplaxtinin have been synthesized [21,22].…”

“…Since it is known that tiplaxtinin and TM5275 promote PAI-1 substrate behavior, however, these inhibitors may prevent the conformational change in β-sheet A of PAI-1 necessary to accommodate insertion of the PAI-1 RCL during the protease inhibition reaction [25]. If tiplaxtinin or TM5275 were to complex with PAI-1 at the vitronectin-binding site, it has been suggested that these inhibitors would not be effective since the majority of circulating PAI-1 is bound to vitronectin; nevertheless, the available data confirm significant in vivo efficacy for these drugs [13][14][15][16][17][18][19][20]27]. Figure 1.…”

TGF-β1–induced PAI-1 contributes to a profibrotic network in patients with eosinophilic esophagitis

“…PAI-1 is elevated in human asthma and promotes airway remodeling in murine asthma models (21, 23–28). PAI-1 overexpression, triggered by viruses and allergens, is associated with airway fibrosis while PAI-1 deficiency protects mice from fibrotic airway remodeling (21, 23–26, 29).…”

Small molecule PAI-1 functional inhibitor attenuates vascular smooth muscle cell migration and survival: Implications for the therapy of vascular disease

“…Due to the complexity of PAI-1 structure and function, several low-molecular weight antagonists of PAI-1 have been developed to evaluate specific contributions of this SERPIN to disease pathologies (7). Tiplaxtinin (PAI-039), one of the most well-studied small-molecule inhibitors, attenuates asthmatic episodes, hyperlipidemia, hyperglycemia and angiogenesis (7–14).…”

“…Tiplaxtinin (PAI-039), one of the most well-studied small-molecule inhibitors, attenuates asthmatic episodes, hyperlipidemia, hyperglycemia and angiogenesis (7–14). The specific mechanism by which tiplaxtinin antagonizes the anti-fibrinolytic activity of PAI-1 involves promotion of a substrate-like conformation resulting in PAI-1 cleavage and impaired uPA and tPA inhibition (15,16).…”