Association of elevated plasminogen activator inhibitor 1 levels with diminished lung function in patients with asthma

Cho, Seong; Kang, Joseph; Lyttle, Christopher S.; Harris, Kathleen E.; Daley, Brendan; Grammer, Leslie C.; Avila, Pedro C.; Kumar, Rajesh; Schleimer, Robert P.

doi:10.1016/j.anai.2010.12.021

Cited by 29 publications

(34 citation statements)

References 26 publications

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“…Recent studies have shown that asthmatic patients with increased body weight and diminished lung function have elevated PAI-1 levels, suggesting that the negative association between obesity and poor lung function may in part be mediated by PAI-1 [48]. PAI-1 plays a role in increasing collagen deposition during allergic asthma [35] and promoting AHR as well as airway remodeling [49].…”

Section: Discussionmentioning

confidence: 99%

High-fat diet promotes lung fibrosis and attenuates airway eosinophilia after exposure to cockroach allergen in mice

Greenberg

Hosseinkhani

et al. 2013

Experimental Lung Research

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Obesity is an important risk factor for asthma but the mechanistic basis for this association is not well understood. In the current study, the impact of obesity on lung inflammatory responses after allergen exposure was investigated. C57BL/6 mice maintained on a high-fat diet (HFD) or a normal diet (ND) after weaning were sensitized and challenged with cockroach allergen (CRA). Airway inflammation was assessed based on inflammatory cell recruitment, measurement of lung Th1-Th2 cytokines, chemokines, eicosanoids, and other proinflammatory mediators as well as airway hyperresponsiveness (AHR). CRA-challenged mice fed a HFD exhibited significantly decreased allergen-induced airway eosinophilia along with reduced lung IL-5, IL-13, LTC4, CCL11, and CCL2 levels as well as reduced mucus secretion and smooth muscle mass compared to ND fed mice. However, allergen-challenged HFD fed mice demonstrated significantly increased PAI-1 and reduced PGE2 levels in the lung relative to corresponding ND fed mice. Interestingly, saline-exposed HFD fed mice demonstrated elevated baseline levels of TGF-α1, arginase-1, hypoxia-inducible factor-1α, and lung collagen expression associated with decreased lung function compared to corresponding ND fed mice. These studies indicate that a HFD inhibits airway eosinophilia while altering levels of PAI-1 and PGE2 in response to CRA in mice. Further, a HFD can lead to the development of lung fibrosis even in the absence of allergen exposure which could be due to innate elevated levels of specific profibrotic factors, potentially affecting lung function during asthma.

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Section: Discussionmentioning

confidence: 99%

High-fat diet promotes lung fibrosis and attenuates airway eosinophilia after exposure to cockroach allergen in mice

Greenberg

Hosseinkhani

et al. 2013

Experimental Lung Research

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“…A number of genes that are involved in changes in cellular function and trafficking are induced by TGFβ1 including periostin which increases eosinophil trafficking (18) and phospholamban which induces TGFβ1-mediated esophageal smooth muscle cell contraction in culture (17). Among the genes that are induced by TGFβ1 is the serine protease inhibitor, plasminogen activator inhibitor-1 (PAI-1/serpinE1) which promotes tissue fibrosis in asthma (21–24). However, the role of PAI-1, its induction in EoE, or its role in esophageal fibrosis has not been previously studied.…”

Section: Introductionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Rawson

Yang

Newbury

et al. 2016

Journal of Allergy and Clinical Immunology

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Background Eosinophilic esophagitis is an allergic disease of increasing worldwide incidence. Complications are due to tissue remodeling and involve transforming growth factor-β1 (TGFβ1) mediated fibrosis. Plasminogen Activator Inhibitor-1 (PAI-1/serpinE1) can be induced by TGFβ1 but its role in EoE is not known. Objective To understand the expression and role of PAI-1 in EoE. Methods We used esophageal biopsy specimens and plasma samples from control and EoE subjects, primary human esophageal epithelial cells, and EoE fibroblasts in immunohistochemistry, quantitative PCR, and immunoassay experiments to understand the induction of PAI-1 by TGFβ1, the relationship between PAI-1 and esophageal fibrosis, and the role of PAI-1 in fibrotic gene expression. Results PAI-1 expression was significantly elevated in epithelial cells of active EoE biopsies as compared with inactive EoE or control biopsies (p<0.001). Treatment of primary esophageal epithelial cells with recombinant TGFβ1 increased PAI-1 transcription, intracellular protein expression, and secretion. Esophageal PAI-1 expression correlated with basal zone hyperplasia, a fibrosis, and markers of esophageal remodeling including vimentin, TGFβ1, collagen I, fibronectin, and matrix metalloproteases and plasma PAI-1 levels correlated with plasma TGFβ1. PAI-1 inhibition significantly decreased baseline and TGFβ1-induced fibrotic gene expression. Conclusions PAI-1 is significantly elevated in the EoE epithelium, reflects fibrosis, and its inhibition decreases TGFβ1-induced gene expression. Epithelial PAI-1 may serve as a marker of EoE severity and form part of a TGFβ1-induced pro-fibrotic network.

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“…We also demonstrated that PAI-1 expression was elevated in the airways of patients with fatal asthma, and the 4G allele of PAI-1, which is associated with high plasma levels of PAI-1, was preferentially transmitted from parents with asthma to their children (7). In addition, our recent data showed that elevated levels of plasma PAI-1 were associated with a decline of lung function in subjects with asthma (8). Other studies have also shown that PAI-1 levels in induced sputum samples from subjects with asthma were increased compared with healthy control subjects (9,10).…”

mentioning

confidence: 81%

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

Lee¹,

Eren

Vaughan

et al. 2012

Am J Respir Cell Mol Biol

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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...

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Association of elevated plasminogen activator inhibitor 1 levels with diminished lung function in patients with asthma

Cited by 29 publications

References 26 publications

High-fat diet promotes lung fibrosis and attenuates airway eosinophilia after exposure to cockroach allergen in mice

High-fat diet promotes lung fibrosis and attenuates airway eosinophilia after exposure to cockroach allergen in mice

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

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

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