The impact of the PAI-1 4G/5G polymorphism on the outcome of patients with ALI/ARDS

Tsangaris, Iraklis; Tsantes, Argiris; Bonovas, Stefanos; Lignos, Michalis; Kopterides, Petros; Gialeraki, A.; Rapti, Eleni; Orfanos, Stylianos E.; Dimopoulou, Ioanna; Travlou, Αnthi; Armaganidis, Apostolos

doi:10.1016/j.thromres.2008.07.018

Cited by 28 publications

(16 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, PAI-1 acts as an acute phase protein (APP) during APR such as acute lung injury (ALI), inflammation, and sepsis [7, 21–24] and is closely associated with poor outcome in ALI patients [25, 26]. Since autophagy is also a known mechanism that regulates cell death and inflammation, we assessed the relationship between PAI-1 and autophagy in the regulation of inflammation.…”

Section: Discussionmentioning

confidence: 99%

Plasminogen Activator Inhibitor-1 Regulates LPS Induced Inflammation in Rat Macrophages through Autophagy Activation

Wang

Ren

Zhu

et al. 2014

The Scientific World Journal

View full text Add to dashboard Cite

Background. The mechanisms by which plasminogen activator inhibitor-1 (PAI-1) regulates inflammation, especially in acute respiratory distress syndrome (ARDS), are largely unknown. Objective. To assess the relationship between PAI-1 and autophagy in inflammatory reactions induced by LPS in rat NR8383 cells. Methods. ELISA was used to assess the amounts of TNF-α, IL-1β, and PAI-1 in cell culture supernatants; TLR4, MyD88, PAI-1, LC3, Beclin1, and mTOR protein and mRNA levels were determined by western blot and quantitative RT-PCR, respectively; western blot was used to determine NF-κB protein levels. To further evaluate the role of PAI-1, the PAI-1 gene was downregulated and overexpressed using the siRNA transfection technology and the pCDH-PAI-1, respectively. Finally, the GFP Positive Expression Rate Method was used to determine the rate of GFP-LC3 positive NR8383 cells. Results. In LPS-induced NR8383 cells, TNF-α, IL-1β, and PAI-1 expression levels increased remarkably. Upon PAI-1 knockdown, TNF-α, IL-1β, PAI-1, TLR4, MyD88, NF-κB, LC3, and Beclin1 levels were decreased, while mTOR increased. Conversely, overexpression of PAI-1 resulted in increased amounts of TNF-α, IL-1β, PAI-1, TLR4, MyD88, NF-κB, LC3, and Beclin1. However, no significant change was observed in mTOR expression. Conclusions. In NR8383 cells, PAI-1 contributes in the regulation of LPS-induced inflammation, likely by promoting autophagy.

show abstract

Section: Discussionmentioning

confidence: 99%

Plasminogen Activator Inhibitor-1 Regulates LPS Induced Inflammation in Rat Macrophages through Autophagy Activation

Wang

Ren

Zhu

et al. 2014

The Scientific World Journal

View full text Add to dashboard Cite

show abstract

“…Reduced uPA activity in parallel with substantive elevations in PAI-1 in both bronchoalveolar lavage and blood were observed in acute respiratory diseases (4,30,31,62,81). The hallmark of these diseases is dysfunctional fluid homeostasis in the airways and alveolar compartment (29,40,54).…”

Section: Discussionmentioning

confidence: 99%

Regulation of epithelial sodium channels in urokinase plasminogen activator deficiency

Chen

Zhao

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

Epithelial sodium channels (ENaC) govern transepithelial salt and fluid homeostasis. ENaC contributes to polarization, apoptosis, epithelial-mesenchymal transformation, etc. Fibrinolytic proteases play a crucial role in virtually all of these processes and are elaborated by the airway epithelium. We hypothesized that urokinase-like plasminogen activator (uPA) regulates ENaC function in airway epithelial cells and tested that possibility in primary murine tracheal epithelial cells (MTE). Both basal and cAMP-activated Na(+) flow through ENaC were significantly reduced in monolayers of uPA-deficient cells. The reduction in ENaC activity was further confirmed in basolateral membrane-permeabilized cells. A decrease in the Na(+)-K(+)-ATPase activity in the basolateral membrane could contribute to the attenuation of ENaC function in intact monolayer cells. Dysfunctional fluid resolution was seen in uPA-disrupted cells. Administration of uPA and plasmin partially restores ENaC activity and fluid reabsorption by MTEs. ERK1/2, but not Akt, phosphorylation was observed in the cells and lungs of uPA-deficient mice. On the other hand, cleavage of γ ENaC is significantly depressed in the lungs of uPA knockout mice vs. those of wild-type controls. Expression of caspase 8, however, did not differ between wild-type and uPA(-/-) mice. In addition, uPA deficiency did not alter transepithelial resistance. Taken together, the mechanisms for the regulation of ENaC by uPA in MTEs include augmentation of Na(+)-K(+)-ATPase, proteolysis, and restriction of ERK1/2 phosphorylation. We demonstrate for the first time that ENaC may serve as a downstream signaling target by which uPA controls the biophysical profiles of airway fluid and epithelial function.

show abstract

“…Several studies have suggested that pre-B-cell colonyenhancing factor (PBEF) gene polymorphisms were associated with susceptibility and prognosis of ALI [23,24]. The plasminogen activator inhibitor-1 (PAI-1) 4G allele was associated with worse outcome in ALI/ARDS [25]. A prospective cohort demonstrated that the AC genotype at position −1221 in the NQO1 gene caused decreased transcription and was associated with a lower incidence of ALI following major trauma [26].…”

Section: Discussionmentioning

confidence: 99%

Haplotype analysis of ApoAI gene and sepsis-associated acute lung injury

Hao

2014

Lipids Health Dis

View full text Add to dashboard Cite

BackgroundApolipoprotein A1 (ApoA1) is the major apoprotein constituent of high density lipoprotein (HDL) which exerts innate protective effects in systemic inflammation. However, its role in the acute lung injury (ALI) has not been well studied. In the present study we investigated the association between polymorphisms of ApoA1 gene and ALI in a Chinese population.MethodsThree polymorphisms of the ApoA1 gene (rs11216153, rs2070665, and rs632153) were genotyped by TaqMan method in 290 patients with sepsis-associated ALI, 285 patients sepsis alone and 330 age- and sex-matched healthy controls.ResultsWe found rs11216153 polymorphism of ApoA1 was associated with ALI, the GG genotype and G allele was common in the ALI patients (76.9%, 88.1%, respectively) than both in the control subjects (55.8%, 75.8%, respectively) and in the sepsis alone patients (58.2%, 78.4%, respectively). Haplotype consisting of these three SNPs strengthened the association with ALI susceptibility. The frequency of haplotype GTG in the ALI samples was significantly higher than that in the healthy control group (OR = 2.261, 95% CI: 1.735 ~ 2.946, P <0.001) and the sepsis alone group (OR = 1.789, 95% CI: 1.373 ~ 2.331.P < 0.001). Carriers of the haplotype TTG had a lower risk for ALI compared with healthy control group (OR = 0.422, 95% CI: 0.310 ~ 0.574, P < 0.001) and sepsis alone group (OR = 0.491, 95% CI: 0.356 ~ 0.676, P <0.001).ConclusionsThese results indicated that genetic variants in the ApoA1 gene might be associated with susceptibility to sepsis-associated ALI in Han Chinese population.

show abstract

The impact of the PAI-1 4G/5G polymorphism on the outcome of patients with ALI/ARDS

Cited by 28 publications

References 39 publications

Plasminogen Activator Inhibitor-1 Regulates LPS Induced Inflammation in Rat Macrophages through Autophagy Activation

Plasminogen Activator Inhibitor-1 Regulates LPS Induced Inflammation in Rat Macrophages through Autophagy Activation

Regulation of epithelial sodium channels in urokinase plasminogen activator deficiency

Haplotype analysis of ApoAI gene and sepsis-associated acute lung injury

Contact Info

Product

Resources

About