Plasminogen activator inhibitor type-1 deficiency exaggerates LPS-induced acute lung injury through enhancing Toll-like receptor 4 signaling pathway
Mice lacking plasminogen activator inhibitor-1 (PAI-1) did not affect lung injury induced by gram-positive bacteria pneumococcal pneumonia but worsened lung injury induced by gram-negative bacteria Klebsiella. The exact mechanisms have not been completely elucidated. In this study, we examined the signaling pathway of Toll-like receptor 4 (TLR4) with/without PAI-1 in acute lung injury (ALI) induced by lipopolysaccharides (LPS) in mice. PAI-1 knockout mice (n=60) and wild-type mice (n=60) were exposed to LPS intratracheal instillation. Different groups of mice were then sacrificed at 0 and 8 h after LPS instillation. PAI-1-/- mice showed increased excess lung water and elevated cytokines production and release. In addition, expression of TLR4 was up-regulated and the phosphorylation activation of extracellular regulating kinase (ERK) and c-Jun N-terminal kinase (JNK) were also increased in PAI-1 knockout mice compared to wild-type mice. Inversely, interleukin (IL)-1 receptor-associated kinase-M (IRAK-M) and suppressor of cytokine signaling 1 (SOCS1) were both significantly reduced in PAI-1-/-mice after LPS challenge. PAI-1 deletion increased lung injury induced by LPS through up-regulation of TLR4, ERK and C-JNK and down-regulation of TLR4 negative regulators.
Available from: PubMed Central
- "Wu et al.  found that TLR4 played a critical role in LPS-induced ALI and transfection of adenovirus Ad-siTLR4 could effectively downregulate TLR4 expression in vitro and in vivo, accompanied by alleviation of LPS-induced lung injury. A recent study demonstrated that plasminogen activator inhibitor type-1 (PAI-1) increased the expression of TLR4 to promote lung injury . Thus a therapeutic strategy against these abnormalities and targets could be effective for ARDS treatment. "
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ABSTRACT: Acute lung injury (ALI) is a serious clinical syndrome with a high rate of mortality. In this study, the effects of triptolide on lipopolysaccharide (LPS)-induced ALI in rats were investigated.
Sixty-five male Sprague Dawley rats(approved by ethics committee of the First Affiliated Hospital of Soochow University) were randomly divided into five groups. The control group was injected with 2.5 mL saline/kg body weight via the tail vein and intraperitoneally with 1% dimethyl sulfoxide (DMSO) (n = 5). The L group was administered with 0.2% LPS dissolved in saline (5 mg/kg) to induce ALI via the tail vein (n = 15). The TP1, TP2, and TP3 groups were treated as rats in the L group and then intraperitoneally injected with 25, 50, and 100 mug triptolide/kg body weight, respectively (15 rats per group). Blood samples from the left heart artery were taken for blood gas analysis at 1 hour before injection and at 1, 3, 6, and 12 hours after saline and DMSO administration in the control group, LPS injection in the L group, and triptolide injection in the TP1, TP2, and TP3 groups. Lung wet-to-dry weight (W/D) ratio, diffuse alveolar damage (DAD) score, TNF-alpha levels, and mRNA and protein expression of toll-like receptor 4 (TLR4) were analyzed.
Compared with the control group, the arterial partial pressure of oxygen (PaO2) declined (P <0.05), the W/D ratio and DAD score increased (P <0.05), and TNF-alpha levels in serum and bronchoalveolar lavage fluid (BALF) and mRNA and protein expression of TLR4 were significantly increased in the L group (P <0.05). Compared with the L group, PaO2 significantly increased in the TP2 and TP3 groups (P <0.05), while the W/D ratio and DAD score were significantly decreased in the TP2 and TP3 groups (P <0.05). TNF-alpha levels and mRNA and protein expression of TLR4 were significantly decreased in the TP2 and TP3 groups compared with the L group (P <0.05).
Triptolide can ameliorate LPS-induced ALI by reducing the release of the inflammatory mediator TNF-alpha and inhibiting TLR4 expression.
12/2013; 18(1):58. DOI:10.1186/2047-783X-18-58
Available from: Benita Westerlund-Wikström
- "Levels of PAI-1 are increased in infections by several Gram-negative pathogens, including Y. pestis, and are associated with unfavorable outcomes and enhanced mortality (Park et al., 1997; Zeeleder et al., 2006; Song et al., 2007; Comer et al., 2010; Kager et al., 2011; Lim et al., 2011). In accordance, infection models in PAI-1 knockout mice have shown that PAI-1 is protective in defense against sepsis caused by Klebsiella pneumoniae, Burkholderia pseudomallei, and Y. enterocolitica (Renckens et al., 2007; Hua et al., 2011; Kager et al., 2011; Luo et al., 2011) and lung infections by Haemophilus influenzae and P. aeruginosa (Goolaerts et al., 2011; Lim et al., 2011). These studies indicate that dampening the plasmin formation during acute inflammatory response helps the host to control bacterial infections, and contrariwise, inactivation of PAI-1 leads to low expression of pro-inflammatory cytokines and chemokines and low recruitment of leukocytes. "
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ABSTRACT: The outer membrane protease Pla belongs to the omptin protease family spread by horizontal gene transfer into Gram-negative bacteria that infect animals or plants. Pla has adapted to support the life style of the plague bacterium Yersinia pestis. Pla has a β-barrel fold with 10 membrane-spanning β strands and five surface loops, and the barrel surface contains bound lipopolysaccharide (LPS) that is critical for the conformation and the activity of Pla. The biological activity of Pla is influenced by the structure of the surface loops around the active site groove and by temperature-induced LPS modifications. Several of the putative virulence-related functions documented for Pla in vitro address control of the human hemostatic system, i.e., coagulation and fibrinolysis. Pla activates human plasminogen to the serine protease plasmin and activates the physiological plasminogen activator urokinase. Pla also inactivates the protease inhibitors alpha-2-antiplasmin and plasminogen activator inhibitor 1 (PAI-1) and prevents the activation of thrombin-activatable fibrinolysis inhibitor (TAFI). These functions enhance uncontrolled fibrinolysis which is thought to improve Y. pestis dissemination and survival in the mammalian host, and lowered fibrin(ogen) deposition has indeed been observed in mice infected with Pla-positive Y. pestis. However, Pla also inactivates an anticoagulant, the tissue factor (TF) pathway inhibitor, which should increase fibrin formation and clotting. Thus, Pla and Y. pestis have complex interactions with the hemostatic system. Y. pestis modifies its LPS upon transfer to the mammalian host and we hypothesize that the contrasting biological activities of Pla in coagulation and fibrinolysis are influenced by LPS changes during infection.
Frontiers in Cellular and Infection Microbiology 07/2013; 3:35. DOI:10.3389/fcimb.2013.00035 · 3.72 Impact Factor
Available from: Alexander D Cornet
- "Although PAI–1 knockout mice were protected from lung fibrosis after bleomycin induced lung injury , PAI–1 knockout mice were not protected against acid induced ALI . Further PAI–1 knockout mice displayed worsened lung injury after pulmonary challenge with Klebsiella bacteria . In our study we observed neither improvement nor worsening of pulmonary inflammation and lung injury. "
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ABSTRACT: Critically ill patients frequently develop acute lung injury (ALI). Disturbed alveolar fibrin turnover, a characteristic feature of ALI, is the result of both activation of coagulation and inhibition of fibrinolysis. Nebulized fibrinolytic agents could exert lung-protective effects, via promotion of fibrinolysis as well as anti-inflammation.
Rats were challenged intratracheally with Pseudomonas aeruginosa, resulting in pneumonia as a model for direct ALI, or received an intravenous bolus infusion of lipopolysaccharide, as a model for indirect ALI. Rats were randomized to nebulization of normal saline (placebo), recombinant tissue plasminogen activator (rtPA), or monoclonal antibodies against plasminogen activator inhibitor-type 1 (anti-PAI-1).
Nebulized rtPA or anti-PA1-1 enhanced the bronchoalveolar fibrinolytic system, as reflected by a significant reduction of PAI-1 activity levels in bronchoalveolar lavage fluid, and a consequent increase in plasminogen activator activity (PAA) levels to supranormal values. Both treatments also significantly affected systemic fibrinolysis as reflected by a significant increase in PAA levels in plasma to supranormal levels. Neither nebulized rtPA nor anti-PA1-1 affected pulmonary inflammation. Neither treatment affected bacterial clearance of P. aeruginosa from the lungs in case of pneumonia.
Local treatment with rtPA or anti-PA1-1 affects pulmonary fibrinolysis but not inflammation in models of direct or indirect ALI in rats.
PLoS ONE 02/2013; 8(2):e55262. DOI:10.1371/journal.pone.0055262 · 3.23 Impact Factor
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