Thrombin-Activatable Fibrinolysis Inhibitor Protects against Acute Lung Injury by Inhibiting the Complement System

Naito, Makoto; Taguchi, Osamu; Kobayashi, Tetsu; Takagi, Takehiro; D’Alessandro-Gabazza, Corina N.; Matsushima, Yuki; Boveda-Ruiz, Daniel; Gil-Bernabe, Paloma; Μatsumoto, Takahiro; Chelakkot-Govindalayathil, Ayshwarya-Lakshmi; Toda, Masaaki; Yasukawa, Atsushi; Hataji, Osamu; Morser, John; Takei, Yoshiyuki; Gabazza, Esteban C.

doi:10.1165/rcmb.2012-0454oc

Cited by 28 publications

(29 citation statements)

References 30 publications

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“…Mice deficient in TAFI are protected against vascular remodeling in the lung associated with pulmonary hypertension (20). During LPS-induced acute lung injury, TAFI has been shown to be protective, possibly by regulation of the complement pathway (21). However, in a model of abdominal sepsis, TAFI-deficient mice did not show any decrease in fibrin accumulation in the lung (22).…”

Section: Discussionmentioning

confidence: 99%

Antifibrinolytic Mechanisms in Acute Airway Injury after Sulfur Mustard Analog Inhalation

Rancourt

Ahmad

Veress

et al. 2014

Am J Respir Cell Mol Biol

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Acute lung injury in response to mustard gas (sulfur mustard [SM]) inhalation results in formation of fibrin casts, which obstruct the airway. The objective of this study was to identify fibrinolytic pathways that could be contributing to the persistence of airway casts after SM exposure. Rats were exposed to the SM analog, 2-chloroethyl ethyl sulfide, via nose-only aerosol inhalation. At 4 and 18 hours after exposure, animals were killed and airway-capillary leak estimated by measuring bronchoalveolar lavage fluid (BALF) protein and IgM content. The fibrin clot-degrading and plasminogen-activating capabilities of BALF were also assessed by activity assays, whereas Western blotting was used to determine the presence and activities of plasminogen activator inhibitor-1, thrombin activatable fibrinolytic inhibitor and α2-antiplasmin. Measurement of tissue-specific steady-state mRNA levels was also conducted for each fibrinolytic inhibitor to assess whether its synthesis occurs in lung or at extrapulmonary sites. The results of this study demonstrate that fibrin-degrading and plasminogen-activating capabilities of the airways become impaired during the onset of 2-chloroethyl ethyl sulfide-induced vascular leak. Findings of functionally active reservoirs of plasminogen activator inhibitor-1, thrombin activatable fibrinolysis inhibitor, and α2-antiplasmin in BALF indicate that airway fibrinolysis is inhibited at multiple levels in response to SM.

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Section: Discussionmentioning

confidence: 99%

Antifibrinolytic Mechanisms in Acute Airway Injury after Sulfur Mustard Analog Inhalation

Rancourt

Ahmad

Veress

et al. 2014

Am J Respir Cell Mol Biol

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“…In acute lung injury caused by instillation of LPS, Cpb2 − / − mice had exacerbated disease as compared with WT mice . The use of a C5a receptor antagonist demonstrated that CPB2 protected against injury via inactivation of C5a.…”

Section: Roles For Cpb2 Explored In Cpb2−/− Micementioning

confidence: 99%

Carboxypeptidase B2 and carboxypeptidase N in the crosstalk between coagulation, thrombosis, inflammation, and innate immunity

Leung

Morser

2018

Journal of Thrombosis and Haemostasis

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Two basic carboxypeptidases, carboxypeptidase B2 (CPB2) and carboxypeptidase N (CPN) are present in plasma. CPN is constitutively active, whereas CPB2 circulates as a precursor, procarboxypeptidase B2 (proCPB2), that needs to be activated by the thrombin-thrombomodulin complex or plasmin bound to glycosaminoglycans. The substrate specificities of CPB2 and CPN are similar; they both remove C-terminal basic amino acids from bioactive peptides and proteins, thereby inactivating them. The complement cascade is a cascade of proteases and cofactors activated by pathogens or dead cells, divided into two phases, with the second phase only being triggered if sufficient C3b is present. Complement activation generates anaphylatoxins: C3a, which stimulates macrophages; and C5a, which is an activator and attractant for neutrophils. Pharmacological intervention with inhibitors has shown that CPB2 delays fibrinolysis, whereas CPN is responsible for systemic inactivation of C3a and C5a. Among mice genetically deficient in either CPB2 or CPN, in a model of hemolytic-uremic syndrome, Cpb2 mice had the worst disease, followed by Cpn mice, with wild-type (WT) mice being the most protected. This model is driven by C5a, and shows that CPB2 is important in inactivating C5a. In contrast, when mice were challenged acutely with cobra venom factor, the reverse phenotype was observed; Cpn mice had markedly worse disease than Cpb2 mice, and WT mice were resistant. These observations need to be confirmed in humans. Therefore, CPB2 and CPN have different roles. CPN inactivates C3a and C5a generated spontaneously, whereas proCPB2 is activated at specific sites, where it inactivates bioactive peptides that would overwhelm CPN.

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“…The acute inflammatory condition of the pancreas is often subsequent to infectious attacks that may consequently result in multisystem organ dysfunction, including that of acute lung injury (ALI) . The incidence of ALI in cases of AP remains a complex medical issue, which is associated with high rates of mortality ranging from 30% to 40% . ALI occurrence in patients with severe AP exhibits significant variations often depending on predisposing factors, which often dictate outcomes and poor prognoses in an independent fashion .…”

Section: Introductionmentioning

confidence: 99%

Retracted: microRNA‐542‐5p protects against acute lung injury in mice with severe acute pancreatitis by suppressing the mitogen‐activated protein kinase signaling pathway through the negative regulation of P21‐activated kinase 1

Wang

et al. 2018

J of Cellular Biochemistry

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Severe acute pancreatitis (SAP) is a condition associated with high rates of mortality and lengthy hospital stays. In the current study, SAP mouse models were established in BALB/c wild-type and P21-activated kinase 1 (PAK1) knockdown mice with the objective of determining the expression of microRNA-542-5p (miR-542-5p) and the subsequent elucidation of the mechanism by which it influences acute lung injury (ALI) by mediating mitogen-activated protein kinase (MAPK) signaling and binding to PAK1. The targeting relationship between miR-542-5p and PAK1 was verified using the bioinformatics prediction website and by the means of a dual-luciferase reporter assay. Following the SAP model establishment, the mice were assigned into various groups with the introduction of different mimic and inhibitors in an attempt to investigate the effects involved with miR-542-5p on inflammatory reactions among mice with SAP-associated ALI. Our results indicated that PAK1 was targeted and negatively mediated by miR-542-5p. Mice with SAP-associated ALI exhibited an increased wet-to-dry weight ratio, myeloperoxidase activity, serum amylase activity, TNF-α, interleukin-1 beta (IL-1β), and intercellular adhesion molecule-1 (ICAM-1) contents, p-p38MAPK, p-ERK1/2, and p-JNK protein levels as well as PAK1 positive expression, while decreased miR-542-5p levels were observed. Functionally, overexpression of miR-542-5p improves ALI in mice with SAP via inhibition of the MAPK signaling pathway by binding to PAK1.Based on the evidence from experimental models, miR-542-5p was shown to improve ALI among mice with SAP, while suggesting that the effect may be related to the inactivation of the MAPK signaling pathway and downregulation of PAK1 gene. Thus, miR-542-5p could serve as a promising target for ALI treatment.

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Thrombin-Activatable Fibrinolysis Inhibitor Protects against Acute Lung Injury by Inhibiting the Complement System

Cited by 28 publications

References 30 publications

Antifibrinolytic Mechanisms in Acute Airway Injury after Sulfur Mustard Analog Inhalation

Antifibrinolytic Mechanisms in Acute Airway Injury after Sulfur Mustard Analog Inhalation

Carboxypeptidase B2 and carboxypeptidase N in the crosstalk between coagulation, thrombosis, inflammation, and innate immunity

Retracted: microRNA‐542‐5p protects against acute lung injury in mice with severe acute pancreatitis by suppressing the mitogen‐activated protein kinase signaling pathway through the negative regulation of P21‐activated kinase 1

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