FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2029073026> ?p ?o ?g. }

• W2029073026 endingPage "2330" @default.
• W2029073026 startingPage "2327" @default.
• W2029073026 abstract "In this issue, Nishii et al. [1] from Mie University in Japan provide interesting evidence that mice over-expressing protein C inhibitor (PCI) are protected from monocrotaline-induced pulmonary hypertension, due in part to the ability of PCI to inhibit thrombin and down-regulate coagulation. The transgenic mouse over-expressing PCI has enhanced lung secretion of PCI, and the clinical, biochemical and pathological parameters show a reduction in pulmonary hypertension in this experimental model. The pathophysiological role of the human plasma serine protease inhibitor (serpin), protein C inhibitor (PCI, also named plasminogen activator inhibitor-3, systematic name of SERPINA5) has remained elusive since its description in the 1980s [2, 3]. From its name, PCI is an inhibitor of activated protein C (APC) [4-14]. However, PCI also inhibits thrombin (IIa) [8-10, 12], factor Xa and factor XIa [8, 11-14], kallikrein [8, 10, 12, 15-17], urokinase-plasminogen activator and tissue-plasminogen activator (t-PA) [8, 18-23], acrosin [24-26], prostate specific antigen [27, 28], and remarkably, thrombin-thrombomodulin [29-31], which is responsible for generating APC (Fig. 1). The broad protease inhibitory profile of PCI has led many to postulate both specific and generic roles for this serpin. To further complicate matters, the tissue distribution of PCI in humans compared with mice is quite different. Humans show a broad tissue expression pattern for PCI, including the liver, kidney, pancreas, prostate, testes and ovaries [32-37]. Thus, this explains why human PCI (hPCI) is found not only in circulating blood, but also in urine, saliva, amniotic fluid, milk, tears and other body fluids [32]. In contrast, the mouse and rat express PCI only in the reproductive organs and it is not found in the circulating blood [34, 38-42]. Through the creation of a PCI knockout mouse by homologous recombination, one non-hemostatic function of PCI was determined [26]. Male PCI−/− mice were infertile due to abnormal spermatogenesis caused by loss of the Sertoli cell barrier. Unopposed proteolytic activity in these mice brought about the degradation of the cell barrier [26]. Two transgenic mouse models expressing hPCI have been developed. The first was described by Wagenaar et al. [43], in which hPCI was expressed in the liver and found in the circulation. The second hPCI transgenic mouse was described by Hayashi et al. [44] and it expressed hPCI not only in the liver, but also in the kidney, heart, brain, lung and reproductive organs. Role of protein C inhibitor and other serpins (antithrombin, heparin cofactor II, and plasminogen activator inhibitor-1) in the regulation of serine proteases thrombin, activated protein C (APC), APC generation by thrombin-thrombomodulin, and tissue plasminogen activator. All are key proteases in blood coagulation, fibrinolysis, and inflammatory processes. Concerning human health, the presence of PCI in various lung diseases has been described [45]. Fujimoto et al. [45] reported that bronchoalveolar lavage fluid contained increased amounts of both PCI and thrombin-activatable fibrinolysis inhibitor (TAFI) in patients with interstitial lung disease (ILD), particularly in patients with cryptogenic-organizing pneumonia, collagen vascular disease-associated ILD, and sarcoidosis. One explanation of their findings was that the levels of intra-alveolar PCI inhibited both APC activity and activation, which contributed to the pathogenesis of ILD. Therefore, a key question asked in the current study by Nishii et al. [1] was concerning the contribution of PCI to the pathogenesis of pulmonary hypertension. This study uses the hPCI over-expressing transgenic mouse described by Hayashi et al. [44] to begin to address this question regarding pulmonary hypertension, and also provides data on the physiological function of PCI (Fig. 1). Nishii et al. [1] treat mice with monocrotaline to induce pulmonary hypertension. This murine model is representative of pulmonary hypertension caused by a known etiology and not a secondary consequence of cardiovascular disease. Overall, hPCI reduces the disease state in the mouse lung compared with the wild-type mouse. The increase in pressure associated with pulmonary hypertension is not seen in the hPCI over-expressing transgenic mice. Pulmonary hypertension also results in endothelium dysfunction. The vessels in the lungs are hypercoagulant as a result of a decrease in prostaglandin and nitric oxide production. Platelets become activated and will adhere to the vessel wall. Hypercoagulability can be assessed by measuring the formation of thrombin:AT (TAT) complex. Although there is an increase of TAT complex in the hPCI over-expressing transgenic mice when treated with monocrotaline, this increase is significantly less than that in wild-type animals. These results suggest that either there is a decrease in thrombin production that would reduce TAT levels, or the increased presence of PCI is competing with AT to inhibit thrombin, which would also reduce the TAT levels. Either way, the hPCI over-expressing transgenic mouse does not exhibit an increase in activation of coagulation upon treatment with monocrotaline. Although PCI can be procoagulant through its inhibition of the protein C system of proteases, when hPCI is over-expressed in the mouse, its anticoagulant function is more prominent. Fibrinolysis is increased in mice upon treatment with monocrotaline, as indicated by an increase in t-PA activity. As PAI-1 levels are similar between the wild-type and hPCI over-expressing transgenic mice when treated with monocrotaline, the only explanation for a decrease in free t-PA and lowered fibrinolysis in the transgenic mice is the increase in hPCI. Pulmonary vascular endothelium dysfunction also results in the release of various cytokines, such as tumor necrosis factor-alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1), and growth factors, such as platelet-derived growth factor (PDGF) and interleukin-13 (IL-13), that will promote inflammation and vascular wall thickening. The monocrotaline-treated wild-type mice show an increase in all of these protein levels. The hPCI over-expressing transgenic mice treated with monocrotaline exhibit little to no change in these same proteins. Therefore, hPCI reduces the endothelial dysfunction and inflammation associated with pulmonary hypertension. Furthermore, measurements of the pulmonary arteries in the hPCI over-expressing transgenic mouse show a smaller change in vessel wall and lumen area upon monocrotaline treatment. Overall, their results suggest that hPCI inhibits thrombin, a pro-inflammatory and pro-migratory factor, thus, reducing the effects of monocrotaline-induced pulmonary hypertension. The data presented in this paper raise more questions than answers about the in vivo protease specificity of PCI. Their results suggest that PCI exerts both anti-inflammatory and anticoagulant action by inhibiting thrombin, a known participant in coagulation, inflammation and tissue remodeling. This function of PCI is more prominent than its role as an inhibitor of APC. Inhibition of APC alone would result in an increase in coagulation and inflammation, and a reduction of tissue remodeling, which was not seen in the mouse model described. PCI is also antifibrinolytic through its inhibition of t-PA. Whether or not PCI can be used therapeutically for treating pulmonary hypertension remains to be studied. With the aid of new ELISAs reported for PCI-protease complexes [46-49], these tools can provide answers regarding the role of PCI in coagulation and inflammation. The authors state that they have no conflict of interest. Work in the authors’ laboratory is supported in part by Research Grant HL-32656 from the National Institutes of Health and BCTR0503475 and BCTR45206 from the Susan G. Komen Breast Cancer Foundation (F. C. Church). Current stipend support for L. M. Beaulieu is through F31 NS054590-01A1 (NRSA-NIH), and previously from the Integrative Vascular Biology Program (T32 HL69768, NIH) and from the Susan G. Komen Breast Cancer Foundation (BCTR0503475). We thank Dr D. M. Monroe for his insight and helpful comments during the preparation of this Commentary." @default.
• W2029073026 created "2016-06-24" @default.
• W2029073026 creator A5047441263 @default.
• W2029073026 creator A5073856682 @default.
• W2029073026 date "2006-11-01" @default.
• W2029073026 modified "2023-09-30" @default.
• W2029073026 title "Is protein C inhibitor antithrombotic and protective in pulmonary hypertension?" @default.
• W2029073026 cites W118698600 @default.
• W2029073026 cites W1512865667 @default.
• W2029073026 cites W1516487765 @default.
• W2029073026 cites W1517450192 @default.
• W2029073026 cites W1519445164 @default.
• W2029073026 cites W1539813719 @default.
• W2029073026 cites W1562054825 @default.
• W2029073026 cites W1569894631 @default.
• W2029073026 cites W158681976 @default.
• W2029073026 cites W1599771874 @default.
• W2029073026 cites W1967496809 @default.
• W2029073026 cites W1973854172 @default.
• W2029073026 cites W1982382998 @default.
• W2029073026 cites W1988472915 @default.
• W2029073026 cites W1988722656 @default.
• W2029073026 cites W1989493467 @default.
• W2029073026 cites W1994653201 @default.
• W2029073026 cites W1997658029 @default.
• W2029073026 cites W2006122994 @default.
• W2029073026 cites W2011708104 @default.
• W2029073026 cites W2015861384 @default.
• W2029073026 cites W2023803728 @default.
• W2029073026 cites W2032858201 @default.
• W2029073026 cites W2033226026 @default.
• W2029073026 cites W2036687837 @default.
• W2029073026 cites W2038733492 @default.
• W2029073026 cites W2040434023 @default.
• W2029073026 cites W2047916400 @default.
• W2029073026 cites W2054559258 @default.
• W2029073026 cites W2056440360 @default.
• W2029073026 cites W2068493423 @default.
• W2029073026 cites W2074683258 @default.
• W2029073026 cites W2075474522 @default.
• W2029073026 cites W2075796903 @default.
• W2029073026 cites W2096611320 @default.
• W2029073026 cites W2150615418 @default.
• W2029073026 cites W2155758822 @default.
• W2029073026 cites W2156522109 @default.
• W2029073026 cites W2163086793 @default.
• W2029073026 cites W2176451254 @default.
• W2029073026 cites W2333961730 @default.
• W2029073026 cites W2413507176 @default.
• W2029073026 cites W2416513274 @default.
• W2029073026 cites W2461653914 @default.
• W2029073026 cites W2470438175 @default.
• W2029073026 cites W2472015541 @default.
• W2029073026 cites W316983608 @default.
• W2029073026 cites W95127911 @default.
• W2029073026 doi "https://doi.org/10.1111/j.1538-7836.2006.02214.x" @default.
• W2029073026 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4070371" @default.
• W2029073026 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/16981887" @default.
• W2029073026 hasPublicationYear "2006" @default.
• W2029073026 type Work @default.
• W2029073026 sameAs 2029073026 @default.
• W2029073026 citedByCount "3" @default.
• W2029073026 countsByYear W20290730262021 @default.
• W2029073026 countsByYear W20290730262022 @default.
• W2029073026 crossrefType "journal-article" @default.
• W2029073026 hasAuthorship W2029073026A5047441263 @default.
• W2029073026 hasAuthorship W2029073026A5073856682 @default.
• W2029073026 hasBestOaLocation W20290730262 @default.
• W2029073026 hasConcept C126322002 @default.
• W2029073026 hasConcept C164705383 @default.
• W2029073026 hasConcept C2777015399 @default.
• W2029073026 hasConcept C2780930700 @default.
• W2029073026 hasConcept C71924100 @default.
• W2029073026 hasConcept C98274493 @default.
• W2029073026 hasConceptScore W2029073026C126322002 @default.
• W2029073026 hasConceptScore W2029073026C164705383 @default.
• W2029073026 hasConceptScore W2029073026C2777015399 @default.
• W2029073026 hasConceptScore W2029073026C2780930700 @default.
• W2029073026 hasConceptScore W2029073026C71924100 @default.
• W2029073026 hasConceptScore W2029073026C98274493 @default.
• W2029073026 hasIssue "11" @default.
• W2029073026 hasLocation W20290730261 @default.
• W2029073026 hasLocation W20290730262 @default.
• W2029073026 hasLocation W20290730263 @default.
• W2029073026 hasLocation W20290730264 @default.
• W2029073026 hasOpenAccess W2029073026 @default.
• W2029073026 hasPrimaryLocation W20290730261 @default.
• W2029073026 hasRelatedWork W2546345250 @default.
• W2029073026 hasRelatedWork W2596550892 @default.
• W2029073026 hasRelatedWork W2615510955 @default.
• W2029073026 hasRelatedWork W2766845515 @default.
• W2029073026 hasRelatedWork W2900348376 @default.
• W2029073026 hasRelatedWork W2906583422 @default.
• W2029073026 hasRelatedWork W3159138021 @default.
• W2029073026 hasRelatedWork W4206060802 @default.
• W2029073026 hasRelatedWork W4251778690 @default.
• W2029073026 hasRelatedWork W1968744067 @default.
• W2029073026 hasVolume "4" @default.

• next