MMP-8 Oulun Yliopiston väitöskirjana. Suoraan suomeksi!

LÄHDE: 

	Pradhan-Palikhe, Pratikshya Matrix metalloproteinase-8 as a diagnostic tool for the inflammatory and malignant diseases
	University of Oulu, Faculty of Medicine, Institute of Dentistry, Department of Diagnostics and Oral Medicine University of Helsinki, Faculty of Medicine, Institute of Dentistry, Department of Cell Biology of Oral Diseases, Biomedicum Helsinki Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital

Tiivistelmä (Suora sitaatti)

Matriksin metalloproteinaasit (MMP:t) ovat sinkkiriippuvaisia endopeptidaaseja, jotka kuuluvat laajaan proteiineja pilkkovaan proteolyyttiseen entsyymi perheeseen.
MMP:ien tehtävä on pilkkoa ja uudelleen muokata soluväliaineen proteiineja kasvun, elinten kehityksen ja kudosten uusiutumisen aikana, mutta MMP:t toimivat aktiivisesti myös patologisissa prosesseissa, kuten tulehdustiloissa ja syövissä.
 Syövissä MMP:en vaikutus voi johtaa ei-toivottuun kudostuhoon.

 Yksi laajimmin tutkituista MMP-ryhmän entsyymeistä on MMP-8, jonka alunpitäen ajateltiin ilmenevän vain neutrofiileissä. Nykytietämyksen mukaan MMP-8:aa ilmentyy myös mm. makrofaageissa, plasmasoluissa, T-soluissa, endoteelisoluissa, sileälihassoluissa, suun limakalvon epiteelisoluissa ja fibroplasteissa. MMP-8:aa on aikaisemmin tutkittu erityisesti tulehdustiloissa ja pahanlaatuisissa kasvaimissa.

 Korkean MMP-8 seerumipitoisuuden on havaittu liittyvän valtimokovettumatautiin ja huonoon ennusteeseen sydän- ja verisuonisairauksissa, kun taas kohonnut MMP-8:n pitoisuus plasmassa suojaa imusolmuke-etäpesäkkeiltä.

 Tiedetään, että tietyt muutokset MMP-8:n geenissä voivat muuttaa sen promoottoriaktiviteettia ja täten säädellä geenin ilmentymistä.  MMP-8:n geenimuutokset vaikuttanevat raskauden kulkuun sekä keuhko- ja rintasyövän ennusteeseen.

 Tutkimushypoteesimme mukaan MMP-8:n seerumipitoisuudet riippuvat vaihtelusta MMP-8:aa koodaavassa geenissä ja niitä voidaan pitää uusina riskinarvioinnin merkkiaineina tautitiloissa.

Tavoitteenamme oli osoittaa yleisesti MMP:ien ja erityisesti MMP-8:n sekä näiden proteinaasien säätelytekijöiden merkitys tietyissä tulehdustiloissa ja maligniteeteissa, kuten sepelvaltimotaudissa ja pään ja kaulan alueen syövissä.

 Havaitsimme, että korkea MMP-8 seerumipitoisuus ja alhainen myeloperoksidaasitaso yhdistyvät vahvasti valtimotautiriskiin.

 Lisäksi osoitimme, että tietty MMP-8:n geenimuunnos on suojaava tekijä valtimotaudille ja että MMP-8:n seerumikonsentraatio on siitä riippuvainen terveillä tutkituilla.

 Tämän lisäksi todensimme, että MMP:n kudosestäjän (tissue inhibitor of matrix metalloproteinases, TIMP-1) plasmapitoisuus liittyy pään ja kaulan alueen levyepiteelisyöpää sairastavien potilaiden eloonjääntiin ja että TIMP-1:n genotyyppi liittyy sen plasmapitoisuuteen ainoastaan naisilla.

Tulostemme mukaan seerumin MMP-8-pitoisuutta voidaan pitää hyvänä riskinarviointivälineenä verisuonitaudeissa sekä TIMP-1-pitoisuutta vastaavasti pään ja kaulan alueen levyepiteelisyövissä.
 Saadut tulokset tukevat olettamustamme, jonka mukaan MMP-8 on tärkeä tautimarkkeri. Tämä on lisännyt kiinnostusta selvittää MMP:ien merkitystä laajemmin muissa tulehdustiloissa ja syövissä.
 Jos tulokset saadaan toistetuksi laajemmassa tutkimusaineistossa, seerumin MMP-8:sta voidaan kehittää kliinisten ja analyyttisten laboratorioiden käyttöön sopiva diagnostinen menetelmä.

MMP- kaskadi iskemisessä halvauksessa

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3615191/

Frontiers Media SA

Matrix Metalloproteinases and Blood-Brain Barrier Disruption in Acute Ischemic Stroke

Shaheen E. Lakhan, Annette Kirchgessner, [...], and Aidan Leonard

Additional article information

Abstract

Ischemic stroke continues to be one of the most challenging diseases in translational neurology. Tissue plasminogen activator (tPA) remains the only approved treatment for acute ischemic stroke, but its use is limited to the first hours after stroke onset due to an increased risk of hemorrhagic transformation over time resulting in enhanced brain injury. 

 In this review we discuss the role of matrix metalloproteinases (MMPs) in blood-brain barrier (BBB) disruption as a consequence of ischemic stroke.

 MMP-9 in particular appears to play an important role in tPA-associated hemorrhagic complications. Reactive oxygen species (ROS) can enhance the effects of tPA on MMP activation through the loss of caveolin-1 (cav-1), a protein encoded in the cav-1 gene that serves as a critical determinant of BBB permeability. 

 This review provides an overview of MMPs’ role in BBB breakdown during acute ischemic stroke. The possible role of MMPs in combination treatment of acute ischemic stroke is also examined.

Keywords: '

MMPs  matrix metalloproteinases, 

BBB blood-brain barrier,

 stroke, 

caveolin-1, 

ROS  reactive oxygen species

• Introduction

Stroke is the third leading cause of death in industrialized countries (Lo et al., 2003) and the most frequent cause of permanent disability in adults worldwide (Donnan et al., 2008). Acute ischemic stroke is the most common form of stroke and results from sudden blood vessel occlusion by a thrombus or embolism, resulting in an almost immediate loss of oxygen and glucose to the cerebral tissue. Although different mechanisms are involved in the pathogenesis of stroke, increasing evidence shows that ischemic injury and inflammation account for its pathogenic progression (Muir et al., 2007). Cerebral ischemia initiates cascades of pathological events, including vasogenic edema, disruption of the blood-brain barrier (BBB), intracranial hemorrhage (ICH), astroglial activation, and neuronal death. This ultimately causes irreversible neuronal injury in the ischemic core within minutes of the onset (Dimagl et al., 1999).

Despite advances in understanding the pathophysiology of cerebral ischemia, treatment options for acute ischemic stroke remain very limited (Donnan et al., 2008). Intravenous recombinant tissue plasminogen activator (tPA) remains the only FDA-approved thrombolytic therapy for reestablishing blood flow and salvaging brain tissue after acute ischemic stroke (Lijnen and Collen, 1987; National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, 1995). By degrading fibrin clots, tPA acts as a thrombolytic agent through the activation of plasminogen to plasmin (Lijnen and Collen, 1987).

Although tPA administered within 4.5h or less of symptom onset improves the functional outcome in patients (Miller et al., 2012; Wardlaw et al., 2012), it induces a 10-fold increase of symptomatic intracranial hemorrhage (ICH) (National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, 1995).

 Furthermore, delayed reperfusion with tPA beyond 3h is associated with an increased risk of hemorrhagic transformation (HT) with enhanced brain injury (Clark et al., 1999).

Moreover, tPA may cause injury to the BBB by activating matrix metalloproteinases (MMPs) (Wang et al., 2003).

 Thus, the therapeutic application of tPA is limited to specific clinical settings (National Institute of Neurological Disorders and Stroke t-PA Stroke Study Group, 1997). There is a pressing need to identify new combination therapies that can prevent tPA-associated ICH as well as extend the time window for thrombolysis without reducing its benefits.

Recent studies suggest that tPA adverse effects are mediated through MMPs, a family of >20 zinc-dependent enzymes that increase BBB permeability by degrading components of the extracellular matrix (ECM) and tight junctions (TJ) in endothelial cells (ECs) (Lapchak et al., 2000; Lijnen, 2001; Briasoulis et al., 2012).

 Increased expression and activation of MMPs plays a pivotal role in thrombolysis-mediated BBB leakage and edema, resulting in intracranial hemorrhage (Lapchak et al., 2000; Sumii and Lo, 2002). Reactive oxygen species (ROS) and its signaling pathways can enhance the effects of tPA on MMP activation (Harada et al., 2012).

•  In this review we provide an overview of the role of MMPs in BBB breakdown during acute ischemic stroke and the potential for MMP inhibition in the treatment of stroke.

• Structural Components of the BBB/Neurovascular Unit

The BBB is a dynamic interface between the peripheral circulation and the CNS. It controls the influx and efflux of biological substances needed for the brain metabolic processes, as well as for neuronal function. Thus, the functional and structural integrity of the BBB is vital in maintaining brain homeostasis.

The structure of the BBB has been discussed in reviews elsewhere (Sandoval and Witt, 2008; Abbott et al., 2010). Briefly, the anatomical substrate of the BBB is the cerebral microvascular endothelium, which together with the closely associated astrocytes, pericytes, neurons, and the ECM, constitute a “neurovascular unit” that is essential for the health and function of the CNS (del Zoppo, 2009). Cell–cell interactions in the neurovascular unit form the basis for brain function. Dysfunctional signaling in the neurovascular unit underlies the basis for disease. Alterations in microvessel integrity may have other effects within the neurovascular unit that affect neuronal function. The mechanisms of neurovascular unit response to stroke are not fully understood. However, any fully effective stroke therapy must include both prevention of cell death as well as repair of integrated neurovascular function.

The microcapillary endothelium is composed of TJs and follow a biphasic time course. Morphologically, BBB opening correlates with a redistribution of the TJ and AJ proteins from the plasma membrane to the cytoplasm as well as reorganization of the endothelial actin cytoskeleton.
 The extent of BBB disruption is associated with the type, severity, and duration of ischemic insults.
The molecular mechanisms underlying BBB opening are not fully understood, although several MMPs are believed to regulate BBB permeability and function during ischemic stroke (Mun-Bryce and Rosenberg, 1998).

The expression of MMPs in the adult brain is very low to undetectable, but clinical and experimental studies have shown that several MMPs are upregulated and activated after ischemic stroke (Lee et al., 2007; McColl et al., 2008). 

 MMPs disrupt the BBB by degrading the TJ proteins and basal lamina proteins, thereby leading to BBB leakage, leukocyte infiltration, brain edema, and hemorrhage. 

 Evidence suggests that MMP-2 and MMP-9 play different roles in BBB disruption during ischemic stroke.

•  MMP-2 KO( knock out)  does not provide neuroprotection in mouse models of permanent and transient MCAO (Asahi et al., 2001b). Consistently, in vitro data show that MMP-2 is not toxic to neurons in hippocampal slice preparations (Cunningham, 2005).

•  In contrast, MMP-9 KO (knock out)  provides strong neuroprotection in the same animal models, and in vitro MMP-9 is toxic to neurons in hippocampal slice preparations and in cultured primary cortical neurons (Asahi et al., 2000b).

In support of these data, a clinical study (Lucivero et al., 2007) reported an increase in plasma MMP-2 only in patients with lacunar (mild) stroke early (within 12h) and this was related to better outcome. In contrast, an increase in plasma MMP-9 was observed later (at day 7) and related to more severe stroke.

Matrix metalloproteinases are thought to have beneficial roles in stroke recovery. 

Shortly after an ischemic insult, a cascade of events is initiated in an attempt to repair the damage, a process similar to that found in wound healing (National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, 1995; Wardlaw et al., 2012). 

Following injury, blood vessels are dependent on the plasminogen activator system and

 on MMPs for their regeneration (Suzuki et al., 2009). 

It may be that a balanced level of MMP activity is important for vascular remodeling after ischemic brain injury (Yang and Rosenberg, 2011). Therefore, extended inhibition of MMPs, especially through the use of broad-spectrum inhibitors, might prove deleterious (National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, 1995; Donnan et al., 2008).

• MMP-2 (gelatinase A)

Matrix metalloproteinase-2 is one of the two described human gelatinases in the MMP family, named for their ability to proteolytically degrade gelatine (denatured collagen) (see Table ​Table11 for a list of MMPs and their putative roles in acute ischemic stroke). MMP-2 is ubiquitously expressed as a 72-kDa proenzyme and subject to extensive glycosylation (Klein and Bischoff, 2011).

(KUVA)

• 3 tuntia halvauksesta   NNP-2:n aiheuttama  BBB läpivuoto

A  study provided indirect evidence that MMP-2 played a key role in initial opening of the BBB after cerebral ischemia (Rosenberg et al., 1998). In a rat model of transient MCAO, the initial opening of the BBB occurred as early as 3h after reperfusion and increased activation of MMP-2 correlated with the early opening of the BBB and the degradation of the TJ proteins claudin-5 and occludin in both cerebral hemispheres (Rosenberg et al., 1992; Yang et al., 2007). Experimental data clearly demonstrated an increase in MMP-2 at 3h, along with increased expression of the MMP-2 activators, MT1-MMP and furin.

A synthetic MMP inhibitor (BB-1101) blocked the increase in brain MMP-2 levels, but it did not have any effect on stroke lesion size at 48h after MCAO and had significant adverse effects on neurologic function in rats at 3 and 4weeks after MCAO (Rosenberg et al., 1992, 1998; Yang et al., 2007).
 In contrast, direct injection of MMP-2 into the rat brain resulted in the disruption of the BBB with subsequent hemorrhage, and this effect was inhibited by co-administration of TIMP-2 (Rosenberg et al., 1992). Thus, the early degradation of TJ proteins seems to be associated with a marked increase in MMP-2 in the early phase of ischemia.

Suofu et al. (2012) recently assessed the effects of MMP-2 KO, MMP-9 KO, and MMP-2/9 double KO (dKO) in protecting against mechanical reperfusion-induced HT and other brain injuries after the early stages of cerebral ischemia in mice of the same genetic background.

 Both MMP-2 and MMP-9 specifically attack the type IV collagen, laminin, and fibronectin, which are the major components of the basal lamina around the cerebral blood vessels. MCAO was performed and reperfusion was started at 1 or 1.5h after onset of MCAO. Mice were sacrificed 8h later. Both pro- and active-MMP-2 and MMP-9 levels were significantly elevated in the early ischemic brain. After the early stages of ischemia and reperfusion, the hemorrhagic incidence was reduced in the cortex of MMP-2 KO mice. The hemorrhagic volume was also significantly decreased in the cortexes of MMP-2 and/or -9 KO mice. In the basal ganglia, MMP-2 KO and MMP-2/9 dKO mice displayed a remarkable decrease in hemorrhagic volume, but MMP-9 deletion did not protect against hemorrhage. MMP-2 and/or -9 KO mice displayed significantly decreased infarction volume in both the cortex and striatum, in addition to improved neurological function. The results suggested that MMP-2 deficiency as well as MMP-2 and MMP-9 double deficiency were more protective than MMP-9 deficiency alone against HT after the early stages of ischemia and reperfusion.

• MMP-3 (stromelysin-1)

Matrix metalloproteinase-3 (stromelysin-1) was first described in 1985 as a 51-kDa protein secreted by rabbit fibroblasts (Chin et al., 1985). MMP-3 could be distinguished from collagenases by the inability to degrade type I collagen. The substrate specificity of MMP-3 is broad and MMP-3 has been found to degrade

JATKUU (Suomennettava myöh,)

Elastaasi ja aortan aneurysma. hypereglykemia kohotaa PAI-1 ilmenemää.

Hakusana:
ELASTASE and Aortic Aneyrysm- association
Search Pub Med 222 answers.
Results: 1 to 20 of 222

• (1) Hyperglykemian merkitys aortan aneurysmassa.

Miyama N, Dua MM et al. Hyperglycemia limits experimental aortic aneurysm progression.
J Vasc Surg. 2010 Jul 31.PMID: 20678880

CONCLUSIONS: Hyperglycemia reduces progression of experimental AAA disease; lowering of serum glucose levels with insulin treatment diminishes this protective effect. Identifying mechanisms of hyperglycemic aneurysm inhibition may accelerate development of novel clinical therapies for AAA disease

• (2) Ateroskleroosin ja vatsa-aortan aneurysmataudin riskiin  assosioituu kohonnut MMP-8 ja alentunut myeloperoksidaasi.

Pradhan-Palikhe P, Vikatmaa P et al.  Elevated MMP-8 and decreased myeloperoxidase concentrations associate significantly with the risk for peripheral atherosclerosis disease and abdominal aortic aneurysm. Scand J Immunol. 2010 Aug;72(2):150-7.PMID: 20618774
. Combination of high MMP-8 and low MPO level in serum eventually reflecting selectively modified neutrophil degranulation may indicate increased risk for arterial disease.

• (3) Transglutaminaasi 2 aktivoitumisen protektiivinen vaikutus  vatsa-aortan kehittymisen suhteen koe-eläimessä. TG2 mahdollisesti on  extrasellulaarimatriksia suojaava.

Munezane T, Hasegawa T et al. Activation of transglutaminase type 2 for aortic wall protection in a rat abdominal aortic aneurysm formation. J Vasc Surg. 2010 Jul 6 ]PMID: 20615646
 ---Similar mRNA upregulation of TNF-alpha, interleukin-1beta, matrix metalloproteinases (MMP)-2, MMP-9, and tissue inhibitors of metalloproteinases (TIMP)-1 and TIMP-2 was observed in the AAAs, and TG2 and TNF-alpha were colocalized in the aortic walls at 1 week.---
 Ex vivo experiments showed that mRNA expressions of TNF-alpha, MMP-2, and MMP-9 in the cultured AAA tissue were decreased by exogenous TG2, whereas were increased by cystamine (TG2 inhibitor) . TNF-alpha exposure to the AAA tissues was significantly upregulated TG2 mRNA expression (P = .0333).
CONCLUSION: TG2 expression and activity in AAA formation were enhanced, possibly due to compensatory reaction. TG2 has a potential role of ECM protector in aortic walls during remodeling of the AAAs.

• (4)  Vatsa-aortan aneurysman nopeaa kasvua heijastava seikka. Hp 2-1 fenotyyppi.   Elastaasi ja CRP koholla. 

Wiernicki I, Safranow K et al.  Haptoglobin 2-1 phenotype predicts rapid growth of abdominal aortic aneurysms. J Vasc Surg. 2010 Jun 4.
Elastase and C-reactive protein (CRP) levels are elevated in patients with AAAs.
Haptoglobin (Hp) polymorphism is associated with the prevalence and clinical evolution of many inflammatory diseases and atherosclerosis. Circulating neutrophils and neutrophil-associated proteases are an important initial component of experimental abdominal aortic aneurysm (AAA) formation.
CONCLUSIONS: The Hp 2-1 phenotype showed a strong association with increased rates of the expansion of AAAs and may be a useful independent predictor of growth rate. Further large follow-up studies will be needed to investigate the pathomechanisms of association and the role of elastase and inflammation in the progression of AAA

• (5) Hyperglysemia moduloi PAI-1 ilmenemää ja aortan diametria kokeellisessa aneurysmassa koe-eläimellä. Fibrinolyyttisellä tiellä on osuutta  vatsa-aortan aneurysman patofysiologiassa

Dua MM, Miyama N et al. Hyperglycemia modulates plasminogen activator inhibitor-1 expression and aortic diameter in experimental aortic aneurysm disease. Surgery. 2010 Aug;148(2):429-35. Epub 2010 Jun 19.PMID: 20561659
CONCLUSION: Hyperglycemia increases PAI-1 expression and attenuates AAA diameter in experimental AAA disease. These results emphasize the role of the fibrinolytic pathway in AAA pathophysiology, and suggest a candidate mechanism for hyperglycemic inhibition of AAA disease. Copyright 2010 Mosby, Inc. All rights reserved.

• (6.) Vatsa-aortan aneurysman ohuen trombin kattamassa pinnassa  on matrixia hajoittava proteolyyttinen aktiivisuus suurempaa kuin paksussa trombissa. Aortan elastiinin  säilyminen on tärkeää , jotta aneurysman muodostus estyisi. Jos trombi vaikuttaa ohuelta, elastaasiaktiivisuus voi olla kiihtyneempää.

Wiernicki I, Stachowska E et al. .Enhanced matrix-degrading proteolytic activity within the thin thrombus-covered wall of human abdominal aortic aneurysms.
Atherosclerosis. 2010 May 6.PMID: 20537648 

OBJECTIVE: The maintenance of an arterial elastin's integrity is essential in the prevention of abdominal aortic aneurysm (AAA) development. So far, the effect of intraluminal thrombus (ILT) thickness on the elastolytic activity within the AAA wall has not been studied. In the present study the hypothesis that thin thrombus is associated with enhanced proteolytic activity within human AAA wall was investigated

• (7). Jos trombiinilla aktivoituvan fibrinolyysin estäjän  karboksypeptidaasin (CPB)  aktiivisuus puuttuu, vatsa-aortan aneurysman muodostus kiihtyy koe-eläimellä.Katso kuva: http://atvb.ahajournals.org/content/30/7/1363/F5.large.jpg

Schultz G, Tedesco MM et al. Enhanced abdominal aortic aneurysm formation in thrombin-activatable procarboxypeptidase B-deficient mice. Arterioscler Thromb Vasc Biol. 2010 Jul;30(7):1363-70. Epub 2010 Apr 29.PMID: 20431069 [PubMed - indexed for MEDLINE]Related citations

OBJECTIVE: To determine whether procarboxypeptidase B (pCPB)(-/-) mice are susceptible to accelerated abdominal aortic aneurysm (AAA) development secondary to unregulated OPN-mediated mural inflammation in the absence of CPB inhibition. METHODS AND RESULTS: Thrombin/thrombomodulin cleaves thrombin-activatable pCPB or thrombin-activatable fibrinolysis inhibitor, activating CPB, which inhibits the generation of plasmin and inactivates proinflammatory mediators (complement C5a and thrombin-cleaved osteopontin [OPN]). Apolipoprotein E(-/-)OPN(-/-) mice are protected from experimental AAA formation. Murine AAAs were created via intra-aortic porcine pancreatic elastase (PPE) infusion. Increased mortality secondary to AAA rupture was observed in pCPB(-/-) mice at the standard PPE dose. At reduced doses of PPE, pCPB(-/-) mice developed larger AAAs than wild-type controls (1.01+/-0.27 versus 0.68+/-0.05 mm; P=0.02 [mean+/-SD]). C5(-/-) and OPN(-/-) mice were not protected against AAA development. Treatment with tranexamic acid inhibited plasmin generation and abrogated enhanced AAA progression in pCPB(-/-) mice. CONCLUSIONS: This study establishes the role of CPB in experimental AAA disease, indicating that CPB has a broad anti-inflammatory role in vivo. Enhanced AAA formation in the PPE model is the result of increased plasmin generation, not unregulated C5a- or OPN-mediated mural inflammation.
 TÄTÄ ASIAA TÄYTYY KATSOA TARKEMMIN. Muistiin 16.4. 2014. Päivitys jatkuu.

8.

Acoustic radiation force impulse imaging on ex vivo abdominal aortic aneurysm model.

Tierney AP, Dumont DM, Callanan A, Trahey GE, McGloughlin TM.

Ultrasound Med Biol. 2010 May;36(5):821-32. Epub 2010 Apr 9.PMID: 20381946 [PubMed - indexed for MEDLINE]Related citations

9.

Efficacy of neutrophil elastase inhibitor on type A acute aortic dissection.

Niino T, Hata M, Sezai A, Yoshitake I, Unosawa S, Fujita K, Shimura K, Osaka S, Minami K.

Thorac Cardiovasc Surg. 2010 Apr;58(3):164-8. Epub 2010 Apr 7.PMID: 20376727 [PubMed - indexed for MEDLINE]Related citations
BACKGROUND: Surgery for type A acute aortic dissection (AAD) is associated with a high mortality and incidence of postoperative complications, including acute respiratory failure and coagulopathy. Aim of the study was to investigate the effects of sivelestat on pulmonary function and coagulopathy in patients undergoing surgery for AAD.
METHODS: The platelet count, antithrombin III (AT III) level, leukocyte count, C-reactive protein (CRP) level, prothrombin time (PT), activated partial thrombin time (APTT), and prothrombin time-international normalized ratio (PT-INR) were measured.
 RESULTS: The postoperative decrease of AT III and the platelet count on admission to the intensive care unit (ICU) and 3 hours later were significantly less in group I. The leukocyte count and the values of CRP, PT, APTT, and PT-INR did not differ significantly between the groups. The duration of mechanical ventilation after surgery tended to be shorter in group I.
 CONCLUSIONS: Sivelestat significantly reduced the postoperative decreases in AT III and platelet count in patients undergoing emergency surgery for AAD. Georg Thieme Verlag KG Stuttgart New York

10.
Thrombus versus wall biological activities in experimental aortic aneurysms.
Coutard M, Touat Z, Houard X, Leclercq A, Michel JB.
J Vasc Res. 2010;47(4):355-66. Epub 2009 Dec 16.PMID: 20016209 [PubMed - indexed for MEDLINE]Free ArticleRelated citations

11.
A novel rat model of abdominal aortic aneurysm using a combination of intraluminal elastase infusion and extraluminal calcium chloride exposure.
Tanaka A, Hasegawa T, Chen Z, Okita Y, Okada K.
J Vasc Surg. 2009 Dec;50(6):1423-32.PMID: 19958989 [PubMed - indexed for MEDLINE]Related citations
CONCLUSION: The rat AAA model using a combination of intraluminal elastase infusion and extraluminal calcium chloride exposure is simple and easy to perform and is highly reliable and reproducible to create a saccular aneurysm similar to human AAAs. This model could be more useful to clarify AAA pathogenesis, mechanisms, and treatment interventions in experimental researches.

12.
Smooth muscle phenotypic modulation is an early event in aortic aneurysms.
Ailawadi G, Moehle CW, Pei H, Walton SP, Yang Z, Kron IL, Lau CL, Owens GK.
J Thorac Cardiovasc Surg. 2009 Dec;138(6):1392-9.PMID: 19931668 [PubMed - indexed for MEDLINE]Related citations

13.
Nitric oxide induces the progression of abdominal aortic aneurysms through the matrix metalloproteinase inducer EMMPRIN.
Lizarbe TR, Tarín C, Gómez M, Lavin B, Aracil E, Orte LM, Zaragoza C.
Am J Pathol. 2009 Oct;175(4):1421-30. Epub 2009 Sep 24.PMID: 19779140 [PubMed - indexed for MEDLINE]Related citations

14.
Decreased collagen and increased matrix metalloproteinase-13 in experimental abdominal aortic aneurysms in males compared with females.
Cho BS, Roelofs KJ, Ford JW, Henke PK, Upchurch GR Jr.
Surgery. 2010 Feb;147(2):258-67. Epub 2009 Sep 20.PMID: 19767051 [PubMed - indexed for MEDLINE]Related citations

15.
Expression of annexin II in experimental abdominal aortic aneurysms.
Hayashi T, Morishita E, Ohtake H, Oda Y, Asakura H, Nakao S.
Int J Hematol. 2009 Oct;90(3):336-42. Epub 2009 Sep 16.PMID: 19756921 [PubMed - indexed for MEDLINE]Related citations
Annexin II is a receptor of tissue-type plasminogen activator (t-PA). We have previously identified annexin II by immunolocalization in human atherosclerotic abdominal aortic aneurysms (AAAs). To investigate possible interactions between annexin II and AAA development, we examined annexin II mRNA and protein expression in a rat model of experimental AAA. AAAs were induced in rats by transient aortic infusion of elastase.

16.
Critical role of mast cell chymase in mouse abdominal aortic aneurysm formation.
Sun J, Zhang J, Lindholt JS, Sukhova GK, Liu J, He A, Abrink M, Pejler G, Stevens RL, Thompson RW, Ennis TL, Gurish MF, Libby P, Shi GP.
Circulation. 2009 Sep 15;120(11):973-82. Epub 2009 Aug 31.PMID: 19720934 [PubMed - indexed for MEDLINE]Free PMC ArticleFree textRelated citations
CONCLUSIONS: High chymase-positive mast cell content in human AAA lesions, greatly reduced AAA formation in Mcpt4(-/-) mice, and significant correlation of serum chymase levels with human AAA expansion rate suggests participation of mast cell chymase in the progression of human and mouse AAA.

17.
Immune cells and molecular mediators in the pathogenesis of the abdominal aortic aneurysm.
Rizas KD, Ippagunta N, Tilson MD 3rd.
Cardiol Rev. 2009 Sep-Oct;17(5):201-10. Review.PMID: 19690470 [PubMed - indexed for MEDLINE]Related citations
Abdominal aortic aneurysm is a multifactorial disease with genetic risk factors and an immunologic component. Immune cells, including macrophages, neutrophils, mast cells, B- and T- lymphocytes, along with vascular smooth muscle cells and adventitial fibroblasts, produce cytokines and enzymes, promoting an inflammatory reaction, extracellular matrix (ECM) degradation, and neovascularization. Among the different enzymes secreted by immune and stromal cells, matrix metalloproteinase (MMP)-2, MMP-9, MMP-12, cathepsins, and neutrophil elastase (NE)  cause medial degeneration. Chymase causes smooth muscle cell apoptosis, and MMP-3, MMP-8, and MMP-13 cause adventitial collagen degradation, promoting abdominal aortic aneurysm rupture. At the same time chemokines (interleukin 8, macrophage inflammatory protein 1 alpha, monocyte chemotactic protein-1) cause recruitment and proliferation of inflammatory cells, whereas cytokines (vascular endothelial growth factor and transforming growth factor-beta) promote neoangiogenesis.

18.
Fusiform aneurysm model in rabbit carotid artery.
Reinald N, Fournier B, Naveau A, Couty L, Lemitre M, Seguier S, Coulomb B, Gogly B, Lafont A, Durand E.
J Vasc Res. 2010;47(1):61-8. Epub 2009 Aug 7.PMID: 19672109 [PubMed - indexed for MEDLINE]Related citations

19.
Creation of murine experimental abdominal aortic aneurysms with elastase.
Azuma J, Asagami T, Dalman R, Tsao PS.
J Vis Exp. 2009 Jul 23;(29). pii: 1280. doi: 10.3791/1280.PMID: 19629030 [PubMed - indexed for MEDLINE]Related citations

20.
Gender-dependent differential phosphorylation in the ERK signaling pathway is associated with increased MMP2 activity in rat aortic smooth muscle cells.
Ehrlichman LK, Ford JW, Roelofs KJ, Tedeschi-Filho W, Futchko JS, Ramacciotti E, Eliason JL, Henke PK, Upchurch GR Jr.
J Surg Res. 2010 May 1;160(1):18-24. Epub 2009 May 8.PMID: 19592018 [PubMed - indexed for MEDLINE]Related citations

These data provide evidence implicating alterations in p-ERK signaling via the up-regulation of MMPs as a potential explanation for gender-related discrepancies in AAA formation