TIMP-2 reduces proteolytic opening of blood-brain barrier by type IV collagenase

Rosenberg, Gary A.; Kornfeld, Mario; Estrada, Eduardo Y.; Kelley, Robert O.; Liotta, Lance A.; Stetler-Stevenson, William G.

doi:10.1016/0006-8993(92)90681-x

Cited by 273 publications

(182 citation statements)

References 15 publications

Supporting

Mentioning

170

Contrasting

Unclassified

Order By: Relevance

“…40,83 The rise in MMP-2 correlates with early opening of the BBB and degradation of the TJPs claudin-5 and occludin in rodent MCAO models. 78,80,84,85 In addition, direct injection of MMP-2 into rodent brain disrupts the BBB and results in hemorrhage, further supporting a role of MMP-2 in early BBB disruption and HT in stroke. 84 Though MMP-2 is associated with early BBB disruption after stroke, its role in HT and effect on stroke outcome remains less clear.…”

Section: Early and Delayed Hemorrhagic Transformationmentioning

confidence: 89%

“…78,80,84,85 In addition, direct injection of MMP-2 into rodent brain disrupts the BBB and results in hemorrhage, further supporting a role of MMP-2 in early BBB disruption and HT in stroke. 84 Though MMP-2 is associated with early BBB disruption after stroke, its role in HT and effect on stroke outcome remains less clear. In primates, brain levels of MMP-2 were not significantly increased in animals with HT compared with those without.…”

Section: Early and Delayed Hemorrhagic Transformationmentioning

confidence: 89%

See 1 more Smart Citation

Hemorrhagic Transformation after Ischemic Stroke in Animals and Humans

Jickling

Liu

Stamova

et al. 2013

J Cereb Blood Flow Metab

461

369

View full text Add to dashboard Cite

Hemorrhagic transformation (HT) is a common complication of ischemic stroke that is exacerbated by thrombolytic therapy. Methods to better prevent, predict, and treat HT are needed. In this review, we summarize studies of HT in both animals and humans. We propose that early HT (o18 to 24 hours after stroke onset) relates to leukocyte-derived matrix metalloproteinase-9 (MMP-9) and brain-derived MMP-2 that damage the neurovascular unit and promote blood-brain barrier (BBB) disruption. This contrasts to delayed HT (418 to 24 hours after stroke) that relates to ischemia activation of brain proteases (MMP-2, MMP-3, MMP-9, and endogenous tissue plasminogen activator), neuroinflammation, and factors that promote vascular remodeling (vascular endothelial growth factor and high-moblity-group-box-1). Processes that mediate BBB repair and reduce HT risk are discussed, including transforming growth factor beta signaling in monocytes, Src kinase signaling, MMP inhibitors, and inhibitors of reactive oxygen species. Finally, clinical features associated with HT in patients with stroke are reviewed, including approaches to predict HT by clinical factors, brain imaging, and blood biomarkers. Though remarkable advances in our understanding of HT have been made, additional efforts are needed to translate these discoveries to the clinic and reduce the impact of HT on patients with ischemic stroke.

show abstract

Section: Early and Delayed Hemorrhagic Transformationmentioning

confidence: 89%

Section: Early and Delayed Hemorrhagic Transformationmentioning

confidence: 89%

Hemorrhagic Transformation after Ischemic Stroke in Animals and Humans

Jickling

Liu

Stamova

et al. 2013

J Cereb Blood Flow Metab

461

369

View full text Add to dashboard Cite

show abstract

“…Even though collagenase does not discriminate among different brain tissues, it produces massive bleeding and mortality, similar to that in human ICH. This model has been used extensively in investigations of ICH (Brown et al, 1995;DeBow et al, 2003;Del Bigio et al, 1996;Elger et al, 1994;Lyden et al, 1997;MacLellan et al, 2002;Matsushita et al, 2000;Rosenberg and Navratil, 1997;Rosenberg et al, 1992), including studies on the long-term deficits after collagenase-induced ICH (Chesney et al, 1995). Another animal model used to determine ICH pathophysiology and to evaluate therapeutic treatment (Andaluz et al, 2002) is the direct injection of autologous blood into the rat caudate nucleus (Nath et al, 1986), a model used in numerous studies (Bullock et al, 1984;Huang et al, 2002;Jiang et al, 2002;Mendelow, 1993;Nath et al, 1987;Thulborn et al, 1990;Xue and Del Bigio, 2000;Wu et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

MMP-9 Deficiency Enhances Collagenase-Induced Intracerebral Hemorrhage and Brain Injury in Mutant Mice

Tang

Zhou

et al. 2004

J Cereb Blood Flow Metab

160

141

View full text Add to dashboard Cite

Summary:Matrix metalloproteinase-9 (MMP-9) participates in the disregulation of blood-brain barrier during hemorrhagic transformation, and exacerbates brain injury after cerebral ischemia. However, the consequences of long-term inhibition or deficiency of MMP-9 activity (which might affect normal collagen or matrix homeostasis) remains to be determined. The authors investigated how MMP-9 gene deficiency enhances hemorrhage and increases mortality and neurologic deficits in a collagenase-induced intracerebral hemorrhage (ICH) model in MMP-9-knockout mice. MMP-9-knockout and corresponding wild-type mice at 20 to 35 weeks were used to model an aged population (because advanced age is a significant risk factor in human ICH). Collagenase VII-S (0.5 L, 0.075 U) was injected into the right basal ganglia in mice and mortality, neurologic deficits, brain edema, and hemorrhage size measured. In addition, MMP-9 activity, brain collagen content, blood coagulation, cerebral arterial structure, and expressions of several MMPs were examined. Increased hemorrhage and brain edema that correlated with higher mortality and neurologic deficits were found in MMP-9-knockout mice. No apparent structural changes were observed in cerebral arteries, even though brain collagen content was reduced in MMP-9-knockout mice. MMP-9-knockout mice did exhibit an enhanced expression of MMP-2 and MMP-3 in response to ICH. The results indicate that a deficiency of MMP-9 gene in mutant mice increases collagenase-induced hemorrhage and the resulting brain injury. The intriguing relationship between MMP-9 deficiency and collagenase-induced ICH may reflect the reduction in collagen content and an enhanced expression of MMP-2 and MMP-3. Key Words: MMP-9-Intracerebral hemorrhage-Collagenase-Edema-Blood-brain barrier-Coagulation.Spontaneous intracerebral hemorrhage (ICH) is one of the most serious stroke events, and results in high mortality and morbidity in patients (Bernardini and DeShaies, 2001;Panagos et al., 2002;Woo and Broderick, 2002). Mortality in ICH is often as high as 50% within the first month after ICH, with 50% of these deaths occurring within 48 hours (Broderick, 1993). The mechanisms of ICH-induced early brain injury (e.g. brain edema) have been investigated (Altumbabic et al., 1998;Del Bigio et al., 1999;Xi et al., 2002); however, the complete etiology of early brain injury in ICH is incompletely understood.Matrix metalloproteinases (MMPs) are involved in the pathogenesis of cerebral vascular disorders, particularly the formation and rupture of aneurysms. For example, pro-MMP-2 has been implicated as a significant component within arterial walls of intracerebral aneurysms that leads to subarachnoid hemorrhage (Todor et al., 1998). Other studies also support elevated MMP (elastase and collagenase) activity in ruptured vessels in subarachnoid hemorrhage but not in unruptured aneurysms (Gaetani et al., 1999). MMPs are also involved in the hemorrhagic transformation after cerebral ischemia, especially after thrombolysis (Hosomi et al., 2001;M...

show abstract

“…TIMP-2 blocked the MMP-2-induced BBB opening in MMPinduced injury in the brain (Rosenberg et al, 1992). Damage to the BBB was blocked, and symptomatic improvement occurred in experimental allergic encephalomyelitis (EAE) with hydroxymate treatment (Gijbels et al, 1994;Hewson et al, 1995;Clements et al, 1997).…”

Section: Synthetic Mmp Inhibitorsmentioning

confidence: 99%

Matrix metalloproteinases in neuroinflammation

Rosenberg

2002

Glia

Self Cite

781

667

View full text Add to dashboard Cite

Matrix metalloproteinases (MMPs) are a gene family of neutral proteases that are important in normal development, wound healing, and a wide variety of pathological processes, including the spread of metastatic cancer cells, arthritic destruction of joints, atherosclerosis, and neuroinflammation. In the central nervous system (CNS), MMPs have been shown to degrade components of the basal lamina, leading to disruption of the blood-brain barrier (BBB), and to contribute to the neuroinflammatory response in many neurological diseases. Brain cells express both constitutive and inducible MMPs in response to cellular stress. MMPs are tightly regulated to avoid unwanted proteolysis. Secreted as inactive enzymes, the MMPs require activation by other proteases and free radicals. The MMPs are part of a larger class of metalloproteinases (MPs), which includes the recently discovered ADAMs (a disintegrin and metalloproteinase domain) and ADAMTS (a disintegrin and metalloproteinase thrombospondin) families. MPs have complex roles at the cell surface and within the extracellular matrix. At the cell surface, they act as sheddases, releasing growth factors, death receptors, and death-inducing ligands, making them important in cell survival and death. Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors that regulate the activity of the MMPs. Synthetic inhibitors have been developed for the treatment of arthritis and cancer. These hydroxymate-based compounds have been shown to reduce injury in experimental allergic encephalomyelitis (EAE), experimental allergic neuritis (EAN), cerebral ischemia, intracerebral hemorrhage, and viral and bacterial infections. MPs have both beneficial and detrimental roles; understanding their expression in various CNS insults will allow for the use of MMP inhibitors in the treatment of neurological disorders. GLIA 39: 279 -291, 2002.

show abstract

TIMP-2 reduces proteolytic opening of blood-brain barrier by type IV collagenase

Cited by 273 publications

References 15 publications

Hemorrhagic Transformation after Ischemic Stroke in Animals and Humans

Hemorrhagic Transformation after Ischemic Stroke in Animals and Humans

MMP-9 Deficiency Enhances Collagenase-Induced Intracerebral Hemorrhage and Brain Injury in Mutant Mice

Matrix metalloproteinases in neuroinflammation

Contact Info

Product

Resources

About